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STMN2 overexpression promotes cell proliferation and EMT in pancreatic cancer mediated by WNT/β-catenin signaling

Abstract

STMN2, as a key regulator in microtubule disassembly and dynamics, has recently been shown to participate in cancer development. However, the corresponding role in pancreatic ductal adenocarcinoma (PC), to our knowledge, has not been reported yet. In the current study, we systematically investigate the potential role of STMN2 in the progression of PC in vitro and vivo. Overexpression of STMN2 was prevalently observed in 81 human cases of PC tissues compared with that in the paired adjacent pancreas (54.3% vs 18.5%, P < 0.01), which was positively associated with multiple advanced clinical stages of PC patients (tumor size, T stage, lymph-node metastasis and the poor prognosis). Meanwhile, a close correlation between high STMN2 and cytoplasmic/nuclear β-catenin expression (P = 0.007) was observed in PC tissues and cell lines. STMN2 overexpression induced EMT and cell proliferation in vitro via stimulating EMT-like cellular morphology, cell motility and proliferation, and the change of EMT (Snail1, E-cadherin and Vimentin) and Cyclin D1 signaling. However, XAV939 inhibited STMN2 overexpression-enhanced EMT and proliferation. Conversely, KY19382 reversed STMN2 silencing- inhibited EMT and cell proliferation in vitro. Furthermore, activated STMN2 and β-catenin were co-localized in cytoplasm/nuclear in vitro. β-catenin/TCF-mediated the transcription of STMN2 by the potential binding sites (TTCAAAG). Finally, STMN2 promoted subcutaneous tumor growth following the activation of EMT and Cyclin D1 signaling. STMN2 overexpression promotes the aggressive clinical stage of PC patients and promotes EMT and cell proliferation in vitro and vivo. β-catenin/TCF-mediated the transcription of STMN2.

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Fig. 1: The expression of STMN2 and β-catenin in human PC and adjacent pancreas with the prognosis of PC patients.
Fig. 2: The expression of STMN2 in PC specimens and cell lines and the silencing and overexpressing effect of STMN2 in vitro.
Fig. 3: Cellular morphology (x200 magnification) in vitro.
Fig. 4: STMN2 promoted mobility in vitro mediated by WNT/β-catenin signaling.
Fig. 5: STMN2 promoted cell proliferation in vitro mediated by WNT/β-catenin signaling.
Fig. 6: STMN2 promoted EMT and Cyclin D1 signaling mediated by WNT/β-catenin signaling.
Fig. 7: IF and Chip assays.
Fig. 8: STMN2 promoted subcutaneous tumor size in vivo.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Survival Rates for Pancreatic Cancer. https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosisstaging/survival-rates.html. Accessed 15 March 2021.

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of pancreatic cancer: from epidemiology to practice. Clin Gastroenterol Hepatol. 2020;19:876–84.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Luu T. Epithelial-mesenchymal transition and its regulation mechanisms in pancreatic cancer. Front Oncol. 2021;11:646399.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Grenningloh G, Soehrman S, Bondallaz P, Ruchti E, Cadas H. Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth. J Neurobiol. 2004;58:60–9.

    Article  CAS  PubMed  Google Scholar 

  6. Conde C, Caceres A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 2009;10:319–32.

    Article  CAS  PubMed  Google Scholar 

  7. Riederer BM, Pellier V, Antonsson B, Di Paolo G, Stimpson SA, Lutjens R, et al. Regulation of microtubule dynamics by the neuronal growth-associated protein SCG10, Proc. Natl Acad Sci USA. 1997;94:741–5.

    Article  CAS  Google Scholar 

  8. Bieche I, Maucuer A, Laurendeau I, Lachkar S, Spano AJ, Frankfurter A, et al. Expression of stathmin family genes in human tissues: non-neural-restricted expression for SCLIP. Genomics. 2003;81:400–10.

    Article  CAS  PubMed  Google Scholar 

  9. Paradis V, Dargere D, Bieche Y, Asselah T, Marcellin P, Vidaud M, et al. SCG10 expression on activation of hepatic stellate cells promotes cell motility through interference with microtubules. Am J Pathol. 2010;177:1791–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu Z, Chatterjee TK, Fisher RA. RGS6 interacts with SCG10 and promotes neuronal differentiation. Role of the G gamma subunit-like (GGL) domain of RGS6. J Biol Chem. 2002;277:37832–9.

    Article  CAS  PubMed  Google Scholar 

  11. Zhong FJ, Sun B, Cao MM, Xu C, Li YM, Yang LY. STMN2 mediates nuclear translocation of Smad2/3 and enhances TGFβ signaling by destabilizing microtubules to promote epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2021;506:128–41.

    Article  CAS  PubMed  Google Scholar 

  12. Rogers DA, Schor NF. Kidins220/ARMS depletion is associated with the neural-to Schwann-like transition in a human neuroblastoma cell line model. Exp Cell Res. 2013;319:660–9.

    Article  CAS  PubMed  Google Scholar 

  13. Prudencio M, Humphrey J, Pickles S, Brown AL, Hill SE, Kachergus JM, et al. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia. J Clin Invest. 2020;130:6080–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maleki Dana P, Sadoughi F, Mansournia MA, Mirzaei H, Asemi Z, Yousefi B. Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases. Biogerontology. 2021. https://doi.org/10.1007/s10522-021-09934-x.

  15. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24:7443–54.

    Article  CAS  PubMed  Google Scholar 

  16. Lee H-S, Lee DC, Park M-H, Yang S-J, Lee JJ, Kim DM, et al. STMN2 is a novel target of betacatenin/TCF-mediated transcription in human hepatoma cells. Biochem Biophys Res Commun. 2006;345:1059–67.

    Article  CAS  PubMed  Google Scholar 

  17. Lee H-S, Park M-H, Yang S-J, Park KC, Kim N-S, Kim Y-S, et al. Novel candidate targets of Wnt/betacatenin signaling in hepatoma cells. Life Sci. 2007;80:690–8.

    Article  CAS  PubMed  Google Scholar 

  18. Sheng W, Wang G, Tang J, Shi X, Cao R, Sun J, et al. Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress. J Exp Clin Cancer Res. 2020;39:209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang S, Wang T, Wang L, Zhong L, Li K. Overexpression of RNF126 promotes the development of colorectal cancer via enhancing p53 ubiquitination and degradation. Onco Targets Ther. 2020;13:10917–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Saukkonen K, Hagström J, Mustonen H, Juuti A, Nordling S, Kallio P, et al. PROX1 and β-catenin are prognostic markers in pancreatic ductal adenocarcinoma. BMC Cancer. 2016;16:472.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kim K, Lu Z, Hay ED. Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int. 2002;26:463–76.

    Article  CAS  PubMed  Google Scholar 

  22. Huang L, Chen S, Fan H, Ji D, Chen C, Sheng W. GINS2 promotes EMT in pancreatic cancer via specifically stimulating ERK/MAPK signaling. Cancer Gene Ther. 2020. https://doi.org/10.1038/s41417-020-0206-7.

  23. Zhang R, Gao X, Zuo J, Hu B, Yang J, Zhao J, et al. STMN1 upregulation mediates hepatocellular carcinoma and hepatic stellate cell crosstalk to aggravate cancer by triggering the MET pathway. Cancer Sci. 2020;111:406–17.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang HQ, Guo X, Guo SQ, Wang Q, Chen XQ, Li XN, et al. STMN1 in colon cancer: expression and prognosis in Chinese patients. Eur Rev Med Pharm Sci. 2016;20:2038–44.

    Google Scholar 

  25. Suzuki K, Watanabe A, Araki K, Yokobori T, Harimoto N, Gantumur D, et al. High STMN1 expression is associated with tumor differentiation and metastasis in clinical patients with pancreatic cancer. Anticancer Res. 2018;38:939–44.

    CAS  PubMed  Google Scholar 

  26. Bai T, Yokobori T, Altan B, Ide M, Mochiki E, Yanai M, et al. High STMN1 level is associated with chemo-resistance and poor prognosis in gastric cancer patients. Br J Cancer. 2017;116:1177–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bao P, Yokobori T, Altan B, Iijima M, Azuma Y, Onozato R, et al. High STMN1 expression is associated with cancer progression and chemo-resistance in lung squamous cell carcinoma. Ann Surg Oncol. 2017;24:4017–24.

    Article  PubMed  Google Scholar 

  28. Jiang YG, Luo Y, He DL, Li X, Zhang LL, Peng T, et al. Role of Wnt/beta-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha. Int J Urol. 2007;14:1034–9.

    Article  CAS  PubMed  Google Scholar 

  29. Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33:62.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stacey DW. Cyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. Curr Opin Cell Biol. 2003;15:158–63.

    Article  CAS  PubMed  Google Scholar 

  31. Montalto FI, De Amicis F. Cyclin D1 in cancer: a molecular connection for cell cycle control, adhesion and invasion in tumor and stroma. Cells. 2020;9:2648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Thanks for the technical supports from both central laboratory and general laboratory at the First Hospital of China Medical University.

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Conception and design: MRS and SYW; acquisition of data: LW, QZ, and TLW; analysis and interpretation of data: MRS, LW, QZ, and TLW. writing, review, and revision of the manuscript: MRS and SYW.

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Correspondence to Shiyang Wang.

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The present study was approved by the Ethics Committee of the first hospital of China Medical University. The processing of clinical tissue samples is in strict compliance with the ethical standards of the Declaration of Helsinki. All patients signed written informed consent.

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Shao, M., Wang, L., Zhang, Q. et al. STMN2 overexpression promotes cell proliferation and EMT in pancreatic cancer mediated by WNT/β-catenin signaling. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00568-w

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