FUT8-AS1/miR-944/Fused in Sarcoma/Transcription Factor 4 Feedback Loop Participates in the Development of Oral Squamous Cell Carcinoma through Activation of Wnt/β-Catenin Signaling Pathway

      As a common type of head and neck squamous cell carcinoma, oral squamous cell carcinoma (OSCC) is a lethal and deforming disease. Long noncoding RNAs have emerged as critical modulators in different malignancies. However, the role of fucosyltransferase 8 antisense RNA 1 (FUT8-AS1) in OSCC still remains elusive. In this study, quantitative RT-PCR and Western blot were used for the measurement of RNAs and proteins. Mechanism assays explored the putative correlation among genes. In vitro assays evaluated the changes in OSCC cell malignant phenotype, whereas in vivo assays highlighted the influence of FUT8-AS1 on tumor growth. FUT8-AS1, aberrantly up-regulated in OSCC tissues and cells, could exacerbate OSCC cell malignant behaviors. The cancerogenic property of FUT8-AS1 in OSCC was further confirmed via animal experiments. Furthermore, FUT8-AS1 enhanced the expression of transcription factor 4 (TCF4) via sponging miR-944 and recruiting fused in sarcoma (FUS), thus affecting OSCC cell biological behaviors via modulation on Wnt/β-catenin signaling activity. In addition, TCF4 was validated as the transcriptional activator of FUT8-AS1. To conclude, TCF4-mediated FUT8-AS1 could exacerbate OSCC cell malignant behaviors and facilitate tumor growth via modulation on miR-944/FUS/TCF4.

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        • Thomson P.J.
        Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction.
        J Oral Pathol Med. 2018; 47: 803-807
        • De Paz D.
        • Kao H.K.
        • Huang Y.
        • Chang K.P.
        Prognostic stratification of patients with advanced oral cavity squamous cell carcinoma.
        Curr Oncol Rep. 2017; 19: 65
        • Chan J.J.
        • Tay Y.
        Noncoding RNA:RNA regulatory networks in cancer.
        Int J Mol Sci. 2018; 19: 1310
        • Qu X.
        • Alsager S.
        • Zhuo Y.
        • Shan B.
        HOX transcript antisense RNA (HOTAIR) in cancer.
        Cancer Lett. 2019; 454: 90-97
        • Shuai Y.
        • Ma Z.
        • Lu J.
        • Feng J.
        LncRNA SNHG15: a new budding star in human cancers.
        Cell Prolif. 2020; 53: e12716
        • Li L.
        • Wang Y.
        • Zhang X.
        • Huang Q.
        • Diao Y.
        • Yin H.
        • Liu H.
        Long non-coding RNA HOXD-AS1 in cancer.
        Clin Chim Acta. 2018; 487: 197-201
        • Zhang L.
        • Meng X.
        • Zhu X.W.
        • Yang D.C.
        • Chen R.
        • Jiang Y.
        • Xu T.
        Long non-coding RNAs in oral squamous cell carcinoma: biologic function, mechanisms and clinical implications.
        Mol Cancer. 2019; 18: 102
        • Gomes C.C.
        • de Sousa S.F.
        • Calin G.A.
        • Gomez R.S.
        The emerging role of long noncoding RNAs in oral cancer.
        Oral Surg Oral Med Oral Pathol Oral Radiol. 2017; 123: 235-241
        • Wang X.
        • Li H.
        • Shi J.
        LncRNA HOXA11-AS promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by suppression of miR-214-3p expression.
        Biomed Res Int. 2019; 2019: 8645153
        • Yang Y.
        • Chen D.
        • Liu H.
        • Yang K.
        Increased expression of lncRNA CASC9 promotes tumor progression by suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway in oral squamous cell carcinoma.
        Cell Death Dis. 2019; 10: 41
        • Braga E.A.
        • Fridman M.V.
        • Moscovtsev A.A.
        • Filippova E.A.
        • Dmitriev A.A.
        • Kushlinskii N.E.
        LncRNAs in ovarian cancer progression, metastasis, and main pathways: ceRNA and alternative mechanisms.
        Int J Mol Sci. 2020; 21: 8855
        • Yang X.Z.
        • Cheng T.T.
        • He Q.J.
        • Lei Z.Y.
        • Chi J.
        • Tang Z.
        • Liao Q.X.
        • Zhang H.
        • Zeng L.S.
        • Cui S.Z.
        LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway.
        Mol Cancer. 2018; 17: 126
        • Dai D.
        • Feng X.D.
        • Zhu W.Q.
        • Bao Y.N.
        LncRNA BLACAT1 regulates the viability, migration and invasion of oral squamous cell carcinoma cells by targeting miR-142-5p.
        Eur Rev Med Pharmacol Sci. 2019; 23: 10313-10323
        • Chen D.L.
        • Lu Y.X.
        • Zhang J.X.
        • Wei X.L.
        • Wang F.
        • Zeng Z.L.
        • Pan Z.Z.
        • Yuan Y.F.
        • Wang F.H.
        • Pelicano H.
        • Chiao P.J.
        • Huang P.
        • Xie D.
        • Li Y.H.
        • Ju H.Q.
        • Xu R.H.
        Long non-coding RNA UICLM promotes colorectal cancer liver metastasis by acting as a ceRNA for microRNA-215 to regulate ZEB2 expression.
        Theranostics. 2017; 7: 4836-4849
        • Gong F.
        • Dong D.
        • Zhang T.
        • Xu W.
        Long non-coding RNA FENDRR attenuates the stemness of non-small cell lung cancer cells via decreasing multidrug resistance gene 1 (MDR1) expression through competitively binding with RNA binding protein HuR.
        Eur J Pharmacol. 2019; 853: 345-352
        • Zhang Y.
        • Chen W.
        • Pan T.
        • Wang H.
        • Zhang Y.
        • Li C.
        LBX2-AS1 is activated by ZEB1 and promotes the development of esophageal squamous cell carcinoma by interacting with HNRNPC to enhance the stability of ZEB1 and ZEB2 mRNAs.
        Biochem Biophys Res Commun. 2019; 511: 566-572
        • Shergalis A.
        • Bankhead 3rd, A.
        • Luesakul U.
        • Muangsin N.
        • Neamati N.
        Current challenges and opportunities in treating glioblastoma.
        Pharmacol Rev. 2018; 70: 412-445
        • Stavast C.J.
        • Erkeland S.J.
        The non-canonical aspects of microRNAs: many roads to gene regulation.
        Cells. 2019; 8: 1465
        • Ma Y.
        • Han J.
        • Luo X.
        FOXD1-AS1 upregulates FOXD1 to promote oral squamous cell carcinoma progression.
        Oral Dis. 2021; ([Epub ahead of print] doi:10.1111/odi.14002)
        • Prossomariti A.
        • Piazzi G.
        • D'Angelo L.
        • Miccoli S.
        • Turchetti D.
        • Alquati C.
        • Montagna C.
        • Bazzoli F.
        • Ricciardiello L.
        miR-155 is downregulated in familial adenomatous polyposis and modulates WNT signaling by targeting AXIN1 and TCF4.
        Mol Cancer Res. 2018; 16: 1965-1976
        • Schmitz S.U.
        • Grote P.
        • Herrmann B.G.
        Mechanisms of long noncoding RNA function in development and disease.
        Cell Mol Life Sci. 2016; 73: 2491-2509
        • Wen L.
        • Li Y.
        • Jiang Z.
        • Zhang Y.
        • Yang B.
        • Han F.
        miR-944 inhibits cell migration and invasion by targeting MACC1 in colorectal cancer.
        Oncol Rep. 2017; 37: 3415-3422
        • Ji J.
        • Peng Y.
        • Niu T.
        • Lin Y.
        • Lin Y.
        • Li X.
        • Wu X.
        • Huang Z.
        • Zhong L.
        • Zhang S.
        miR-944 inhibits cell migration and invasion by targeting MACC1 in nasopharyngeal carcinoma.
        Int J Clin Exp Pathol. 2018; 11: 1167-1174
        • Chen B.
        • Xu P.
        • Wang J.
        • Zhang C.
        The role of miRNA in polycystic ovary syndrome (PCOS).
        Gene. 2019; 706: 91-96
        • Yao Y.
        • Chen S.
        • Lu N.
        • Yin Y.
        • Liu Z.
        LncRNA JPX overexpressed in oral squamous cell carcinoma drives malignancy via miR-944/CDH2 axis.
        Oral Dis. 2021; 27: 924-933
        • Pereira B.
        • Billaud M.
        • Almeida R.
        RNA-binding proteins in cancer: old players and new actors.
        Trends Cancer. 2017; 3: 506-528
        • Ferrè F.
        • Colantoni A.
        • Helmer-Citterich M.
        Revealing protein-lncRNA interaction.
        Brief Bioinformatics. 2016; 17: 106-116
        • Feng Y.
        • Yang Y.
        • Zhao X.
        • Fan Y.
        • Zhou L.
        • Rong J.
        • Yu Y.
        Circular RNA circ0005276 promotes the proliferation and migration of prostate cancer cells by interacting with FUS to transcriptionally activate XIAP.
        Cell Death Dis. 2019; 10: 792
        • Yang Z.
        • Dong X.
        • Pu M.
        • Yang H.
        • Chang W.
        • Ji F.
        • Liu T.
        • Wei C.
        • Zhang X.
        • Qiu X.
        LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop contributes to the proliferation of gastric cancer.
        Gastric Cancer. 2020; 23: 449-463
        • Xie P.
        • Guo Y.
        LINC00205 promotes malignancy in lung cancer by recruiting FUS and stabilizing CSDE1.
        Biosci Rep. 2020; 40 (BSR20190701)
        • Zhu H.
        • Zheng T.
        • Yu J.
        • Zhou L.
        • Wang L.
        LncRNA XIST accelerates cervical cancer progression via upregulating Fus through competitively binding with miR-200a.
        Biomed Pharmacother. 2018; 105: 789-797
        • Zhang Z.
        • Tu K.
        • Liu F.
        • Liang M.
        • Yu K.
        • Wang Y.
        • Luo Y.
        • Yang B.
        • Qin Y.
        • He D.
        • Jiang G.
        • Huang O.
        • Zou Y.
        FoxM1 promotes the migration of ovarian cancer cell through KRT5 and KRT7.
        Gene. 2020; 757: 144947
        • Liu L.
        • Zeng Z.
        • Yi J.
        • Zuo L.
        • Lv J.
        • Yuan J.
        • Lin Z.
        • Luo R.
        • Feng X.
        Expression and clinical significance of transcription factor 4 (TCF4) in epithelial ovarian cancer.
        Cancer Biomark. 2019; 24: 213-221
        • Zheng H.E.
        • Wang G.
        • Song J.
        • Liu Y.
        • Li Y.M.
        • Du W.P.
        MicroRNA-495 inhibits the progression of non-small-cell lung cancer by targeting TCF4 and inactivating Wnt/β-catenin pathway.
        Eur Rev Med Pharmacol Sci. 2018; 22: 7750-7759
        • Yu Y.
        • Zhao J.D.
        • Yang H.
        MiR-299-3p inhibits proliferation and invasion of cervical cancer cell via targeting TCF4.
        Eur Rev Med Pharmacol Sci. 2019; 23: 5621-5627
        • Ji X.
        • Guo H.
        • Yin S.
        • Du H.
        miR-139-5p functions as a tumor suppressor in cervical cancer by targeting TCF4 and inhibiting Wnt/β-catenin signaling.
        Onco Targets Ther. 2019; 12: 7739-7748
        • Dykes I.M.
        • Emanueli C.
        Transcriptional and post-transcriptional gene regulation by long non-coding RNA.
        Genomics Proteomics Bioinformatics. 2017; 15: 177-186
        • Sun Y.
        • Xu J.
        TCF-4 regulated lncRNA-XIST promotes M2 polarization of macrophages and is associated with lung cancer.
        Onco Targets Ther. 2019; 12: 8055-8062