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TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer

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Abstract

Background

Tetraspanin 8 (TSPAN8), a transmembrane glycoprotein, is implicated in various pathological conditions including human malignancies. However, the roles and underlying mechanisms of TSPAN8 in promoting gastric cancer(GC) progression are yet to be fully understood.

Methods and results

Our study found that TSPAN8 expression was significantly elevated in GC tissues. We also observed a positive correlation between high TSPAN8 expression and various clinicopathological characteristics of GC, including tumor differentiation, invasion depth, lymph node metastasis, and clinical stage. Moreover, the elevated TSPAN8 expression was indicative of poor prognosis. Functionally, we observed that knockdown of TSPAN8 significantly attenuated while overexpression of TSPAN8 promoted GC cell migration and invasion. In vivo experiments, knockdown of TSPAN8 suppressed lung metastasis in nude mice. We further explored the underlying mechanisms of TSPAN8 and found that it regulated EGFR expression in GC cells by accelerating phosphorylation of EGFR and AKT.

Conclusions

Our study reveals that TSPAN8 plays a significant role in promoting tumor metastasis by activating the EGFR/AKT pathway, indicating that it may serve as a promising therapeutic target of gastric cancer.

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Data availability

Data will be made available on request.

References

  1. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F (2020) Gastric cancer. Lancet 396:635–648

    Article  CAS  PubMed  Google Scholar 

  2. Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, Farjah F, Gerdes H, Gibson MK, Hochwald S, Hofstetter WL, Ilson DH, Keswani RN, Kim S, Kleinberg LR, Klempner SJ, Lacy J, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Outlaw D, Park H, Perry KA, Pimiento J, Poultsides GA, Reznik S, Roses RE, Strong VE, Su S, Wang HL, Wiesner G, Willett CG, Yakoub D, Yoon H, McMillian N, Pluchino LA (2022) Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 20:167–192

    Article  CAS  PubMed  Google Scholar 

  3. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H (2016) Gastric cancer. Lancet 388:2654–2664

    Article  PubMed  Google Scholar 

  4. Wang X, Che X, Liu C, Fan Y, Bai M, Hou K, Shi X, Zhang X, Liu B, Zheng C, Liu Y, Qu X (2018) Cancer-associated fibroblasts-stimulated interleukin-11 promotes metastasis of gastric cancer cells mediated by upregulation of MUC1. Exp Cell Res 368:184–193

    Article  CAS  PubMed  Google Scholar 

  5. Moretto E, Longatti A, Murru L, Chamma I, Sessa A, Zapata J, Hosy E, Sainlos M, Saint-Pol J, Rubinstein E, Choquet D, Broccoli V, Schiavo G, Thoumine O, Passafaro M (2019) TSPAN5 enriched microdomains provide a platform for dendritic spine maturation through Neuroligin-1 clustering. Cell Rep 29:1130–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mazzocca A, Birgani MT, Sabba C, Carloni V (2014) Tetraspanin-enriched microdomains and hepatocellular carcinoma progression. Cancer Lett 351:23–29

    Article  CAS  PubMed  Google Scholar 

  7. Seipold L, Saftig P (2016) The emerging role of tetraspanins in the Proteolytic Processing of the amyloid precursor protein. Front Mol Neurosci 9:149

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yunta M, Lazo PA (2003) Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal 15:559–564

    Article  CAS  PubMed  Google Scholar 

  9. Charrin S, Jouannet S, Boucheix C, Rubinstein E (2014) Tetraspanins at a glance. J Cell Sci 127:3641–3648

    CAS  PubMed  Google Scholar 

  10. Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811

    Article  CAS  PubMed  Google Scholar 

  11. Berditchevski F, Odintsova E (2016) ErbB receptors and tetraspanins: casting the net wider. Int J Biochem Cell Biol 77:68–71

    Article  CAS  PubMed  Google Scholar 

  12. Sigismund S, Avanzato D, Lanzetti L (2018) Emerging functions of the EGFR in cancer. Mol Oncol 12:3–20

    Article  PubMed  Google Scholar 

  13. Termini CM, Gillette JM (2017) Tetraspanins function as regulators of Cellular Signaling. Front Cell Dev Biol 5:34

    Article  PubMed  PubMed Central  Google Scholar 

  14. Agaesse G, Barbollat-Boutrand L, El KM, Berthier-Vergnes O, Masse I (2017) p53 targets TSPAN8 to prevent invasion in melanoma cells. Oncogenesis 6:e309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Akiel MA, Santhekadur PK, Mendoza RG, Siddiq A, Fisher PB, Sarkar D (2016) Tetraspanin 8 mediates AEG-1-induced invasion and metastasis in hepatocellular carcinoma cells. FEBS Lett 590:2700–2708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Park CS, Kim TK, Kim HG, Kim YJ, Jeoung MH, Lee WR, Go NK, Heo K, Lee S (2016) Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis. Oncogene 35:4540–4548

    Article  CAS  PubMed  Google Scholar 

  17. Guo Q, Xia B, Zhang F, Richardson MM, Li M, Zhang JS, Chen F, Zhang XA (2012) Tetraspanin CO-029 inhibits colorectal cancer cell movement by deregulating cell-matrix and cell-cell adhesions. PLoS ONE 7:e38464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yue S, Mu W, Zoller M (2013) Tspan8 and CD151 promote metastasis by distinct mechanisms. Eur J Cancer 49:2934–2948

    Article  CAS  PubMed  Google Scholar 

  19. El KM, Agaesse G, Barbollat-Boutrand L, Pommier RM, de la Fouchardiere A, Larue L, Caramel J, Puisieux A, Berthier-Vergnes O, Masse I (2019) Tspan8-beta-catenin positive feedback loop promotes melanoma invasion. Oncogene 38:3781–3793

    Article  Google Scholar 

  20. Wei L, Li Y, Suo Z (2015) TSPAN8 promotes gastric cancer growth and metastasis via ERK MAPK pathway. Int J Clin Exp Med 8:8599–8607

    PubMed  PubMed Central  Google Scholar 

  21. Hemler ME (2014) Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer 14:49–60

    Article  CAS  PubMed  Google Scholar 

  22. Zhang HS, Liu HY, Zhou Z, Sun HL, Liu MY (2020) TSPAN8 promotes colorectal cancer cell growth and migration in LSD1-dependent manner. Life Sci 241:117114

    Article  CAS  PubMed  Google Scholar 

  23. Voglstaetter M, Thomsen AR, Nouvel J, Koch A, Jank P, Navarro EG, Gainey-Schleicher T, Khanduri R, Gross A, Rossner F, Blaue C, Franz CM, Veil M, Puetz G, Hippe A, Dindorf J, Kashef J, Thiele W, Homey B, Greco C, Boucheix C, Baur A, Erbes T, Waller CF, Follo M, Hossein G, Sers C, Sleeman J, Nazarenko I (2019) Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles. J Pathol 248:421–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhu H, Wu Y, Zheng W, Lu S (2015) CO-029 is overexpressed in gastric cancer and mediates the effects of EGF on gastric cancer cell proliferation and invasion. Int J Mol Med 35:798–802

    Article  CAS  PubMed  Google Scholar 

  25. Zhan Z, Zhong L, Feng M, Guo Y (2019) A positive tetraspanin 8 (TSPAN8)/beta-Catenin Regulatory Loop enhances the stemness of Colorectal Cancer cells. Med Sci Monit 25:9594–9601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Anami K, Oue N, Noguchi T, Sakamoto N, Sentani K, Hayashi T, Naito Y, Oo HZ, Yasui W (2016) TSPAN8, identified by Escherichia coli ampicillin secretion trap, is associated with cell growth and invasion in gastric cancer. Gastric Cancer 19:370–380

    Article  CAS  PubMed  Google Scholar 

  27. Li L, Yang D, Cui D, Li Y, Nie Z, Wang J, Liang L (2018) Quantitative proteomics analysis of the role of tetraspanin-8 in the drug resistance of gastric cancer. Int J Oncol 52:473–484

    CAS  PubMed  Google Scholar 

  28. Labelle M, Hynes RO (2012) The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov 2:1091–1099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou Q, Huang T, Jiang Z, Ge C, Chen X, Zhang L, Zhao F, Zhu M, Chen T, Cui Y, Li H, Yao M, Li J, Tian H (2020) Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway. Oncogene 39:2140–2155

    Article  CAS  PubMed  Google Scholar 

  30. Lim SM, Syn NL, Cho BC, Soo RA (2018) Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Treat Rev 65:1–10

    Article  CAS  PubMed  Google Scholar 

  31. Tang M, Yin G, Wang F, Liu H, Zhou S, Ni J, Chen C, Zhou Y, Zhao Y (2015) Downregulation of CD9 promotes pancreatic cancer growth and metastasis through upregulation of epidermal growth factor on the cell surface. Oncol Rep 34:350–358

    Article  CAS  PubMed  Google Scholar 

  32. Wang GP, Han XF (2015) CD9 modulates proliferation of human glioblastoma cells via epidermal growth factor receptor signaling. Mol Med Rep 12:1381–1386

    Article  CAS  PubMed  Google Scholar 

  33. Odintsova E, van Niel G, Conjeaud H, Raposo G, Iwamoto R, Mekada E, Berditchevski F (2013) Metastasis suppressor tetraspanin CD82/KAI1 regulates ubiquitylation of epidermal growth factor receptor. J Biol Chem 288:26323–26334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Humbert PO, Pryjda TZ, Pranjic B, Farrell A, Fujikura K, de Matos SR, Karim R, Kozieradzki I, Cronin S, Neely GG, Meyer TF, Hagelkruys A, Richardson HE, Penninger JM (2022) TSPAN6 is a suppressor of ras-driven cancer. Oncogene 41:2095–2105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li J, Chen X, Zhu L, Lao Z, Zhou T, Zang L, Ge W, Jiang M, Xu J, Cao Y, Du S, Yu Y, Fan G, Wang H (2021) SOX9 is a critical regulator of TSPAN8-mediated metastasis in pancreatic cancer. Oncogene 40:4884–4893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu X, An L, Fan G, Zang L, Huang W, Li J, Liu J, Ge W, Huang Y, Xu J, Du S, Cao Y, Zhou T, Yin H, Yu L, Jiao S, Wang H (2022) EGFR signaling promotes nuclear translocation of plasma membrane protein TSPAN8 to enhance tumor progression via STAT3-mediated transcription. Cell Res 32:359–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

This research was supported by the National Natural Science Foundation of China (No. 82002919), the Xuzhou Science and Technology Project (KC20101, KC21198) and Jiangsu Province Key Laboratory of Anesthesiology Open Project Fund (XZSYSKF2019023).

Author information

Authors and Affiliations

  1. Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China

    Lin Zhang, Yuting Xu, Enmin Cai, Maojin Zheng & Qingling Wang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Lin Zhang

  3. Department of Physiology, Xuzhou Medical University, Xuzhou, 221004, China

    Lei Liu

  4. Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Shibao Li

Authors
  1. Lin Zhang
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  2. Yuting Xu
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  4. Maojin Zheng
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  5. Lei Liu
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  6. Qingling Wang
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Contributions

Qingling Wang and Shibao Li conceived and designed the experiments. Lin Zhang, Yuting Xu, Maojin Zheng and Enmin Cai carried out the operation of the experiment. Lin Zhang, Lei Liu and Zhuo Sun collected and analyzed the data. Lin Zhang and Shibao Li wrote the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Qingling Wang or Shibao Li.

Ethics declarations

Ethics approval

All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The animal protocol used in this study was reviewed and approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (No: L20210226419). The study on GC tissues was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2017-QL007-1). The patient’s informed consent was obtained.

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All authors declared that they had no potential conflict of interest.

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Lin Zhang, Yuting Xu and Enmin Cai contributed equally to this work.

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Zhang, L., Xu, Y., Cai, E. et al. TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer. Mol Biol Rep 50, 7955–7965 (2023). https://doi.org/10.1007/s11033-023-08662-4

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  • DOI: https://doi.org/10.1007/s11033-023-08662-4

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