Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR–PI3K–AKT pathway

Oncogene volume 39, pages 1213–1230 (2020)Cite this article

Subjects

A Correction to this article was published on 07 November 2019

This article has been updated

Abstract

Versican has been reported to participate in carcinogenesis in several malignant tumors. However, the accurate role of VersicanV1, a predominant isoform of Versican in liver, remains an enigma in hepatocellular carcinoma (HCC). The expression of VersicanV1 in HCC tissues and adjacent tissues was detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western Blot (WB) and inmumohistochemistry (IHC). Gain and loss of function assays were performed to examine the role of VersicanV1 in proliferation and metastasis of HCC. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in vitro and PET-CT (positron emission tomography/computed tomography) analysis in vivo were applied to evaluate the effects of VersicanV1 on glycolysis. RNA sequencing, Co-IP (Co-immunoprecipitation) and MS (mass spectrometry) were utilized to investigate the molecular mechanisms. Our current study reveals that VersicanV1, regulated by direct interaction with Linc01225, is significantly upregulated in HCC tissues and correlates with poor prognosis. Both in vitro and in vivo experiments show that knockdown of VersicanV1 in HCC cells attenuates cancer cells malignancy. Further studies identify the positive role of VersicanV1 in aerobic glycolysis. Mechanistic investigation discovers the activation of EGFR–PI3K–AKT pathway in HCC cells expressing high VersicanV1. Moreover, EGF-like motif is indispensable for VersicanV1 to promote Warburg effect of HCC cells and subsequently, proliferation, invasion, and metastasis ability via activation of EGFR–PI3K–AKT axis. In sum, our research highlights a novel role of VersicanV1 in the progression of HCC, suggesting that VersicanV1 is an indicator for prognosis and a potential therapeutic target of HCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

References

  1. Worns MA, Galle PR. HCC therapies–lessons learned. Nat Rev Gastroenterol Hepatol. 2014;11:447–52.

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: a cancer J clinicians. 2011;61:69–90.

    Google Scholar 

  3. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15:1243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014;14:430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wu YJ, La Pierre DP, Wu J, Yee AJ, Yang BB. The interaction of versican with its binding partners. Cell Res. 2005;15:483–94.

    Article  CAS  PubMed  Google Scholar 

  6. Dours-Zimmermann MT, Zimmermann DR. A novel glycosaminoglycan attachment domain identified in two alternative splice variants of human versican. J Biol Chem. 1994;269:32992–8.

    Article  CAS  PubMed  Google Scholar 

  7. Sakko AJ, Ricciardelli C, Mayne K, Suwiwat S, LeBaron RG, Marshall VR, et al. Modulation of prostate cancer cell attachment to matrix by versican. Cancer Res. 2003;63:4786–91.

    CAS  PubMed  Google Scholar 

  8. Nara Y, Kato Y, Torii Y, Tsuji Y, Nakagaki S, Goto S, et al. Immunohistochemical localization of extracellular matrix components in human breast tumours with special reference to PG-M/versican. Histochem J. 1997;29:21–30.

    Article  CAS  PubMed  Google Scholar 

  9. Nikitovic D, Zafiropoulos A, Katonis P, Tsatsakis A, Theocharis AD, Karamanos NK, et al. Transforming growth factor-beta as a key molecule triggering the expression of versican isoforms v0 and v1, hyaluronan synthase-2 and synthesis of hyaluronan in malignant osteosarcoma cells. IUBMB Life. 2006;58:47–53.

    Article  CAS  PubMed  Google Scholar 

  10. Paulus W, Baur I, Dours-Zimmermann MT, Zimmermann DR. Differential expression of versican isoforms in brain tumors. J Neuropathol Exp Neurol. 1996;55:528–33.

    Article  CAS  PubMed  Google Scholar 

  11. Kodama J, Hasengaowa, Kusumoto T, Seki N, Matsuo T, Ojima Y, et al. Prognostic significance of stromal versican expression in human endometrial cancer. Annals of oncology: official journal of the European Society for. Med Oncol. 2007;18:269–74.

    CAS  Google Scholar 

  12. Pukkila M, Kosunen A, Ropponen K, Virtaniemi J, Kellokoski J, Kumpulainen E, et al. High stromal versican expression predicts unfavourable outcome in oral squamous cell carcinoma. J Clin Pathol. 2007;60:267–72.

    Article  PubMed  Google Scholar 

  13. Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, et al. Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer. Clin Cancer Res. 1998;4:963–71.

    CAS  PubMed  Google Scholar 

  14. Ricciardelli C, Brooks JH, Suwiwat S, Sakko AJ, Mayne K, Raymond WA, et al. Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer. Clinical cancer research: an official journal of the American Association for. Cancer Res. 2002;8:1054–60.

    Google Scholar 

  15. Suwiwat S, Ricciardelli C, Tammi R, Tammi M, Auvinen P, Kosma VM, et al. Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer. Clin Cancer Res. 2004;10:2491–8.

    Article  CAS  PubMed  Google Scholar 

  16. Voutilainen K, Anttila M, Sillanpaa S, Tammi R, Tammi M, Saarikoski S, et al. Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. Int J Cancer. 2003;107:359–64.

    Article  CAS  PubMed  Google Scholar 

  17. Asano K, Nelson CM, Nandadasa S, Aramaki-Hattori N, Lindner DJ, Alban T, et al. Stromal versican regulates tumor growth by promoting angiogenesis. Sci Rep. 2017;7:17225.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Edwards IJ. Proteoglycans in prostate cancer. Nat Rev Urol. 2012;9:196–206.

    Article  CAS  PubMed  Google Scholar 

  19. Mitsui Y, Shiina H, Kato T, Maekawa S, Hashimoto Y, Shiina M, et al. Versican promotes tumor progression, metastasis and predicts poor prognosis in renal carcinoma. Mol Cancer Res. 2017;15:884–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xia L, Huang W, Tian D, Zhang L, Qi X, Chen Z, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology. 2014;59:958–73.

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Zhang W, Tang J, Huang R, Li J, Xu D, et al. LINC01225 promotes occurrence and metastasis of hepatocellular carcinoma in an epidermal growth factor receptor-dependent pathway. Cell Death Dis. 2016;7:e2130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen Y, Kwon SW, Kim SC, Zhao Y. Integrated approach for manual evaluation of peptides identified by searching protein sequence databases with tandem mass spectra. J Proteome Res. 2005;4:998–1005.

    Article  CAS  PubMed  Google Scholar 

  23. Cattaruzza S, Schiappacassi M, Ljungberg-Rose A, Spessotto P, Perissinotto D, Morgelin M, et al. Distribution of PG-M/versican variants in human tissues and de novo expression of isoform V3 upon endothelial cell activation, migration, and neoangiogenesis in vitro. J Biol Chem. 2002;277:47626–35.

    Article  CAS  PubMed  Google Scholar 

  24. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  25. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.

    Article  CAS  PubMed  Google Scholar 

  26. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu Y, Chen L, Cao L, Sheng W, Yang BB. Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and beta1-integrin. J Cell Sci. 2004;117:2227–37.

    Article  CAS  PubMed  Google Scholar 

  28. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–9.

    Article  CAS  PubMed  Google Scholar 

  29. Yarden Y, Shilo BZ. SnapShot: EGFR signaling pathway. Cell. 2007;131:1018.

    Article  PubMed  Google Scholar 

  30. Du WW, Yang BB, Shatseva TA, Yang BL, Deng Z, Shan SW, et al. Versican G3 promotes mouse mammary tumor cell growth, migration, and metastasis by influencing EGF receptor signaling. PLoS One. 2010;5:e13828.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Xiang YY, Dong H, Wan Y, Li J, Yee A, Yang BB, et al. Versican G3 domain regulates neurite growth and synaptic transmission of hippocampal neurons by activation of epidermal growth factor receptor. J Biol Chem. 2006;281:19358–68.

    Article  CAS  PubMed  Google Scholar 

  32. Wang RY, Chen L, Chen HY, Hu L, Li L, Sun HY, et al. MUC15 inhibits dimerization of EGFR and PI3K–AKT signaling and is associated with aggressive hepatocellular carcinomas in patients. Gastroenterology 2013; 145: 1436–48.e1431–12.

  33. Casey RC, Oegema TR Jr., Skubitz KM, Pambuccian SE, Grindle SM, Skubitz AP. Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells. Clin Exp Metastasis. 2003;20:143–52.

    Article  CAS  PubMed  Google Scholar 

  34. Desjardins M, Xie J, Gurler H, Muralidhar GG, Sacks JD, Burdette JE, et al. Versican regulates metastasis of epithelial ovarian carcinoma cells and spheroids. J Ovarian Res. 2014;7:70.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Touab M, Villena J, Barranco C, Arumi-Uria M, Bassols A. Versican is differentially expressed in human melanoma and may play a role in tumor development. Am J Pathol. 2002;160:549–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pappas AG, Magkouta S, Pateras IS, Skianis I, Moschos C, Vazakidou ME, et al. Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth. Oncoimmunology. 2019;8:e1537427.

    Article  PubMed  Google Scholar 

  37. Fanhchaksai K, Okada F, Nagai N, Pothacharoen P, Kongtawelert P, Hatano S, et al. Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth. Int J cancer. 2016;138:630–41.

    Article  CAS  PubMed  Google Scholar 

  38. Hope C, Foulcer S, Jagodinsky J, Chen SX, Jensen JL, Patel S, et al. Immunoregulatory roles of versican proteolysis in the myeloma microenvironment. Blood. 2016;128:680–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hope C, Emmerich PB, Papadas A, Pagenkopf A, Matkowskyj KA, Van De Hey DR, et al. Versican-derived matrikines regulate Batf3-dendritic cell differentiation and promote T cell infiltration in colorectal cancer. J Immunol. 2017;199:1933–41.

    Article  CAS  PubMed  Google Scholar 

  40. Bhattacharyya S, Feferman L, Tobacman JK. Arylsulfatase B regulates versican expression by galectin-3 and AP-1 mediated transcriptional effects. Oncogene. 2014;33:5467–76.

    Article  CAS  PubMed  Google Scholar 

  41. Domenzain-Reyna C, Hernandez D, Miquel-Serra L, Docampo MJ, Badenas C, Fabra A, et al. Structure and regulation of the versican promoter: the versican promoter is regulated by AP-1 and TCF transcription factors in invasive human melanoma cells. J Biol Chem. 2009;284:12306–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Onken J, Moeckel S, Leukel P, Leidgens V, Baumann F, Bogdahn U, et al. Versican isoform V1 regulates proliferation and migration in high-grade gliomas. J Neuro-Oncol. 2014;120:73–83.

    Article  CAS  Google Scholar 

  43. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–7.

    Article  CAS  PubMed  Google Scholar 

  44. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366:2–16.

    Article  CAS  PubMed  Google Scholar 

  45. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. New Engl J Med. 2008;358:1160–74.

    Article  CAS  PubMed  Google Scholar 

  46. Buzzai M, Bauer DE, Jones RG, Deberardinis RJ, Hatzivassiliou G, Elstrom RL, et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene. 2005;24:4165–73.

    Article  CAS  PubMed  Google Scholar 

  47. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (Grant Number 2016YFC0905900 to BS), State Key Program of the National Natural Science Foundation (Grant Number 81430062 to BS), Innovative Research Groups of the National Natural Science Foundation (Grant Number 81521004 to BS), National Natural Science Foundation (Grant Number 81702344 to WZ), TianQing Liver Disease Research Fund (Grant Number: TQGB20180095 to WZ) and the Research Innovation Program for Postgraduate of Jiangsu Province (Grant Number SJKY19_1379 to GZ). BS is Yangtze River Scholar of Distinguished Professor.

Author information

Author notes

  1. These authors contributed equally: Guangyan Zhangyuan, Fei Wang, Haitian Zhang, Runqiu Jiang

Authors and Affiliations

  1. Department of Hepatobiliary Surgery of Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, PR China

    Guangyan Zhangyuan, Fei Wang, Haitian Zhang, Runqiu Jiang, Xuewen Tao, Wenjie Zhang & Beicheng Sun

  2. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, PR China

    Guangyan Zhangyuan, Fei Wang, Haitian Zhang, Runqiu Jiang, Xuewen Tao, Decai Yu, Kangpeng Jin, WeiWei Yu, Yang Liu, Yin Yin, Wenjie Zhang & Beicheng Sun

  3. Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China

    Fei Wang, Haitian Zhang, Runqiu Jiang, Kangpeng Jin, Yang Liu, Wenjie Zhang & Beicheng Sun

  4. Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, PR China

    Jintao Shen & Qinfeng Xu

Authors
  1. Guangyan Zhangyuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haitian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Runqiu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xuewen Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Decai Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kangpeng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. WeiWei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yin Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jintao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qinfeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Wenjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Beicheng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wenjie Zhang or Beicheng Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhangyuan, G., Wang, F., Zhang, H. et al. VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR–PI3K–AKT pathway. Oncogene 39, 1213–1230 (2020). https://doi.org/10.1038/s41388-019-1052-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1052-7

This article is cited by

Search

Advanced search

Quick links