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RNA-Binding Proteins in Female Reproductive Pathologies

Open ArchivePublished:April 10, 2017DOI:https://doi.org/10.1016/j.ajpath.2017.01.017
      RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction.
      Post-transcriptional gene regulation (PTGR) is an imperative process for the overall health of eukaryotic cells and mRNAs. With recent advancements in sequencing and proteomics screening techniques, >1500 RNA-binding proteins (RNABPs) have been identified to interact with all classes of RNAs.
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      A census of human RNA-binding proteins.
      These RNABPs form ribonucleoprotein complexes with RNAs and proteins, which are crucial units involved in gene regulation.
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      Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins.
      Most RNABPs are ubiquitously expressed in higher than average levels compared to other proteins.
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      A census of human RNA-binding proteins.
      Post-transcriptional regulation of mRNA has a downstream function in various signaling pathways.
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      The role of transforming growth factor beta signaling in messenger RNA stability.
      Many RNABPs have diverse binding specificity and have been reported to interact with RNAs encoding for functionally relevant genes.
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      Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system.
      Similar to miRNAs, many of these RNABPs coordinate regulation of related mRNAs.
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      RNA regulons: coordination of post-transcriptional events.
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      RNA-binding proteins in human genetic disease.
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      Genome-wide analysis of alternative pre-mRNA splicing and RNA-binding specificities of the Drosophila hnRNP A/B family members.
      Mutations, which result in aberrant expression or functioning of these RNABPs, highlight the importance of these regulatory molecules in many processes central to adequate cellular health, including their contribution to pathologies.
      Next-generation sequencing and other advanced profiling techniques and biochemical methods, such as photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation, have revealed the abundance and diversity of RNABPs and their interactions with multiple RNA subclasses.
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      Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.
      The classification of RNABPs by their interacting RNA targets has allowed for the isolation of specific PTGR pathways involved in human diseases. Although much of the published research on RNABPs has focused on mRNA binding proteins, there are other RNABPs that play a role in PTGR through their interaction with noncoding RNAs (ncRNAs).
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      These ncRNAs may become encoded into ribonucleoprotein complexes, and therefore serve as guides to direct the ribonucleoprotein complexes to search out target transcripts and genome loci.
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      Piwi proteins and piRNAs step onto the systems biology stage.
      Gerstberger et al
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      elegantly generated a census of human RNABPs analyzed for their interactions with different classes of RNA and characterized 122 RNABPs that interact with ncRNAs, including miRNAs, P-element induced wimpy testis (PIWI)-interacting RNAs, and long noncoding RNAs. These ncRNAs, along with their corresponding RNABPs, can control multiple aspects of post-transcriptional mRNA processing via degradation, silencing, or activation of gene loci. For example, miRNAs repress mRNA stability through their association with Argonaute proteins,
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      • Chang S.H.
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      ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages.
      whereas PIWI-interacting RNAs protect the genome from genomic instability by interacting with PIWI proteins.
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      • Lau N.C.
      Piwi proteins and piRNAs step onto the systems biology stage.
      Thus, the relationship between these ncRNAs, RNABPs, and their respective PTGR pathways provides a greater dimension of complexity when analyzing the role of RNABPs in disease pathologies.
      In the female reproductive tract, inflammation is part of the ovulation process and normal endometrial tissue remodeling during menstruation. Inflammation is also necessary for embryo implantation and downstream events in a successful pregnancy.
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      Role of inflammatory mediators in patients with recurrent pregnancy loss.
      Simply put, these processes are tightly regulated by coordinated actions of cytokines, chemokines, decoy receptors, and immune cell networks. These inflammatory mediators are influenced by female sex hormones, estrogen and progesterone.
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      • Sales K.J.
      • Catalano R.D.
      • Norman J.E.
      Inflammatory pathways in female reproductive health and disease.
      Inflammation has also been implicated in most reproductive pathologies.
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      • Sales K.J.
      • Catalano R.D.
      • Norman J.E.
      Inflammatory pathways in female reproductive health and disease.
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      • Goldsmith L.T.
      • Taylor R.N.
      • Bellet D.
      • Taylor H.S.
      Inflammation in reproductive disorders.
      Uncontrolled, delayed, or dysregulated delicate homeostatic inflammatory processes have all been demonstrated to contribute to disease pathogenesis in the reproductive tract, including endometriosis and pregnancy loss.
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      • Dural O.
      • Yasa C.
      • Keskin G.
      • Ozsurmeli M.
      • Buyru F.
      • Serdaroglu H.
      Role of inflammatory mediators in patients with recurrent pregnancy loss.
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      • Yang K.M.
      • Gilman-Sachs A.
      Recurrent pregnancy loss: a disease of inflammation and coagulation.
      Herein, we present an overview of RNABPs that interact with RNAs or other post-transcriptional regulators in the context of inflammation-mediated female reproductive pathologies. We focus on the function of these RNABPs as well as their mechanisms in cancer and non-cancer reproductive pathologies. For the purpose of this review, we will restrict contributions of RNABPs to the pathophysiology of endometriosis, endometrial and ovarian cancer, and pregnancy loss.

      Overview of Post-Transcriptional Gene Regulation Mechanisms

      The formation of a type of ribonucleoprotein complex, the RNA-induced silencing complex, is required for miRNA-mediated gene silencing.
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      • Tomari Y.
      The functions of microRNAs: mRNA decay and translational repression.
      The miRNA-induced silencing complex is composed of miRNAs, which are directly bound by members of the Argonaute protein family.
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      • Bushell M.
      The complexity of miRNA-mediated repression.
      The association of miRNA-induced silencing complex with an mRNA via base pairing allows for the mediation of both mRNA decay and translational repression through the recruitment of various enzyme complexes.
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      • Tomari Y.
      The functions of microRNAs: mRNA decay and translational repression.
      • Wu X.
      • Brewer G.
      The regulation of mRNA stability in mammalian cells: 2.0.
      Deadenylases are first recruited, followed by cytoplasmic mRNA degradation in the 3′-5′ or 5′-3′ direction by the RNA exosome or exoribonuclease 1, respectively.
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      • Wilusz C.J.
      The highways and byways of mRNA decay.
      • Schmid M.
      • Jensen T.H.
      The exosome: a multipurpose RNA-decay machine.
      Many proteins involved in the 5′-3′ mRNA degradation pathway concentrate in granular cytoplasmic foci known as processing bodies, which have also been shown to colocalize with various miRNA-mediated RNA decay factors.
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      The regulation of mRNA stability in mammalian cells: 2.0.
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      The highways and byways of mRNA decay.
      The export of the mRNAs from the nucleus to the cytoplasm is a necessary process for the aforementioned degradation pathway mechanisms to successfully occur. Some RNABPs, such as the Tristetraprolin (TTP; ZFP36) family, exhibit autoregulatory negative feedback loops via binding to their own regulatory elements, such as 3′ untranslated regions, and cause degradation of their own mRNA.
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      The role of mRNA turnover in the regulation of tristetraprolin expression: evidence for an extracellular signal-regulated kinase-specific, AU-rich element-dependent, autoregulatory pathway.
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      • Clark A.R.
      The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself.
      P-body assembly is dependent on the pool of mRNA to be decayed and is induced in response to stresses or other conditions that lead to the inhibition of translation initiation.
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      P-bodies and stress granules: possible roles in the control of translation and mRNA degradation.
      In addition, stress granules are cytoplasmic structures that also form during certain types of cellular stress.
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      • Brewer G.
      The regulation of mRNA stability in mammalian cells: 2.0.
      Translationally repressed mRNAs aggregate within these stress granules, which are then sorted and delivered to processing bodies for degradation.
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      The highways and byways of mRNA decay.
      Both processing bodies and stress granules contain various shared components, including mRNA, eukaryotic translation initiation factor 4E, microribonucleoproteins, and regulators of mRNA stability and translation such as RNABPs.
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      • Anderson P.
      Mammalian stress granules and processing bodies.
      Thus, processing bodies and stress granules are dynamic structures that have been reported to play a critical role via the interplay between RNABPs, mRNA decay, and translation.

      Modulation of Immune-Inflammation Axis by RNABPs

      RNABPs and their role in reproductive pathologies is an emerging field. It has been shown that RNABPs regulate inflammation and immune cell functions, and as a result are implicated in inflammation-associated pathologies. In this review, we have summarized the role of RNABP in inflammation and immune cell modulation because a delicate balance between inflammatory mediators and sex hormones is key to successful female reproductive events.
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      Implications of immune dysfunction on endometriosis associated infertility.
      The role of RNABPs in inflammation and immune cell biology has been highlighted in the context of selected reproductive pathologies.

      Modulation of Inflammation by HuR/TTP Axis RNABPs

      Given that most of the previous investigations on inflammation modulation by RNABPs have been focused on the human antigen-R (HuR)/TTP axis, this review will primarily highlight this axis.
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      • Lai W.S.
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      Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability.
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      The role of tristetraprolin in cancer and inflammation.
      Recently, TTP has been classified as a global post-transcriptional regulator of feedback control in inflammation.
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      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
      Both HuR and TTP are expressed in the nucleus and cytoplasm of a wide variety of cell types of the reproductive tract, including innate immune cells, such as macrophages. TTP activation is dependent on p38-activated MAP kinase-activated protein kinase-2 phosphorylation at the site of serine 52 and 178 in the mouse
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      MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay.
      and 60 and 186 in humans by extracellular signal regulated kinase 2 protein kinase.
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      MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding.
      Phosphorylation of TTP allows preferential binding of 14-3-3-protein in the cytoplasm. The formation of this complex renders TTP ineffective as a destabilizing protein as it leads to the reduction of TTP affinity to AU-rich elements (AREs) on inflammatory cytokine transcripts.
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      • Anderson P.
      MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay.
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      Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways.
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      • Gaestel M.
      The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU–rich element–dependent translation.
      Conversely, some in vitro studies have demonstrated that phosphorylation has no impact on ARE-binding–mediated degradation by TTP.
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      • Dzineku F.
      • Blackshear P.J.
      Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases.
      Phosphorylation status of TTP also has been reported to be associated with CCR4-Not1 deadenylation complex and HuR/TTP MAP kinase-activated protein kinase-2 phosphorylation modulation of ARE-dependent translation.
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      • Ronkina N.
      • Tehrani M.
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      • Laass K.
      • Holtmann H.
      • Kotlyarov A.
      • Gaestel M.
      The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU–rich element–dependent translation.
      Non 14-3-3–bound TTP can bind to the 3′ untranslated region AREs of inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and mediate degradation via 5′-3′ and 3′-5′ pathways aforementioned above (Figure 1).
      Figure thumbnail gr1
      Figure 1Modulation of inflammation by the HuR/TTP axis. The balance between HuR and TTP is shifted in response to external stress stimuli. Under normal conditions (left), P38 activates protein phosphatase 2a (PP2a), which catalyzes the dephosphorylation and activation of TTP. At the same time, PP2a deactivates serine/threonine protein kinase Chk2 (Chk2), which allows cyclin-dependent kinase 1 (Cdk1) to phosphorylate HuR and render it inactive. Phosphorylated HuR can be translocated to the cytoplasm, tipping the balance in favor of TTP, which can bind the mRNAs of inflammatory cytokines and promote their degradation. Under stress conditions (right), P38 activates mitogen-activated protein kinase–activated protein kinase 2 (MK2), which phosphorylates and deactivates TTP and allows it to be translocated to the cytoplasm. At the same time, P38 activates Chk2, which can phosphorylate and deactivate Cdk1. The inhibition of Cdk1 allows HuR to remain dephosphorylated, which adds to the transport of TTP out of the nucleus, tips the balance in favor of HuR, which can bind the mRNAs of inflammatory cytokines and stabilize them to promote their translation, thus promoting the inflammatory response. There are numerous additional players in this pathway that help maintain this balance. Dashed arrow indicates inhibited binding. AAAAA, poly A tail; ARE, AU rich element; ORF, open reading frame; P, phosphorylation; P-bodies, processing bodies.
      Taylor et al
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      A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.
      documented that TTP-deficient mice generated by targeted disruption of Zfp36 gene, although normal at birth, developed systemic autoinflammatory phenotype within 1 to 8 weeks after birth. The hyperinflammatory phenotype was primarily attributed to elevated circulating levels of TNF-α as injection of neutralizing TNF-α antibodies reversed the inflammatory phenotype in TTP-deficient mice. Additional studies in TTP-deficient mice led to the identification of granulocyte-macrophage colony-stimulating factor as another physiological target of TTP.
      • Carballo E.
      • Lai W.S.
      • Blackshear P.J.
      Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability.
      Furthermore, TTP expression is correlated with severity of rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus in humans.
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      • Blanco F.F.
      • Young L.E.
      • Kaza V.
      • Dixon D.A.
      The role of tristetraprolin in cancer and inflammation.
      On the other side of the axis, HuR can bind to most of the same cytokines possessing AREs, such as TNF-α, and stabilize the transcripts. Much like TTP, HuR nucleocytoplasmic shuttling and activation are in part dependent on p38 mitogen-activated protein kinase–mediated phosphorylation,
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      p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S checkpoint.
      and phosphorylation by checkpoint kinase 2,
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      Phosphorylation of HuR by Chk2 regulates SIRT1 expression.
      protein kinase C,
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      Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2.
      and cyclin-dependent kinase 1 can influence binding activity of HuR on inflammatory mRNAs.
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      Nuclear HuR accumulation through phosphorylation by Cdk1.
      Because NF-κB controls many cytokines involved in inflammation, it is not surprising that the TTP/HuR axis is involved in regulation of several NF-κB signaling–dependent proinflammatory cytokines. Tiedje et al
      • Tiedje C.
      • Diaz-Muñoz M.D.
      • Trulley P.
      • Ahlfors H.
      • Laaß K.
      • Blackshear P.J.
      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
      have elegantly demonstrated that a phosphorylation-dependent inactivation of TTP is required for NF-κB signal transduction. In addition, TTP can impair NF-κB/p65 nuclear translocation in an ARE-mediated decay-independent manner and can ultimately result in TTP-induced cell death.
      • Tiedje C.
      • Diaz-Muñoz M.D.
      • Trulley P.
      • Ahlfors H.
      • Laaß K.
      • Blackshear P.J.
      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
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      • Resch U.
      • Hofer-Warbinek R.
      • de Martin R.
      Tristetraprolin impairs NF-kappaB/p65 nuclear translocation.
      These data clearly suggest that the HuR/TTP axis is a critical regulator of physiological inflammation, and any perturbations in this axis will potentially lead to autoimmune and inflammatory conditions.
      A high number of RNABPs expressed in the reproductive tract regulate the expression of genes encoding inflammatory molecules, either promoting or controlling inflammation.
      • Kafasla P.
      • Skliris A.
      • Kontoyiannis D.L.
      Post-transcriptional coordination of immunological responses by RNA-binding proteins.
      For example, roquin-1,
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      A role for IL-10 in the transcriptional regulation of Roquin-1.
      regnase-1,
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      • Akira S.
      Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay.
      and tristetraprolin
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      • Diaz-Muñoz M.D.
      • Trulley P.
      • Ahlfors H.
      • Laaß K.
      • Blackshear P.J.
      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
      are RNABPs that attenuate inflammatory responses via target mRNA degradation, whereas HuR is often suggested to oppose TTP, thereby promoting inflammation through target mRNA stabilization.
      • Young L.E.
      • Sanduja S.
      • Bemis-Standoli K.
      • Pena E.A.
      • Price R.L.
      • Dixon D.A.
      The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis.
      Mice with germline knockout of TTP display a severe inflammatory phenotype with myeloid hyperplasia and autoimmunity due to excessive TNF production, indicating the role of TTP in the regulation of TNF transcript expression.
      • Qiu L.Q.
      • Stumpo D.J.
      • Blackshear P.J.
      Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype.
      Conversely, the role of HuR in PTGR has been less straightforward. Although HuR participates in the transcript stabilization and expression of proinflammatory cytokine IL-17 in a mouse model of experimental autoimmune encephalomyelitis, it can also act as a negative regulator of macrophage-mediated inflammation.
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      • Atasoy U.
      Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis.
      Overexpression of HuR was shown to act as a translational silencer for TNF, IL-1β, and transforming growth factor-β1, whereby the production of these proteins was decreased after lipopolysaccharide (LPS) challenge in mice compared to controls that did not overexpress HuR.
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      • Kontoyiannis D.L.
      HuR as a negative posttranscriptional modulator in inflammation.
      Some studies have linked interactions between HuR and miRNAs via shared mRNA functional binding sites.
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      • Tominaga K.
      • Gorospe M.
      Functional interplay between RNA-binding protein HuR and microRNAs.
      Indeed, competitive miRNAs, such as miR-637, have been reported to also vie for binding of inflammatory molecules.
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      • Gorospe M.
      • Evans M.K.
      Posttranscriptional regulation of the inflammatory marker C-reactive protein by the RNA-binding protein HuR and microRNA 637.

      Modulation of Immune Cell Development by RNABPs

      In nonpathological conditions, immune cell populations are dynamic and differentiate normally.
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      • McHugh J.
      • Turner M.
      RNA binding proteins as regulators of immune cell biology.
      RNABPs participate in the development and differentiation of lymphoid cells, such as T and B cells. In particular, conditional double knockout of ZFP36L1 and ZFP36L2 in lymphocytes lead to the development of T-lymphoblastic leukemia in double-knockout mice, whereas single knockout of either gene displays no developmental defect, indicating a unique multi-RNABP pathogenesis–dependent role in lymphocytes.
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      • Turner M.
      Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.
      The development of T-lymphoblastic leukemia is attributed to the increased production of Notch homolog 1 (Notch1), elucidating a novel transcript target for ZFP36L1 and ZFP36L2 and the importance of both RNABPs in the developmental regulation of T lymphocytes in the thymus.
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      • Ferrando A.A.
      • Grutz G.
      • Turner M.
      Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.
      The RNABP HuR is also involved in the developmental programming of both T and B cells. Conditional knockout of HuR in thymocytes elucidates its role in thymopoesis as a cell cycle suppressor and modulator of proapoptotic signals.
      • Papadaki O.
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      • Kontoyiannis D.L.
      Control of thymic T cell maturation, deletion and egress by the RNA-binding protein HuR.
      In B cells, the production of HuR protein is up-regulated threefold on stimulation with LPS or with anti-CD40 and IL-4 and IL-5 in vitro compared to unstimulated B cells.
      • Diaz-Muñoz M.D.
      • Bell S.E.
      • Fairfax K.
      • Monzon-Casanova E.
      • Cunningham A.F.
      • Gonzalez-Porta M.
      • Andrews S.R.
      • Bunik V.I.
      • Zarnack K.
      • Curk T.
      • Heggermont W.A.
      • Heymans S.
      • Gibson G.E.
      • Kontoyiannis D.L.
      • Ule J.
      • Turner M.
      The RNA-binding protein HuR is essential for the B cell antibody response.
      Furthermore, B-cell–specific conditional knockout of HuR leads to significantly lower production of all types of immunoglobulin isotypes in the serum of mice, except for IgA when compared to control mouse, indicating that HuR is necessary for antibody production after antigenic challenge.
      • Diaz-Muñoz M.D.
      • Bell S.E.
      • Fairfax K.
      • Monzon-Casanova E.
      • Cunningham A.F.
      • Gonzalez-Porta M.
      • Andrews S.R.
      • Bunik V.I.
      • Zarnack K.
      • Curk T.
      • Heggermont W.A.
      • Heymans S.
      • Gibson G.E.
      • Kontoyiannis D.L.
      • Ule J.
      • Turner M.
      The RNA-binding protein HuR is essential for the B cell antibody response.
      The RNABPs TIA1 cytotoxic granule associated RNA binding protein (TIA-1) cytotoxic granule–associated RNABP and TTP prevent pathological overexpression of TNF-α via inhibition of translation by TIA-1 and degradation of TNF-α transcripts by TTP. Deletion of TIA-1 in mice results in mild arthritis, whereas deletion of TTP results in severe arthritis, as well as cachexia, dermatitis, and autoantibody formation.
      • Taylor G.A.
      • Carballo E.
      • Lee D.M.
      • Lai W.S.
      • Thompson M.J.
      • Patel D.D.
      • Schenkman D.I.
      • Gilkeson G.S.
      • Broxmeyer H.E.
      • Haynes B.F.
      • Blackshear P.J.
      A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.
      Mice containing deletions in both TIA-1 and TTP develop severe arthritis.
      • Phillips K.
      • Kedersha N.
      • Shen L.
      • Blackshear P.J.
      • Anderson P.
      Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.
      RNABP experiments investigating immunomodulation by RNABPs indicate that TIA-1/TTP knockout murine macrophages secrete lower TNF-α protein when stimulated by LPS, indicative that these RNABPs are not only involved in PTGR, but can alter cell variation, which can further exasperate inflammatory pathologies.
      • Phillips K.
      • Kedersha N.
      • Shen L.
      • Blackshear P.J.
      • Anderson P.
      Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.

      The Importance and Contributions of Gene Regulation by RNABPs in Reproduction and Associated Pathologies

      Although the roles of many RNABPs are commonly focused on inflammatory pathways, RNABPs also appear to have a significant role in the initiation and regulation of normal reproductive events. In the female reproductive tract specifically, a number of RNABPs are involved in reproductive events, including but not limited to oocyte maturation, ovulation, endometrial tissue remodeling, embryo implantation, placenta development, and successful pregnancy. We have provided a summary of RNABP contributions in female reproductive pathologies in Figure 2.
      Figure thumbnail gr2
      Figure 2Contributions of RNA-binding proteins (RNABPs) in female reproductive pathologies. The dysregulation of the immune inflammation axis in endometriosis, fetal loss, infertility, and ovarian and endometrial cancer, is mediated in part by RNABPs, which have been shown to be differentially regulated in animal models as well as humans. AUF1, AU-rich element-binding factor 1; eIF4G1, eukaryotic translation initiation factor 4 γ 1; TIA-1, TIA1 cytotoxic granule associated RNA binding protein.

      RNABPs in Embryonic Growth and Placental Development

      RNABPs, including ZFP36/TTP as well as its less-studied family members, ZFP36L1 (Tis11b), ZFP36L2 (Tis11d), and the rodent-specific ZFP36L3, are readily detectable in placental tissues and yolk sac in humans and in mice.
      • Durand S.
      • Abadie P.
      • Angeletti S.
      • Genti-Raimondi S.
      Identification of multiple differentially expressed messenger RNAs in normal and pathological trophoblast.
      • Stumpo D.J.
      • Trempus C.S.
      • Tucker C.J.
      • Huang W.
      • Li L.
      • Kluckman K.
      • Bortner D.M.
      • Blackshear P.J.
      Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism.
      Indeed, we found differential expression of TTP family members in a first-trimester human trophoblast cell line, HTR-8/SVNeo between normoxic and hypoxic conditions, suggesting an abundance of TTP family members in placenta and their potential regulation under hypoxia (K.K., C.T., unpublished data). In fact, RAW264.7 macrophages stimulated with potent inflammatory trigger lipopolysaccharide, under prolonged hypoxic conditions, led to reduced TNF-α protein levels. This decrease in TNF-α was mediated by TTP-dependent destabilization of TNF-α mRNA via a 3′-untranslated region–dependent mechanism, suggesting a regulatory role for TTP in hypoxia-dependent resolution of inflammation.
      • Werno C.
      • Schmid T.
      • Schnitzer S.E.
      • Peters K.
      • Milke L.
      • Brüne B.
      A combination of hypoxia and lipopolysaccharide activates tristetraprolin to destabilize proinflammatory mRNAs such as tumor necrosis factor-alpha.
      Using a knockout mouse model of rodent-specific ZFP36L3, a number of growth factors, including heparin-binding epidermal growth factor, endothelial lipase Lipg, and type 1 transferrin receptor, which is responsible for iron uptake by the placenta for the developing fetus, were shown to be likely targets of ZFP36L3.
      • Stumpo D.J.
      • Trempus C.S.
      • Tucker C.J.
      • Huang W.
      • Li L.
      • Kluckman K.
      • Bortner D.M.
      • Blackshear P.J.
      Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism.
      In addition, ZFP6L2 has been shown to be critical for female fertility because of the crucial role of RNABPs in early embryonic development. The amino-terminal truncated form of ZFP36L2 causes arrest in early embryonic development at the two-cell stage. Disruption of the ZFP36L1 gene in mice results in an embryonic lethal phenotype at the embryonic day 11 because of disruptions in chorioallantoic fusion.
      • Stumpo D.J.
      • Byrd N.A.
      • Phillips R.S.
      • Ghosh S.
      • Maronpot R.R.
      • Castranio T.
      • Meyers E.N.
      • Mishina Y.
      • Blackshear P.J.
      Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family.
      Recent evidence suggests that HuR/embryonic lethal, abnormal vision-like 1 (ELAVL1) elicits transcriptional and post-transcriptional changes in mRNAs important for extraembryonic (placental and yolk sac) as well as embryonic development.
      • Katsanou V.
      • Milatos S.
      • Yiakouvaki A.
      • Sgantzis N.
      • Kotsoni A.
      • Alexiou M.
      • Harokopos V.
      • Aidinis V.
      • Hemberger M.
      • Kontoyiannis D.L.
      The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
      Using ELAVL1 knockout mice (embryonic lethal), the initiation of branching and processes of labyrinth morphogenesis, which are imperative for placental development, are absent from the knockout model, suggesting HuR/ELAVL1 is involved in this initiation of branching.
      • Katsanou V.
      • Milatos S.
      • Yiakouvaki A.
      • Sgantzis N.
      • Kotsoni A.
      • Alexiou M.
      • Harokopos V.
      • Aidinis V.
      • Hemberger M.
      • Kontoyiannis D.L.
      The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.

      RNABPs in Ovulation, Oocyte Maturation, and Female Fertility

      RNABP mRNAs are expressed in the reproductive tract of humans and mice and are influenced by menstrual/estrous cycles.
      • Carrick D.M.
      • Blackshear P.J.
      Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines.
      • Karipcin F.S.
      • Ensari T.A.
      • Kayisli U.A.
      • Guzel E.
      • Kallen C.B.
      • Seli E.
      The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium.
      Female mice with mutations in ZFP36L2 were unable to ovulate even under pharmacological conditions, and attempts to mature oocytes from these mice ex vivo was hindered because of meiotic arrest imposed by cAMP.
      • Ball C.B.
      • Rodriguez K.F.
      • Stumpo D.J.
      • Ribeiro-Neto F.
      • Korach K.S.
      • Blackshear P.J.
      • Birnbaumer L.
      • Ramos S.B.
      The RNA-binding protein, ZFP36L2, influences ovulation and oocyte maturation.
      Using the TTP knockout mouse model, it has also been demonstrated that TTP is critically involved in mouse meiosis, chromosomal arrangement, spindle morphology, and polar body extrusion, all of which are critical events for oocyte maturation.
      • Liu X.
      • Li X.
      • Ma R.
      • Xiong B.
      • Sun S.-C.
      • Liu H.
      • Gu L.
      Tristetraprolin functions in cytoskeletal organization during mouse oocyte maturation.
      Meiotic asymmetry and a lack of oocyte polarization significantly decreases reproductive success in females and likely contributes to infertility.
      • Miao Y.L.
      • Kikuchi K.
      • Sun Q.Y.
      • Schatten H.
      Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility.
      Furthermore, ablation of the Src associated in mitosis of 68 kDa (Sam68) RNABP induces sterility and infertility in females because of its essential role in oocyte maturation and its involvement in the expression of gonadotropin receptors in the ovary.
      • Bianchi E.
      • Barbagallo F.
      • Valeri C.
      • Geremia R.
      • Salustri A.
      • De Felici M.
      • Sette C.
      Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development.
      These data clearly provide evidence that disruptions in RNABPs impede female fertility.

      Post-Transcriptional mRNA Regulation by RNABPs in Endometriosis and Pregnancy Loss

      Endometriosis, a proinflammatory gynecological disease, is characterized by the growth of the endometrial-like tissue outside of uterine cavity. Research to understand the immunological basis behind disease establishment has elucidated aberrant inflammation and immune system dysfunction in endometriosis patients.
      • Herington J.L.
      • Bruner-Tran K.L.
      • Lucas J.A.
      • Osteen K.G.
      Immune interactions in endometriosis.
      The innate arm of the immune system, such as macrophages, is polarized toward the M2 phenotype, which specializes in tissue repair, instead of tissue clearance via phagocytosis.
      • Smith K.A.
      • Pearson C.B.
      • Hachey A.M.
      • Xia D.L.
      • Wachtman L.M.
      Alternative activation of macrophages in rhesus macaques (Macaca mulatta) with endometriosis.
      In addition, increased concentration of inflammatory cytokines in the biological fluids from patients further strengthens the notion of the involvement of immune system in the development of endometriosis.
      • Monsanto S.P.
      • Edwards A.K.
      • Zhou J.
      • Nagarkatti P.
      • Nagarkatti M.
      • Young S.L.
      • Lessey B.A.
      • Tayade C.
      Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients.
      Inflammatory cytokines have also been directly implicated to initiate symptoms of pain and infertility in endometriosis patients.
      • McKinnon B.D.
      • Bertschi D.
      • Bersinger N.A.
      • Mueller M.D.
      Inflammation and nerve fiber interaction in endometriotic pain.
      • Fox C.
      • Morin S.
      • Jeong J.W.
      • Scott R.T.
      • Lessey B.A.
      Local and systemic factors and implantation: what is the evidence?.
      Aberrant activation of RNABPs may participate in this process via PTGR of transcripts encoding for proinflammatory cytokines.
      Recent work from our group has indicated dysregulation of the HuR/TTP axis in patient ectopic lesions compared to matched eutopic endometrium obtained from women with endometriosis (K.K., S.H.A., M. Bidarimath, Y. Nasirzadeh, S.S. Singh, A.T. Fazleabas, S.L. Young, B.A. Lessey, M.K., C.T., unpublished data). In addition, we have demonstrated differential responses of inflammatory cytokines in endometriotic and epithelial endometrial cell lines, suggesting a potential functional role of the HuR/TTP axis in the pathophysiology of endometriosis. Women with endometriosis present decreased TIA-1 and HuR expression, both of which are RNABPs responsible for modulation of proinflammatory cytokines, in the eutopic and ectopic endometrium compared to normal healthy controls.
      • Karipcin F.S.
      • Ensari T.A.
      • Kayisli U.A.
      • Guzel E.
      • Kallen C.B.
      • Seli E.
      The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium.
      • Karalok H.M.
      • Aydin E.
      • Saglam O.
      • Torun A.
      • Guzeloglu-Kayisli O.
      • Lalioti M.D.
      • Kristiansson H.
      • Duke C.M.
      • Choe G.
      • Flannery C.
      • Kallen C.B.
      • Seli E.
      mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium.
      Decreases in regulatory molecules of inflammation likely contribute to the pathogenesis and pathophysiology of endometriosis by contributing to the inflammatory milieu in the peritoneal cavity and symptoms of pain and infertility observed in endometriosis patients. Another RNABP that has been implicated in the pathogenesis of endometriosis is Musashi-1.
      • Yu C.X.
      • Song J.H.
      • Liang L.
      Correlation of changes of (non)exfoliated endometrial organelles and expressions of Musashi-1 and β-catenin with endometriosis in menstrual period.
      This stem cell marker is frequently associated with tumorigenesis and abnormal growth; however, it has also been found to be elevated in the eutopic endometrium of endometriosis patients.
      • Yu C.X.
      • Song J.H.
      • Liang L.
      Correlation of changes of (non)exfoliated endometrial organelles and expressions of Musashi-1 and β-catenin with endometriosis in menstrual period.
      Finally, the RNABP heterogeneous nuclear ribonucleoprotein D0, AUF-1, which mediates the destabilization of the mRNA of DNA methyltransferase 1, is lower in the eutopic endometrium of endometriosis patients.
      • Hsiao K.Y.
      • Wu M.H.
      • Chang N.
      • Yang S.H.
      • Wu C.W.
      • Sun H.S.
      • Tsai S.J.
      Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis.
      Together, correlative evidence of these RNABPs shows promise and points toward involvement via inflammation and immune-modulatory pathogenesis mechanisms. However, many additional studies are required to understand the molecular mechanism of RNABP contributing to the pathogenesis of endometriosis.
      Recurrent pregnancy loss (RPL) is a multifactorial disorder for patients who experience pregnancy failure in the first trimester more than two or three times.
      • Rai R.
      • Regan L.
      Recurrent miscarriage.
      Aberrant maternal inflammation has been linked with thrombosis during fetal loss, and fetal distress molecular pathways influence fetal health outcome. Our group has demonstrated that the TTP family may be involved in spontaneous fetal loss in a porcine model of pregnancy loss.
      • Khalaj K.
      • Wessels J.M.
      • Kridli R.T.
      • Bidarimath M.
      • LaMarre J.
      • Tayade C.
      mRNA destabilizing factors: tristetraprolin expression at the porcine maternal-fetal interface.
      Currently, there are no reports on the direct involvement of RNABPs with recurrent pregnancy loss in humans, but given their presence at the maternal-fetal interface and regulation of several key inflammatory processes, it is logical to assume that RNABPs potentially participate in the pathogenesis of RPL. We have recently shown that TTP and HuR RNABPs are expressed in the placenta, and TTP is involved in the modulation of inflammation-induced RPL via aberrant expression in an LPS-induced mouse model of RPL.
      • Khalaj K.
      • Luna R.L.
      • de França M.E.R.
      • de Oliveira W.H.
      • Peixoto C.A.
      • Tayade C.
      RNA binding protein, tristetraprolin in a murine model of recurrent pregnancy loss.
      In addition, our group has demonstrated differential localization patterns of TTP in placentas obtained from LPS-treated mice.
      • Khalaj K.
      • Luna R.L.
      • de França M.E.R.
      • de Oliveira W.H.
      • Peixoto C.A.
      • Tayade C.
      RNA binding protein, tristetraprolin in a murine model of recurrent pregnancy loss.
      Collectively, we believe that these RNABPs are participating in pathogenesis of pregnancy loss, including RPL via aberrant nucleocytoplasmic localization shuttling and expression.
      Overall, it is apparent that a dysregulation of RNABP contributes to increases in reproductive tract inflammation and immune dysfunction and ultimately contributes to pathogenesis of reproductive pathologies. However, the role of RNABP across different cell types of the female reproductive pathologies is not well characterized and requires further investigation to understand the molecular mechanisms underlying the relationship between RNABP and specific reproductive pathologies.

      Gene Regulatory Mechanisms and RNABPs Implicated in Endometrial and Ovarian Cancer

      RNABPs play important roles in RNA regulation in tumor carcinogenesis and development. Recent research has gone into unraveling RNABP involvement in cancers, including endometrial and ovarian cancer. Although many studies have been correlative and have focused on clinical outcomes and normal tissue compared to carcinoma expression levels, increasingly literature is starting to unveil unique mechanistic interactions between RNABPs and other regulatory factors during cancer development and transformation. Epithelial ovarian cancer is the most deadly gynecological disease,
      • Jemal A.
      • Bray F.
      • Center M.M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      with a median survival of 2 to 4 years.
      • Moss C.
      • Kaye S.B.
      Ovarian cancer: progress and continuing controversies in management.
      Endometrial carcinoma is the most common gynecological malignancy worldwide, and in recent decades the incidence of endometrial carcinoma has been increasing.
      • Siegel R.
      • Ma J.
      • Zou Z.
      • Jemal A.
      Cancer statistics, 2014.
      Sam68 is a KH domain RNABP involved in a wide range of cellular processes, including signal transduction, transcription, RNA metabolism, cell cycle progression, and apoptosis.
      • Bielli P.
      • Busà R.
      • Paronetto M.P.
      • Sette C.
      The RNA-binding protein Sam68 is a multifunctional player in human cancer.
      • Dong L.
      • Che H.
      • Li M.
      • Li X.
      Sam68 is overexpressed in epithelial ovarian cancer and promotes tumor cell proliferation.
      Sam68 features six proline-dominated sequences and a tyrosine-rich area at its C terminus.
      • Bielli P.
      • Busà R.
      • Paronetto M.P.
      • Sette C.
      The RNA-binding protein Sam68 is a multifunctional player in human cancer.
      Signaling proteins that include SH2 or SH3 domains bind at these important regions.
      • Bielli P.
      • Busà R.
      • Paronetto M.P.
      • Sette C.
      The RNA-binding protein Sam68 is a multifunctional player in human cancer.
      The activity of Sam68 may be altered via tyrosine hydroxylase, which interrupts homodimerization, leading to reduced affinity for RNA in vitro.
      • Chen T.
      • Damaj B.B.
      • Herrera C.
      • Lasko P.
      • Richard S.
      Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1, and Qk1: role of the KH domain.
      This RNABP has been associated with poor prognostic roles in a wide variety of cancers, including non–small-cell lung cancer,
      • Zhang Z.
      • Xu Y.
      • Sun N.
      • Zhang M.
      • Xie J.
      • Jiang Z.
      High Sam68 expression predicts poor prognosis in non-small cell lung cancer.
      bladder cancer,
      • Zhang Z.
      • Yu C.
      • Li Y.
      • Jiang L.
      • Zhou F.
      Utility of SAM68 in the progression and prognosis for bladder cancer.
      esophageal squamous cell carcinoma,
      • Wang Y.
      • Liang L.
      • Zhang J.
      • Li M.
      • Zhu J.
      • Gong C.
      • Yang L.
      • Zhu J.
      • Chen L.
      • Ni R.
      Sam68 promotes cellular proliferation and predicts poor prognosis in esophageal squamous cell carcinoma.
      colorectal cancer,
      • Liao W.T.
      • Liu J.L.
      • Wang Z.G.
      • Cui Y.M.
      • Shi L.
      • Li T.T.
      • Zhao X.H.
      • Chen X.T.
      • Ding Y.Q.
      • Song L.B.
      High expression level and nuclear localization of Sam68 are associated with progression and poor prognosis in colorectal cancer.
      and aggressive neuroblastoma.
      • Zhao X.
      • Li Z.
      • He B.
      • Liu J.
      • Li S.
      • Zhou L.
      • Pan C.
      • Yu Z.
      • Zhao X.
      Sam68 is a novel marker for aggressive neuroblastoma.
      Expression of Sam68 at both the mRNA and protein levels in both epithelial ovarian cancer
      • Dong L.
      • Che H.
      • Li M.
      • Li X.
      Sam68 is overexpressed in epithelial ovarian cancer and promotes tumor cell proliferation.
      and endometrial carcinoma is significantly higher in pathological tissue when compared to para-tumor tissue and normal tissue.
      • Wang Y.
      • Zhang W.
      • Wang X.
      • Wang D.
      • Xie J.
      • Tang C.
      • Xi Q.
      • Zhong J.
      • Deng Y.
      Expression of Sam68 correlates with cell proliferation and survival in epithelial ovarian cancer.
      The elevated expression of Sam68 in endometrial cancer is also significantly associated with histological grade, International Federation of Gynecology and Obstetrics stage, and myometrial invasion.
      • Wang Y.
      • Zhang W.
      • Wang X.
      • Wang D.
      • Xie J.
      • Tang C.
      • Xi Q.
      • Zhong J.
      • Deng Y.
      Expression of Sam68 correlates with cell proliferation and survival in epithelial ovarian cancer.
      Sam68 has a proliferative effect on tissues, as demonstrated via siRNA knockdown experiments of this gene in both human endometrial adenocarcinoma (Ishikawa)
      • Wang Y.
      • Zhang W.
      • Wang X.
      • Wang D.
      • Xie J.
      • Tang C.
      • Xi Q.
      • Zhong J.
      • Deng Y.
      Expression of Sam68 correlates with cell proliferation and survival in epithelial ovarian cancer.
      and epithelial ovarian cancer (OVCAR-3) cells.
      • Dong L.
      • Che H.
      • Li M.
      • Li X.
      Sam68 is overexpressed in epithelial ovarian cancer and promotes tumor cell proliferation.
      Furthermore, random homozygous knockout-induced Sam68 deficiencies in nude mice lead to tumor-suppressing effects and increased metastatic tumors.
      • Liu K.
      • Li L.
      • Nisson P.E.
      • Gruber C.
      • Jessee J.
      • Cohen S.N.
      Neoplastic transformation and tumorigenesis associated with sam68 protein deficiency in cultured murine fibroblasts.
      It has also been suggested that its role is dependent on a range of factors, including context and type of tissue.
      • Wang Q.
      • Li Y.
      • Zhou J.
      • Liu J.
      • Qin J.
      • Xing F.
      • Zhang J.
      • Cheng J.
      Clinical significance of Sam68 expression in endometrial carcinoma.
      Determining the biological mechanisms of Sam68 could be valuable as we potentially progress to viewing Sam68 in a therapeutic sense.
      In addition to noncancer reproductive pathologies, HuR has been extensively studied with regard to its roles in a variety of cancers, including epithelial ovarian cancers.
      • Wang H.
      • Ding N.
      • Guo J.
      • Xia J.
      • Ruan Y.
      Dysregulation of TTP and HuR plays an important role in cancers.
      In the cytoplasm, HuR stabilizes mRNA, aiding to translation of its bound transcripts, and may act as a tumor maintenance gene.
      • Wang D.
      • Wang M.
      • Hu C.
      • Shuang T.
      • Zhou Y.
      • Yan X.
      Expression of the ELAV-like protein HuR in the cytoplasm is associated with endometrial carcinoma progression.
      HuR has been shown to be involved in proliferation, apoptosis, angiogenesis, metastasis, invasion, and chemotherapy resistance,
      • Wang H.
      • Ding N.
      • Guo J.
      • Xia J.
      • Ruan Y.
      Dysregulation of TTP and HuR plays an important role in cancers.
      all of which are tightly linked to cancer pathology. In addition to being involved in inflammation regulation covered earlier, HuR regulates many mRNAs that are hallmarks of cancer progression, such as p53, vascular endothelial growth factor, cyclins, and cyclooxygenase 2.
      • Davidson B.
      • Holth A.
      • Hellesylt E.
      • Hadar R.
      • Katz B.
      • Tropé C.G.
      • Reich R.
      HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival.
      Furthermore, HuR expression is significantly increased in both poorly differentiated and advanced stage endometrial carcinomas.
      • Davidson B.
      • Holth A.
      • Hellesylt E.
      • Hadar R.
      • Katz B.
      • Tropé C.G.
      • Reich R.
      HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival.
      Indeed, knockdown of HuR results in decreased cell proliferation and induction of apoptosis in in vitro models using Ishikawa cells.
      • Wang D.
      • Wang M.
      • Hu C.
      • Shuang T.
      • Zhou Y.
      • Yan X.
      Expression of the ELAV-like protein HuR in the cytoplasm is associated with endometrial carcinoma progression.
      In an investigation of HuR associated with ovarian cancer, HuR was found to be present in the nucleus in most cases.
      • Yi X.
      • Zhou Y.
      • Zheng W.
      • Chambers S.K.
      HuR expression in the nucleus correlates with high histological grade and poor disease-free survival in ovarian cancer.
      This nuclear HuR was significantly linked with invasive and high-grade cancers as well as poor disease-free survival.
      • Yi X.
      • Zhou Y.
      • Zheng W.
      • Chambers S.K.
      HuR expression in the nucleus correlates with high histological grade and poor disease-free survival in ovarian cancer.
      Nuclear HuR intensity, through multivariate analysis, was demonstrated to be an independent prognostic factor for poor disease-free survival.
      • Yi X.
      • Zhou Y.
      • Zheng W.
      • Chambers S.K.
      HuR expression in the nucleus correlates with high histological grade and poor disease-free survival in ovarian cancer.
      Together, these data point toward altered phosphorylation status of HuR, resulting in potentially higher inactive HuR that likely contributes to aberrant inflammation in endometrial carcinomas.
      Evidence of complex miRNA-RNABP networks has been reported in ovarian cancer pathogenesis. HuR has also been implicated in ovarian cancer by stabilizing long noncoding RNAs, which contribute to its pathogenesis.
      • Chai Y.
      • Liu J.
      • Zhang Z.
      • Liu L.
      HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer.
      NEAT1, a long noncoding RNA, is up-regulated in ovarian cancer, both within cell lines and patient samples, and HuR has been reported to preserve NEAT1's structural integrity.
      • Chai Y.
      • Liu J.
      • Zhang Z.
      • Liu L.
      HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer.
      Specifically in metastatic high-grade serous ovarian carcinomas, HuR mRNA and protein levels are widely expressed and mRNA levels are connected to poor survival outcomes in high-grade serous ovarian carcinoma patients.
      • Davidson B.
      • Holth A.
      • Hellesylt E.
      • Hadar R.
      • Katz B.
      • Tropé C.G.
      • Reich R.
      HUR mRNA expression in ovarian high-grade serous carcinoma effusions is associated with poor survival.
      La-related protein 1 (LARP1) is an evolutionarily conserved RNABP, and has been associated with many cancers.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      LARP1 knock-down studies have revealed that LARP1 is necessary for both cancer cell survival and chemotherapy resistance.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      In vivo, this RNABP incites tumor formation.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      It increases the amount of available mRNA of genes involved in cell survival, including B-cell lymphoma 2, human epidermal growth factor receptor 3, and Rac-γ serine/threonine-protein kinase, and reduces the amount of available proapoptotic genes, such as BIK, TNFA, and DAPK2.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      It is pertinent to note that within ovarian cancer patients, the tumor's response to chemotherapy is a vital determinant of survival, which makes LARP1 particularly relevant in this kind of cancer.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      This notion is strengthened by the fact that patients with the highest LARP1 mRNA expression have reported significantly worse outcomes, and a heightened risk of death at any time.
      • Bousquet-Antonelli C.
      • Deragon J.M.
      A comprehensive analysis of the La-motif protein superfamily.
      RNABP eukaryotic translation initiation factor 4 γ 1 is a subunit of the eukaryotic translation initiation complex, and it aids in ensuring the establishment of the mRNA-ribosome by recruiting mRNA to the ribosome.
      • Jackson R.J.
      • Hellen C.U.T.
      • Pestova T.V.
      The mechanism of eukaryotic translation initiation and principles of its regulation.
      This is a critical process, as the formation of this complex is the rate-limiting step of the initiation stage of mRNA translation.
      • Jackson R.J.
      • Hellen C.U.T.
      • Pestova T.V.
      The mechanism of eukaryotic translation initiation and principles of its regulation.
      The expression of eukaryotic translation initiation factor 4 γ 1 in serous ovarian cancer at both the mRNA and protein level is significantly up-regulated and associated with clinical tumor stage.
      • Jackson R.J.
      • Hellen C.U.T.
      • Pestova T.V.
      The mechanism of eukaryotic translation initiation and principles of its regulation.
      In addition, patients with low eukaryotic translation initiation factor 4 γ 1 protein reported longer survival time.
      • Jackson R.J.
      • Hellen C.U.T.
      • Pestova T.V.
      The mechanism of eukaryotic translation initiation and principles of its regulation.
      Together, findings of these key RNABPs outline the clinicopathological relevance of these RNABPs in reproductive cancers.
      In addition to dysregulated RNABP expression, aberrant miRNA expression has also been demonstrated in ovarian cancer pathogenesis.
      • Iorio M.V.
      • Visone R.
      • Di Leva G.
      • Donati V.
      • Petrocca F.
      • Casalini P.
      • Taccioli C.
      • Volinia S.
      • Liu C.G.
      • Alder H.
      • Calin G.A.
      • Ménard S.
      • Croce C.M.
      MicroRNA signatures in human ovarian cancer.
      • Iorio M.V.
      • Croce C.M.
      MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics: a comprehensive review.
      Direct connections with miRNAs and RNABPs have been reported with respect to the Drosha and DGCR8 core components in miRNA biogenesis microprocessor, because RNABPs can confer specificity for recruiting and processing different pri-miRNAs.
      • Lee Y.
      • Kim M.
      • Han J.
      • Yeom K.H.
      • Lee S.
      • Baek S.H.
      • Kim V.N.
      MicroRNA genes are transcribed by RNA polymerase II.
      It has been shown that RNA binding molecules p68,
      • Fuller-Pace F.V.
      • Moore H.C.
      RNA helicases p68 and p72: multifunctional proteins with important implications for cancer development.
      p72,
      • Fuller-Pace F.V.
      • Moore H.C.
      RNA helicases p68 and p72: multifunctional proteins with important implications for cancer development.
      KSRP,
      • Trabucchi M.
      • Briata P.
      • Garcia-Mayoral M.
      • Haase A.D.
      • Filipowicz W.
      • Ramos A.
      • Gherzi R.
      • Rosenfeld M.G.
      The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs.
      and TAR DNA-binding protein 43
      • Kawahara Y.
      • Mieda-Sato A.
      TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes.
      all can specifically modulate miRNA maturation via interactions with the miRNA processing complexes. RNABP human DEAD-box protein has been demonstrated to be a regulatory modulator of miRNAs involved in DNA damage via its modulatory effects on the Drosha processing of a select group of miRNAs.
      • Han C.
      • Liu Y.
      • Wan G.
      • Choi H.J.
      • Zhao L.
      • Ivan C.
      • He X.
      • Sood A.K.
      • Zhang X.
      • Lu X.
      The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression.
      Inhibition of this RNABP results in ovarian tumor growth and metastasis in mice and poor clinical outcomes in human patients with serous ovarian cancer.
      • Han C.
      • Liu Y.
      • Wan G.
      • Choi H.J.
      • Zhao L.
      • Ivan C.
      • He X.
      • Sood A.K.
      • Zhang X.
      • Lu X.
      The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression.
      In addition, RNABPs Lin28B and insulin-like growth factor 2 have been shown to be correlated in ovarian cancer.
      • Hsu K.F.
      • Shen M.R.
      • Huang Y.F.
      • Cheng Y.M.
      • Lin S.H.
      • Chow N.H.
      • Cheng S.W.
      • Chou C.Y.
      • Ho C.L.
      Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.
      Although much progress has been made to determine this association between miRNAs and RNABPs in cancer, further studies will need to further elucidate links between their cancer-specific interactions and cancer progression. Moving forward, research in this field may be crucial in finding molecular targets for selected therapies, determining prognosis, and addressing chemoresistance.

      RNABPs as Potential Therapeutic Targets

      Because of their ubiquity, RNABPs at the clinical level have not been used for biomarker detection. Currently, preclinical trials using compounds that attenuate or up-regulate RNABPs have yielded promising findings. Nanotherapy-based drug delivery approaches have become a feasible type of treatment of cancers in the past few years and most recently have been shown to be useful for dermatologic-related pathologies.
      • Navarro G.
      • Pan J.
      • Torchilin V.P.
      Micelle-like nanoparticles as carriers for DNA and siRNA.
      Moreover, nanoparticles have been used in carrying DNA fragments and RNA inhibitors, such as siRNA, and these options may change the future of treating pathologies.
      • Navarro G.
      • Pan J.
      • Torchilin V.P.
      Micelle-like nanoparticles as carriers for DNA and siRNA.
      The improvement in our understanding of HuR has led to novel therapeutic exploration. Cy-3–labeled folic acid–derivatized DNA dendrimer nanocarriers are used as a targeted delivery system of siRNAs. These nanocarriers contain siRNAs for HuR and have already been demonstrated to be successful in suppressing tumor growth in mice with ovarian cancer and significantly increasing their lifespan.
      • Huang Y.H.
      • Peng W.
      • Furuuchi N.
      • Gerhart J.
      • Rhodes K.
      • Mukherjee N.
      • Jimbo M.
      • Gonye G.E.
      • Brody J.R.
      • Getts R.C.
      • Sawicki J.A.
      Delivery of therapeutics targeting the mRNA-binding protein HuR using 3DNA nanocarriers suppresses ovarian tumor growth.
      In addition, HuR nanotherapy in combination with a CXCR4 antagonist has been reported to control lung cancer metastasis via suppression of CXCR4-stromal cell–derived factor 1 axis.
      • Muralidharan R.
      • Panneerselvam J.
      • Chen A.
      • Zhao Y.D.
      • Munshi A.
      • Ramesh R.
      HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer.
      These encouraging results support the continuation of research in this specific field of targeted cancer therapies. However, similar to all mRNA regulators, including miRNAs, specificity to both the gene of interest and site of the targeted biological pose challenges. Indeed, the need to understand the roles of RNABPs in different cell populations has been previously highlighted.
      • Huang Y.H.
      • Peng W.
      • Furuuchi N.
      • Gerhart J.
      • Rhodes K.
      • Mukherjee N.
      • Jimbo M.
      • Gonye G.E.
      • Brody J.R.
      • Getts R.C.
      • Sawicki J.A.
      Delivery of therapeutics targeting the mRNA-binding protein HuR using 3DNA nanocarriers suppresses ovarian tumor growth.
      • Katsanou V.
      • Milatos S.
      • Yiakouvaki A.
      • Sgantzis N.
      • Kotsoni A.
      • Alexiou M.
      • Harokopos V.
      • Aidinis V.
      • Hemberger M.
      • Kontoyiannis D.L.
      The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
      Furthermore, long-term benefits of RNABP biologics have not been evaluated and could also prove to be limiting, especially because of the fact that these are protein-based therapeutics and will likely not be able to be delivered as oral biologics. RNABPs such as the HuR/TTP axis, which primarily target inflammatory cytokines, are early to intermediate responders; thus, targeting this axis may not translate to long-term biologics. Another important aspect to take into consideration is that potential nonspecificity is minimized as nanoparticles can be specifically delivered to the target tissue or organ. In a pharmacological sense, early to intermediate elements usually result in homeostatic changes in the patient short-term, but over time, the homeostatic changes can revert because of other mechanisms, such as miRNA families with the same inflammatory targets being up-regulated in response to down-regulation induced by biologics. When taken together, it comes as no surprise then that RNABPs have been identified as therapeutic targets to treat inflammatory diseases; however, additional research is required to validate the feasibility of this new type of treatment using nanotechnology.
      Since the first anti-TNF biological therapy was authorized by the US Federal Drug Administration, current TNF inhibitors have shown efficacy in dampening inflammation. These drugs are mainly either monoclonal antibodies or fusion proteins that confer the characteristic of being injectable and disintegrate when digested. Indeed, many other therapeutic targets have been developed since, including anti–IL-23, IL-1, IL-6, and interferons, among others, to treat a wide variety of inflammatory pathologies, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and pediatric autoimmune disorders.
      • Rosman Z.
      • Shoenfeld Y.
      • Zandman-Goddard G.
      Biologic therapy for autoimmune diseases: an update.
      However, modulation of inflammatory response is one of the many key points to address severe immunosuppression as well as serious adverse events. Because of these reasons, these therapeutics have a limited safety profile and patients are monitored carefully.
      • Singh J.A.
      • Cameron C.
      • Noorbaloochi S.
      • Cullis T.
      • Tucker M.
      • Christensen R.
      • Ghogomu E.T.
      • Coyle D.
      • Clifford T.
      • Tugwell P.
      • Wells G.A.
      Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.
      Despite the success of biological therapies worldwide, there are still some unmet needs regarding the treatment of immune- and inflammation-mediated disorders. Nevertheless, TTP overexpression in the mouse model has demonstrated the capability to protect mice from autoimmune disorders, which suggest the benefit of a drug that simulates TTP may be a good agent to treat inflammation-mediated pathologies, including reproductive tract pathologies.
      • Patial S.
      • Blackshear P.J.
      Tristetraprolin as a therapeutic target in inflammatory disease.

      Conclusions

      In this review, we highlighted the importance of RNABPs and their contributions to reproductive pathologies. We also sought to highlight unique mechanisms, with an emphasis on the HuR/TTP axis, that these RNABPs influence their target genes to exert their effects in a wide variety of cell types as well as potential use as therapeutic targets. Their unique involvement with NF-κB in regulation of inflammation, cell senescence, and proliferation further highlights their importance in maintaining a homeostatic balance. Furthermore, unique cancer-specific functions of some RNABPs may be at play in endometrial and ovarian cancer. We believe that, although the reproductive field lacks knowledge on RNABPs compared to other molecules involved in PTGR such as miRNAs, RNABPs contribute to these pathologies as much as miRNA networks. Because of the intricate roles of RNABPs in maintaining homeostasis, we believe that rather than evaluating RNABP families in separation, they should be investigated as a ratio. Future investigations should evaluate the unique interplays between PTGR mechanisms shared or in tandem with RNABPs and other regulators as well as the unique roles of RNABPs on translation, success, or failure of the targets, and their unique contributions to reproductive tract pathologies.

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