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Alternol inhibits migration and invasion of human hepatocellular carcinoma cells by targeting epithelial-to-mesenchymal transition

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Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Such deaths are due, in large part, to its propensity to metastasize. We have examined the effect of alternol on human HCC cells and the underlying molecular mechanism. Therapeutic effects of alternol on cancer cell migration and invasion were analyzed with Boyden chamber and wound healing assays. Effects of alternol on the levels of various proteins involved in cancer cell migration and invasion were determined with gelatin zymography, immunofluorescence, and Western blotting. As shown, treatment with alternol has resulted in a concentration-dependent inhibition of cell migration and invasion of HepG2 cells. The inhibition of HCC invasion by alternol was associated with the suppression of MMP-9 expression and reversal of epithelial-to-mesenchymal transition (EMT). The above results indicated that alternol has the ability to inhibit the migration and invasion of human HCC cells by reversing the process of EMT, suggesting that alternol may be developed as an alternative drug for the treatment of HCC.

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References

  1. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.

    Article  PubMed  Google Scholar 

  2. Wong KF, Xu Z, Chen J, Lee NP, Luk JM. Circulating markers for prognosis of hepatocellular carcinoma. Expert Opin Med Diagn. 2013;7:319–29.

    Article  CAS  PubMed  Google Scholar 

  3. Aravalli RN, Cressman EN, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol. 2013;87:227–47.

    Article  CAS  PubMed  Google Scholar 

  4. Psyrri A, Arkadopoulos N, Vassilakopoulou M, Smyrniotis V, Dimitriadis G. Pathways and targets in hepatocellular carcinoma. Expert Rev Anticancer Ther. 2012;12:1347–57.

    Article  CAS  PubMed  Google Scholar 

  5. Fortune BE, Umman V, Gilliland T, Emre S. Liver transplantation for hepatocellular carcinoma: a surgical perspective. J Clin Gastroenterol. 2013;47(Suppl):S37–42.

    Article  PubMed  Google Scholar 

  6. Padhya KT, Marrero JA, Singal AG. Recent advances in the treatment of hepatocellular carcinoma. Curr Opin Gastroenterol. 2013;29:285–92.

    Article  CAS  PubMed  Google Scholar 

  7. Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: an update. Hepatol Res. 2012;43:147–54.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Kakodkar R, Soin AS. Liver transplantation for HCC: a review. Indian J Surg. 2012;74:100–17.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Salhab M, Canelo R. An overview of evidence-based management of hepatocellular carcinoma: a meta-analysis. J Cancer Res Ther. 2011;7:463–75.

    Article  CAS  PubMed  Google Scholar 

  10. Hamed O, Kimchi ET, Sehmbey M, Gusani NJ, Kaifi JT, Staveley-O’Carroll K. Impact of genetic targets on cancer therapy: hepatocellular cancer. Adv Exp Med Biol. 2013;779:67–90.

    Article  PubMed  Google Scholar 

  11. Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, et al. Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta. 1835;2013:46–60.

    Google Scholar 

  12. Muntane J, De la Rosa AJ, Docobo F, Garcia-Carbonero R, Padillo FJ. Targeting tyrosine kinase receptors in hepatocellular carcinoma. Curr Cancer Drug Targets. 2013;13:300–12.

    Article  CAS  PubMed  Google Scholar 

  13. Ganapathy-Kanniappan S, Kunjithapatham R, Geschwind JF. Glyceraldehyde-3-phosphate dehydrogenase: a promising target for molecular therapy in hepatocellular carcinoma. Oncotarget. 2012;3:940–53.

    PubMed  Google Scholar 

  14. Katsuno Y, Lamouille S, Derynck R. TGF-beta signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol. 2013;25:76–84.

    Article  CAS  PubMed  Google Scholar 

  15. Ramakrishna R, Rostomily R. Seed, soil, and beyond: the basic biology of brain metastasis. Surg Neurol Int. 2013;4 (Suppl 4):S256–64.

    Google Scholar 

  16. Reichl P, Haider C, Grubinger M, Mikulits W. TGF-beta in epithelial to mesenchymal transition and metastasis of liver carcinoma. Curr Pharm Des. 2012;18:4135–47.

    Article  CAS  PubMed  Google Scholar 

  17. Chang TM, Hung WC. Transcriptional repression of TWIST1 gene by Prospero-related homeobox 1 inhibits invasiveness of hepatocellular carcinoma cells. FEBS Lett. 2012;586:3746–52.

    Article  CAS  PubMed  Google Scholar 

  18. Qin Q, Xu Y, He T, Qin C, Xu J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 2012;22:90–106.

    Article  CAS  PubMed  Google Scholar 

  19. Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, et al. Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer. 2009;9:240.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Yeung ED, Morrison A, Plumeri D, Wang J, Tong C, Yan X, et al. Alternol exerts prostate-selective antitumor effects through modulations of the AMPK signaling pathway. Prostate. 2012;72:165–72.

    Article  CAS  PubMed  Google Scholar 

  21. Liu X, Wang J, Sun B, Zhang Y, Zhu J, Li C. Cell growth inhibition, G2M cell cycle arrest, and apoptosis induced by the novel compound Alternol in human gastric carcinoma cell line MGC803. Invest New Drugs. 2007;25:505–17.

    Article  PubMed  Google Scholar 

  22. Liu ZZ, Zhu J, Sun B, Liu S, Geng S, Liu X, et al. Alternol inhibits proliferation and induces apoptosis in mouse lymphocyte leukemia (L1210) cells. Mol Cell Biochem. 2007;306:115–22.

    Article  CAS  PubMed  Google Scholar 

  23. Shih YW, Lee YC, Wu PF, Lee YB, Chiang TA. Plumbagin inhibits invasion and migration of liver cancer HepG2 cells by decreasing productions of matrix metalloproteinase-2 and urokinase- plasminogen activator. Hepatol Res. 2009;39:998–1009.

    Article  CAS  PubMed  Google Scholar 

  24. Li X, Yang Z, Song W, Zhou L, Li Q, Tao K, et al. Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. Int J Oncol. 2013;43:793–802.

    CAS  PubMed  Google Scholar 

  25. Sun C, Sun L, Li Y, Kang X, Zhang S, Liu Y. Sox2 expression predicts poor survival of hepatocellular carcinoma patients and it promotes liver cancer cell invasion by activating Slug. Med Oncol. 2013;30:503.

    Article  PubMed  Google Scholar 

  26. Slattery ML, John E, Torres-Mejia G, Stern M, Lundgreen A, Hines L, et al. Matrix metalloproteinase genes are associated with breast cancer risk and survival: the Breast Cancer Health Disparities Study. PLoS One. 2013;8:e63165.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Littlepage LE, Sternlicht MD, Rougier N, Phillips J, Gallo E, Yu Y, et al. Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 2010;70:2224–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Lou L, Chen YX, Jin L, Li X, Tao X, Zhu J, et al. Enhancement of invasion of hepatocellular carcinoma cells through lysophosphatidic acid receptor. J Int Med Res. 2013;41:55–63.

    Article  CAS  PubMed  Google Scholar 

  29. Yang X, Wang D, Dong W, Song Z, Dou K. Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Lett. 2010;295:198–204.

    Article  CAS  PubMed  Google Scholar 

  30. Pan MH, Chiou YS, Chen WJ, Wang JM, Badmaev V, Ho CT. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis. 2009;30:1234–42.

    Article  CAS  PubMed  Google Scholar 

  31. Li X, Xu Y, Chen Y, Chen S, Jia X, Sun T, et al. SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/beta-catenin signal network. Cancer Lett. 2013;336:379–89.

    Article  CAS  PubMed  Google Scholar 

  32. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, et al. Epithelial–mesenchymal transition in hepatocellular carcinoma. Future Oncol. 2009;5:1169–79.

    Article  PubMed  Google Scholar 

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Acknowledgment

This work has been jointly sponsored by a grant from the Natural Science Foundation of China (no. 81072899), the Natural Science Foundation of Liaoning Province, China (2013021081), and the Natural Science Foundation of Chongqing, China (cstc2013jcyjA1587).

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Correspondence to Mei-xia Zhang.

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Xiao-lin Zhu, Yan-li Wang, and Jie-peng Chen contributed equally to this work.

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Zhu, Xl., Wang, Yl., Chen, Jp. et al. Alternol inhibits migration and invasion of human hepatocellular carcinoma cells by targeting epithelial-to-mesenchymal transition. Tumor Biol. 35, 1627–1635 (2014). https://doi.org/10.1007/s13277-013-1224-y

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  • DOI: https://doi.org/10.1007/s13277-013-1224-y

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