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TARDBP promotes ovarian cancer progression by altering vascular endothelial growth factor splicing

Oncogene volume 42, pages 49–61 (2023)Cite this article

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Abstract

Disruptions in alternative splicing regulation play an essential role in ovarian cancer progression. However, the underlying mechanism remains unclear. TAR DNA-binding protein (TARDBP) plays a crucial role in alternative splicing regulation. Herein we found that TARDBP expression was significantly upregulated in OC tissue samples, particularly in cases of metastasis; further, TARDBP expression was markedly upregulated in OC patients with poor prognosis. These findings were validated by extensive tissue microarray data. TARDBP was also found to promote tumorigenesis and metastasis of OC cells in vitro and in vivo. Mechanistically, TARDBP increased the binding of the splicing factor serine/arginine-rich splicing factor 1 (SRSF1) to intron 7 of vascular endothelial growth factor (VEGF), increasing the formation of the proangiogenic VEGF165 isoform and decreasing that of the antiangiogenic VEGF165b isoform. The abnormal alternative splicing event was responsible for the activation of angiogenesis and contributed to the progression of OC. To conclude, TARDBP was found to regulate the alternative splicing of VEGF via SRSF1, induce the formation of VEGF165 but inhibit that of VEGF165b, and promote OC angiogenesis. Hence, TARDBP can serve as an independent prognostic factor and new target for OC cancer therapy.

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Fig. 1: TARDBP expression is significantly up-regulated in OC and associated with worse prognosis.
Fig. 2: TARDBP knockout (KO) inhibits tumorigenesis and metastasis in vitro and in vivo.
Fig. 3: Interaction between TARDBP and SRSF1.
Fig. 4: Down-regulation of SRSF1 expression weakens the enhancement of OC tumorigenesis induced by TARDBP overexpression.
Fig. 5: TARDBP strengthens the binding of SRSF1 to the I7 sequence of VEGF.
Fig. 6: TARDBP and SRSF1 participate in VEGF AS to increase VEGF165 and decrease VEGF165b mRNA and protein levels.
Fig. 7: Effects of TARDBP on HUVECs migration and tube formation ability.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–24.

    Article  Google Scholar 

  2. Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69:280–4.

    Google Scholar 

  3. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68:284–96.

    Article  Google Scholar 

  4. Peres LC, Cushing-Haugen KL, Kobel M, Harris HR, Berchuck A, Rossing MA, et al. Invasive epithelial ovarian cancer survival by histotype and disease stage. J Natl Cancer Inst. 2019;111:60–8.

    Article  Google Scholar 

  5. Nonaka T, Hasegawa M. TDP-43 Prions. Cold Spring Harb Perspect Med. 2018;8.

  6. Ma X, Ying Y, Xie H, Liu X, Wang X, Li J. The regulatory role of RNA metabolism regulator TDP-43 in human cancer. Front Oncol. 2021;11:755096.

    Article  Google Scholar 

  7. Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135:851–67.

    Article  CAS  Google Scholar 

  8. de Boer E, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2020;92:86–95.

    Article  Google Scholar 

  9. Suk TR, Rousseaux M. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol Neurodegener. 2020;15:45.

    Article  CAS  Google Scholar 

  10. Gao J, Wang L, Huntley ML, Perry G, Wang X. Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem. 2018;146:7–20.

    Article  CAS  Google Scholar 

  11. Ke H, Zhao L, Zhang H, Feng X, Xu H, Hao J, et al. Loss of TDP43 inhibits progression of triple-negative breast cancer in coordination with SRSF3. Proc Natl Acad Sci USA. 2018;115:E3426–35.

    Article  CAS  Google Scholar 

  12. Chen X, Fan Z, McGee W, Chen M, Kong R. Wen P, et al. TDP-43 regulates cancer-associated microRNAs. Protein Cell. 2018;9:848–66.

    Article  CAS  Google Scholar 

  13. Guo F, Wang H, Jiang M, Yang Q, Xiang Q, Zhou H, et al. TDP-43 induces EMT and promotes hepatocellular carcinoma metastasis via activating Wnt/beta-catenin signaling pathway. Am J Cancer Res. 2020;10:3285–301.

    CAS  Google Scholar 

  14. Zeng Q, Cao K, Liu R, Huang J, Xia K, Tang J, et al. Identification of TDP-43 as an oncogene in melanoma and its function during melanoma pathogenesis. Cancer Biol Ther. 2017;18:8–15.

    Article  CAS  Google Scholar 

  15. Xiong X, Hou L, Park YP, Molinie B, Gregory RI, Kellis M. Genetic drivers of m(6)A methylation in human brain, lung, heart and muscle. Nat Genet. 2021;53:1156–65.

    Article  CAS  Google Scholar 

  16. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40:1413–5.

    Article  CAS  Google Scholar 

  17. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, et al. Alternative isoform regulation in human tissue transcriptomes. Nature 2008;456:470–6.

    Article  CAS  Google Scholar 

  18. Climente-Gonzalez H, Porta-Pardo E, Godzik A, Eyras E. The functional impact of alternative splicing in cancer. Cell Rep. 2017;20:2215–26.

    Article  CAS  Google Scholar 

  19. Baralle FE, Giudice J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017;18:437–51.

    Article  CAS  Google Scholar 

  20. Kedzierska H, Piekielko-Witkowska A. Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer. Cancer Lett. 2017;396:53–65.

    Article  CAS  Google Scholar 

  21. Bao M, Chen Y, Liu JT, Bao H, Wang WB, Qi YX, et al. Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis. Angiogenesis 2022;25:71–86.

    Article  CAS  Google Scholar 

  22. Barbagallo D, Caponnetto A, Barbagallo C, Battaglia R, Mirabella F, Brex D, et al. The GAUGAA Motif Is Responsible for the Binding between circSMARCA5 and SRSF1 and Related Downstream Effects on Glioblastoma Multiforme Cell Migration and Angiogenic Potential. Int J Mol Sci. 2021;22:1678.

    Article  CAS  Google Scholar 

  23. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell 2019;176:1248–64.

    Article  CAS  Google Scholar 

  24. Koutsioumpa M, Poimenidi E, Pantazaka E, Theodoropoulou C, Skoura A, Megalooikonomou V, et al. Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor. Mol Cancer. 2015;14:19.

    Article  CAS  Google Scholar 

  25. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, et al. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci. 2008;121:3487–95.

    Article  CAS  Google Scholar 

  26. Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem. 2010;285:5532–40.

    Article  CAS  Google Scholar 

  27. Clery A, Krepl M, Nguyen C, Moursy A, Jorjani H, Katsantoni M, et al. Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing. Nat Commun. 2021;12:428.

    Article  CAS  Google Scholar 

  28. Das S, Krainer AR. Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Mol Cancer Res. 2014;12:1195–204.

    Article  CAS  Google Scholar 

  29. Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell. 2011;20:768–80.

    Article  CAS  Google Scholar 

  30. Bonnal SC, Lopez-Oreja I, Valcarcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol. 2020;17:457–74.

    Article  Google Scholar 

  31. Lv Y, Zhang W, Zhao J, Sun B, Qi Y, Ji H, et al. SRSF1 inhibits autophagy through regulating Bcl-x splicing and interacting with PIK3C3 in lung cancer. Signal Transduct Target Ther. 2021;6:108.

    Article  CAS  Google Scholar 

  32. Du JX, Luo YH, Zhang SJ, Wang B, Chen C, Zhu GQ, et al. Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1. J Exp Clin Cancer Res. 2021;40:171.

    Article  CAS  Google Scholar 

  33. Liu H, Gong Z, Li K, Zhang Q, Xu Z, Xu Y. SRPK1/2 and PP1alpha exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma. J Exp Clin Cancer Res. 2021;40:75.

    Article  CAS  Google Scholar 

  34. Zhou X, Wang R, Li X, Yu L, Hua D, Sun C, et al. Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B. J Clin Invest. 2019;129:676–93.

    Article  Google Scholar 

  35. Karaman S, Leppanen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development. 2018;145:dev151019.

    Article  Google Scholar 

  36. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871–82.

    Article  CAS  Google Scholar 

  37. Di Matteo A, Belloni E, Pradella D, Cappelletto A, Volf N, Zacchigna S, et al. Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis. J Exp Clin Cancer Res. 2020;39:275.

    Article  Google Scholar 

  38. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.

    Article  CAS  Google Scholar 

  39. Puszko AK, Sosnowski P, Rignault-Bricard R, Hermine O, Hopfgartner G, Pulka-Ziach K, et al. Urea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties. Int J Mol Sci. 2020;22:72.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Doctoral workstation foundation of Guangdong Second Provincial General Hospital (2020072) and the GuangDong Basic and Applied Basic Research Foundation (2021A1515111033).

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  1. Department of Gynecology, Guangdong Second Provincial General Hospital, 466 Xin-Gang-Zhong Road, Guangzhou, 510317, China

    Yutian He, Zhenbo OuYang, Wenwen Liu, Yu Chen & Qiushi Zhang

  2. Institute of Maternal and Child Health, Guangdong Second Provincial General Hospital, 466 Xin-Gang-Zhong Road, Guangzhou, 510317, China

    Qiushi Zhang

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YH and QZ were responsible conceived the project, designed the experiments, and YH wrote the manuscript. ZOY, WL conducted the in vitro and in vivo cell experiments; YC provided statistical support, analyzed the IHC data.

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Correspondence to Yutian He or Qiushi Zhang.

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He, Y., OuYang, Z., Liu, W. et al. TARDBP promotes ovarian cancer progression by altering vascular endothelial growth factor splicing. Oncogene 42, 49–61 (2023). https://doi.org/10.1038/s41388-022-02539-9

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