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Phosphatidylserine-Specific Phospholipase A1 Limits Aggressiveness of Lung Adenocarcinoma by Lysophosphatidylserine and Protein Kinase A–Dependent Pathway

  • Yue Zhou
    Affiliations
    Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Meijia Chang
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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  • Ning Wang
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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  • Yuan Zhuang
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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  • Fang Wang
    Affiliations
    State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
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  • Xu Zhang
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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  • Min Guo
    Affiliations
    State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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  • Ning Lin
    Correspondence
    Ning Lin, M.D., NHC Contraceptives Adverse Reaction Surveillance Center, Jiangsu Health Development Research Center, Nanjing 210036, China.
    Affiliations
    National Health Commission Contraceptives Adverse Reaction Surveillance Center, Jiangsu Health Development Research Center, Nanjing, China
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  • John Zhong Li
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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  • Qian Wang
    Correspondence
    Address correspondence to Qian Wang, Ph.D., Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China.
    Affiliations
    Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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      Lipid metabolic abnormalities in cancer cells are increasingly being studied. Several studies have reported that phosphatidylserine-specific phospholipase A1 (PLA1A) might be involved in the pathogenesis of cancers. Nevertheless, the function and mechanistic details of PLA1A in lung adenocarcinoma (LUAD) progression remain largely undefined. In the present study, low PLA1A expression was correlated with poor prognosis in patients with LUAD. Results from in vitro and in vivo animal studies showed that overexpressed PLA1A suppressed the proliferation of LUAD cells in vitro and tumor growth in vivo through regulation of cyclin abundance, thereby inducing S-phase arrest. Meanwhile, PLA1A overexpression attenuated migration and invasion of LUAD cells, including by inhibiting the epithelial-mesenchymal transition. Mechanistically, PLA1A overexpression inhibited aggressiveness of LUAD cells through elevated lysophosphatidylserine, which acts via G-protein–coupled receptor 174, further activating cAMP/protein kinase A pathway. Activating G-protein–coupled receptor 174/protein kinase A pathway may involve effects on cell cycle regulators and transcription factors–regulated epithelial-mesenchymal transition. The study uncovered the mechanism through which PLA1A regulates LUAD proliferation, invasion, and migration. These results demonstrate the potential use of PLA1A as a biomarker for diagnosing LUAD, which may therefore potentially serve as a therapeutic target for LUAD.
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      References

        • Vriens K.
        • Christen S.
        • Parik S.
        • Broekaert D.
        • Yoshinaga K.
        • Talebi A.
        • et al.
        Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.
        Nature. 2019; 566: 403-406
        • Piccinin E.
        • Cariello M.
        • Moschetta A.
        Lipid metabolism in colon cancer: role of liver X receptor (LXR) and stearoyl-CoA desaturase 1 (SCD1).
        Mol Aspects Med. 2021; 78: 100933
        • Rizzo A.M.
        • Colombo I.
        • Montorfano G.
        • Zava S.
        • Corsetto P.A.
        Exogenous fatty acids modulate ER lipid composition and metabolism in breast cancer cells.
        Cells. 2021; 10: 175
        • Postle A.D.
        Lipidomics.
        Curr Opin Clin Nutr Metab Care. 2012; 15: 127-133
        • Torre L.A.
        • Siegel R.L.
        • Jemal A.
        Lung cancer statistics.
        Adv Exp Med Biol. 2016; 893: 1-19
        • Hirsch F.R.
        • Scagliotti G.V.
        • Mulshine J.L.
        • Kwon R.
        • Curran Jr., W.J.
        • Wu Y.L.
        • Paz-Ares L.
        Lung cancer: current therapies and new targeted treatments.
        Lancet. 2017; 389: 299-311
        • Moran C.
        Importance of molecular features of non-small cell lung cancer for choice of treatment.
        Am J Pathol. 2011; 178: 1940-1948
        • Guan H.
        • Zhu T.
        • Wu S.
        • Liu S.
        • Liu B.
        • Wu J.
        • Cai J.
        • Zhu X.
        • Zhang X.
        • Zeng M.
        • Li J.
        • Song E.
        • Li M.
        Long noncoding RNA LINC00673-v4 promotes aggressiveness of lung adenocarcinoma via activating WNT/beta-catenin signaling.
        Proc Natl Acad Sci U S A. 2019; 116: 14019-14028
        • Chen Z.
        • Fillmore C.M.
        • Hammerman P.S.
        • Kim C.F.
        • Wong K.K.
        Non-small-cell lung cancers: a heterogeneous set of diseases.
        Nat Rev Cancer. 2014; 14: 535-546
        • Copur M.S.
        • Crockett D.
        • Gauchan D.
        • Ramaekers R.
        • Mleczko K.
        Molecular testing guideline for the selection of patients with lung cancer for targeted therapy.
        J Clin Oncol. 2018; 36: 2006
        • Herbst R.S.
        • Morgensztern D.
        • Boshoff C.
        The biology and management of non-small cell lung cancer.
        Nature. 2018; 553: 446-454
        • Horinouchi H.
        Role of multimodality therapy in cIIIA-N2 non-small cell lung cancer: perspective.
        Jpn J Clin Oncol. 2016; 46: 1174-1178
        • Visca P.
        • Sebastiani V.
        • Botti C.
        • Diodoro M.G.
        • Lasagni R.P.
        • Romagnoli F.
        • Brenna A.
        • De Joannon B.C.
        • Donnorso R.P.
        • Lombardi G.
        • Alo P.L.
        Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma.
        Anticancer Res. 2004; 24: 4169-4173
        • Noto A.
        • Raffa S.
        • De Vitis C.
        • Roscilli G.
        • Malpicci D.
        • Coluccia P.
        • Di Napoli A.
        • Ricci A.
        • Giovagnoli M.R.
        • Aurisicchio L.
        • Torrisi M.R.
        • Ciliberto G.
        • Mancini R.
        Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells.
        Cell Death Dis. 2013; 4: e947
        • Osugi J.
        • Yamaura T.
        • Muto S.
        • Okabe N.
        • Matsumura Y.
        • Hoshino M.
        • Higuchi M.
        • Suzuki H.
        • Gotoh M.
        Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer.
        Lung Cancer. 2015; 88: 310-318
        • Bellini F.
        • Bruni A.
        Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition.
        FEBS Lett. 1993; 316: 1-4
        • Lourenssen S.
        • Blennerhassett M.G.
        Lysophosphatidylserine potentiates nerve growth factor-induced differentiation of PC12 cells.
        Neurosci Lett. 1998; 248: 77-80
        • Lee S.Y.
        • Lee H.Y.
        • Kim S.D.
        • Jo S.H.
        • Shim J.W.
        • Lee H.J.
        • Yun J.
        • Bae Y.S.
        Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells.
        Biochem Biophys Res Commun. 2008; 374: 147-151
        • van Groningen J.J.
        • Egmond M.R.
        • Bloemers H.P.
        • Swart G.W.
        nmd, A novel gene differentially expressed in human melanoma cell lines, encodes a new atypical member of the enzyme family of lipases.
        FEBS Lett. 1997; 404: 82-86
        • Iida Y.
        • Tsuno N.H.
        • Kishikawa J.
        • Kaneko K.
        • Murono K.
        • Kawai K.
        • Ikeda T.
        • Ishihara S.
        • Yamaguchi H.
        • Sunami E.
        • Kitayama J.
        • Yatomi Y.
        • Watanabe T.
        Lysophosphatidylserine stimulates chemotactic migration of colorectal cancer cells through GPR34 and PI3K/Akt pathway.
        Anticancer Res. 2014; 34: 5465-5472
        • Guo L.
        • Zhang P.
        • Chen Z.
        • Xia H.
        • Li S.
        • Zhang Y.
        • Kobberup S.
        • Zou W.
        • Lin J.D.
        Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression.
        J Clin Invest. 2017; 127: 4449-4461
        • Aoki J.
        • Inoue A.
        • Makide K.
        • Saiki N.
        • Arai H.
        Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family.
        Biochimie. 2007; 89: 197-204
        • Gao X.
        • Chen D.
        • Hu X.
        • Zhou Y.
        • Wang Y.
        • Wu C.
        • Chen J.
        • Wang Y.
        • Pei R.
        • Chen X.
        PLA1A participates in the antiviral innate immune response by facilitating the recruitment of TANK-binding kinase 1 to mitochondria.
        J Innate Immun. 2018; 10: 315-327
        • Yang Q.
        • Guo M.
        • Zhou Y.
        • Hu X.
        • Wang Y.
        • Wu C.
        • Yang M.
        • Pei R.
        • Chen X.
        • Chen J.
        Phosphatidylserine-specific phospholipase A1 is the critical bridge for hepatitis C virus assembly.
        Virol Sin. 2019; 34: 521-537
        • Wang Q.
        • Chen J.
        • Wang Y.
        • Han X.
        • Chen X.
        Hepatitis C virus induced a novel apoptosis-like death of pancreatic beta cells through a caspase 3-dependent pathway.
        PLoS One. 2012; 7: e38522
        • Zhou Y.
        • Zhang Z.
        • Wang N.
        • Chen J.
        • Zhang X.
        • Guo M.
        • John Zhong L.
        • Wang Q.
        Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.
        Cell Death Dis. 2018; 9: 429
        • Committee for the Update of the Guide for the Care and Use of Laboratory Animals; National Research Council
        Guide for the Care and Use of Laboratory Animals.
        Eighth Edition. National Academies Press, Washington, DC2011
        • Zeng J.
        • Zhang H.
        • Tan Y.
        • Sun C.
        • Liang Y.
        • Yu J.
        • Zou H.
        Aggregation of lipid rafts activates c-met and c-Src in non-small cell lung cancer cells.
        BMC Cancer. 2018; 18: 611
        • Nema R.
        • Shrivastava A.
        • Kumar A.
        Prognostic role of lipid phosphate phosphatases in non-smoker, lung adenocarcinoma patients.
        Comput Biol Med. 2021; 129: 104141
        • Tang Z.
        • Xie H.
        • Heier C.
        • Huang J.
        • Zheng Q.
        • Eichmann T.O.
        • Schoiswohl G.
        • Ni J.
        • Zechner R.
        • Ni S.
        • Hao H.
        Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis.
        EBioMedicine. 2020; 53: 102696
        • Zhang Y.
        • Frohman M.A.
        Cellular and physiological roles for phospholipase D1 in cancer.
        J Biol Chem. 2014; 289: 22567-22574
        • Kang D.W.
        • Min do S.
        Platelet derived growth factor increases phospholipase D1 but not phospholipase D2 expression via NFkappaB signaling pathway and enhances invasion of breast cancer cells.
        Cancer Lett. 2010; 294: 125-133
        • Lee Y.J.
        • Shin K.J.
        • Jang H.J.
        • Noh D.Y.
        • Ryu S.H.
        • Suh P.G.
        Phospholipase signaling in breast cancer.
        Adv Exp Med Biol. 2021; 1187: 23-52
        • Xu W.
        • Xu Q.
        • Kuang D.
        • Wang Z.
        • Lu Q.
        • Lin Q.
        • Wu H.
        • Chen L.
        Long noncoding RNA SLNCR1 regulates nonsmall cell lung cancer migration, invasion and stemness through interactions with secretory phospholipase A2.
        Mol Med Rep. 2019; 20: 2591-2596
        • Grzelczyk A.
        • Gendaszewska-Darmach E.
        Novel bioactive glycerol-based lysophospholipids: new data -- new insight into their function.
        Biochimie. 2013; 95: 667-679
        • Hla T.
        • Lee M.J.
        • Ancellin N.
        • Paik J.H.
        • Kluk M.J.
        Lysophospholipids--receptor revelations.
        Science. 2001; 294: 1875-1878
        • Uranbileg B.
        • Kurano M.
        • Sato M.
        • Ikeda H.
        • Ishizawa T.
        • Hasegawa K.
        • Kokudo N.
        • Yatomi Y.
        Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma.
        Sci Rep. 2020; 10: 2659
        • Kim K.
        • Kim H.L.
        • Lee Y.K.
        • Han M.
        • Sacket S.J.
        • Jo J.Y.
        • Kim Y.L.
        • Im D.S.
        Lysophosphatidylserine induces calcium signaling through Ki16425/VPC32183-sensitive GPCR in bone marrow-derived mast cells and in C6 glioma and colon cancer cells.
        Arch Pharm Res. 2008; 31: 310-317
        • Kitamura C.
        • Sonoda H.
        • Nozawa H.
        • Kano K.
        • Emoto S.
        • Murono K.
        • Kaneko M.
        • Hiyoshi M.
        • Sasaki K.
        • Nishikawa T.
        • Shuno Y.
        • Tanaka T.
        • Hata K.
        • Kawai K.
        • Aoki J.
        • Ishihara S.
        The component changes of lysophospholipid mediators in colorectal cancer.
        Tumour Biol. 2019; 41 (1010428319848616)
        • Barnes M.J.
        • Cyster J.G.
        Lysophosphatidylserine suppression of T-cell activation via GPR174 requires Galphas proteins.
        Immunol Cell Biol. 2018; 96: 439-445
        • Shinjo Y.
        • Makide K.
        • Satoh K.
        • Fukami F.
        • Inoue A.
        • Kano K.
        • Otani Y.
        • Ohwada T.
        • Aoki J.
        Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174.
        Biochem Biophys Res Commun. 2017; 494: 332-338
        • Barnes M.J.
        • Li C.M.
        • Xu Y.
        • An J.
        • Huang Y.
        • Cyster J.G.
        The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function.
        J Exp Med. 2015; 212: 1011-1020
        • Sugo T.
        • Tachimoto H.
        • Chikatsu T.
        • Murakami Y.
        • Kikukawa Y.
        • Sato S.
        • Kikuchi K.
        • Nagi T.
        • Harada M.
        • Ogi K.
        • Ebisawa M.
        • Mori M.
        Identification of a lysophosphatidylserine receptor on mast cells.
        Biochem Biophys Res Commun. 2006; 341: 1078-1087
        • Inoue A.
        • Ishiguro J.
        • Kitamura H.
        • Arima N.
        • Okutani M.
        • Shuto A.
        • Higashiyama S.
        • Ohwada T.
        • Arai H.
        • Makide K.
        • Aoki J.
        TGFalpha shedding assay: an accurate and versatile method for detecting GPCR activation.
        Nat Methods. 2012; 9: 1021-1029
        • Engemaier E.
        • Rompler H.
        • Schoneberg T.
        • Schulz A.
        Genomic and supragenomic structure of the nucleotide-like G-protein-coupled receptor GPR34.
        Genomics. 2006; 87: 254-264
        • Qiu D.
        • Chu X.
        • Hua L.
        • Yang Y.
        • Li K.
        • Han Y.
        • Yin J.
        • Zhu M.
        • Mu S.
        • Sun Z.
        • Tong C.
        • Song Z.
        Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice.
        Cell Death Dis. 2019; 10: 233
        • Pierce K.L.
        • Premont R.T.
        • Lefkowitz R.J.
        Seven-transmembrane receptors.
        Nat Rev Mol Cell Biol. 2002; 3: 639-650
        • Lefkowitz R.J.
        A brief history of G-protein coupled receptors (Nobel lecture).
        Angew Chem Int Ed Engl. 2013; 52: 6366-6378
        • Godbole A.
        • Lyga S.
        • Lohse M.J.
        • Calebiro D.
        Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription.
        Nat Commun. 2017; 8: 443