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Article

Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma

  • Authors:
    • Jun Sang Bae
    • Sang Jae Noh
    • Kyoung Min Kim
    • Kyu Yun Jang
    • Myoung Ja Chung
    • Dae Gohn Kim
    • Woo Sung Moon
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea, Department of Internal Medicine, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
  • Pages: 129-136
    |
    Published online on: October 30, 2013
       https://doi.org/10.3892/ijo.2013.2154
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Abstract

The epithelial to mesenchymal transition (EMT) is a crucial process in tumor progression. EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. Serum response factor (SRF) is a transcription factor that plays a central role in carcinogenesis and tumor progression in several types of cancers. We investigated the effect of EMT-related SRF, focusing on its promotion of chemoresistance against sorafenib in hepatocellular carcinoma (HCC). We examined SRF and Snail expression in 146 cases of HCCs by immunohistochemistry. We also examined the chemoresistance effect of SRF in HCC cells by transfecting HLE cells with SRF cDNA and SH-J1 cells with SRF antisense cDNA. Expression of SRF and Snail were detected in 37.6% (55 of 146 cases) and in 12.3% (18 of 146 cases) of the HCCs, respectively. None of the tumor-free liver tissues showed SRF or Snail expression. SRF expression was closely correlated with the expression of Snail (p<0.001) and expression of both SRF and Snail showed significant correlation with the high histological grade (p=0.015 and 0.003, respectively). Overexpression of SRF in HLE cells led to increased expression of mesenchymal markers, as well as increased cell growth and colony formation. Overexpression of SRF also led to a significant reduction in the cytotoxic effect of sorafenib in HLE cells. Conversely, inhibition of SRF expression in the SH-J1 cells significantly enhanced the apoptotic effects of sorafenib, along with the reduced expression of mesenchymal markers and restored the expression of E-cadherin. These results suggest that SRF is critical for HCC to acquire a mesenchymal phenotype, which leads to resistance against a sorafenib-mediated apoptotic effect.
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1. 

El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 142:1264–1273. 2012. View Article : Google Scholar : PubMed/NCBI

2. 

Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI

3. 

Avila MA, Berasain C, Sangro B and Prieto J: New therapies for hepatocellular carcinoma. Oncogene. 25:3866–3884. 2006. View Article : Google Scholar : PubMed/NCBI

4. 

Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI

5. 

Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI

6. 

Creighton CJ, Li X, Landis M, et al: Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 106:13820–13825. 2009. View Article : Google Scholar : PubMed/NCBI

7. 

Singh A and Settleman J: EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI

8. 

Kurrey NK, Jalgaonkar SP, Joglekar AV, et al: Snail and slug mediate radioresistance and chemoresistance by antagonizing P53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 27:2059–2068. 2009. View Article : Google Scholar : PubMed/NCBI

9. 

Wang Z, Li Y, Kong D, et al: Acquisition of epithelialmesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69:2400–2407. 2009. View Article : Google Scholar : PubMed/NCBI

10. 

Peinado H, Olmeda D and Cano A: Snail, ZEB and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI

11. 

Treisman R: Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell. 46:567–574. 1986. View Article : Google Scholar : PubMed/NCBI

12. 

Treisman R: Identification and purification of a polypeptide that binds to the c-fos serum response element. EMBO J. 6:2711–2717. 1987.PubMed/NCBI

13. 

Shore P and Sharrocks AD: The MADS-box family of transcription factors. Eur J Biochem. 229:1–3. 1995. View Article : Google Scholar : PubMed/NCBI

14. 

Modak C and Chai J: Serum response factor: look into the gut. World J Gastroenterol. 16:2195–2201. 2010. View Article : Google Scholar : PubMed/NCBI

15. 

Miano JM: Role of serum response factor in the pathogenesis of disease. Lab Invest. 90:1274–1284. 2010. View Article : Google Scholar : PubMed/NCBI

16. 

Psichari E, Balmain A, Plows D, Zoumpourlis V and Pintzas A: High activity of serum response factor in the mesenchymal transition of epithelial tumor cells is regulated by RhoA signaling. J Biol Chem. 277:29490–29495. 2002. View Article : Google Scholar : PubMed/NCBI

17. 

Park MY, Kim KR, Park HS, et al: Expression of the serum response factor in hepatocellular carcinoma: Implications for epithelial-mesenchymal transition. Int J Oncol. 31:1309–1315. 2007.PubMed/NCBI

18. 

Kwon CY, Kim KR, Choi HN, et al: The role of serum response factor in hepatocellular carcinoma: Implications for disease progression. Int J Oncol. 37:837–844. 2010.PubMed/NCBI

19. 

Choi HN, Kim KR, Lee JH, et al: Serum response factor enhances liver metastasis of colorectal carcinoma via alteration of the E-cadherin/β-catenin complex. Oncol Rep. 21:57–63. 2009.PubMed/NCBI

20. 

Farra R, Dapas B, Pozzato G, et al: Serum response factor depletion affects the proliferation of the hepatocellular carcinoma cells HepG2 and JHH6. Biochimie. 92:455–463. 2010. View Article : Google Scholar : PubMed/NCBI

21. 

Wilhelm S, Carter C, Lynch M, et al: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 5:835–844. 2006. View Article : Google Scholar : PubMed/NCBI

22. 

Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM and Lynch M: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 7:3129–3140. 2008. View Article : Google Scholar : PubMed/NCBI

23. 

Kane RC, Farrell AT, Madabushi R, et al: Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist. 14:95–100. 2009. View Article : Google Scholar : PubMed/NCBI

24. 

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual. 7th edition. Springer; New York, NY: 2010

25. 

Kim DG, Park SY, Kim H, Chun YH, Moon WS and Park SH: A comprehensive karyotypic analysis on a newly established sarcomatoid hepatocellular carcinoma cell line SH-J1 by comparative genomic hybridization and chromosome painting. Cancer Genet Cytogenet. 132:120–124. 2002. View Article : Google Scholar

26. 

Bae JS, Choi HN, Noh SJ, et al: Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma. Oncol Lett. 4:213–220. 2012.PubMed/NCBI

27. 

Kim KR, Choi HN, Lee HJ, et al: A peroxisome proliferator-activated receptor γ antagonist induces vimentin cleavage and inhibits invasion in high-grade hepatocellular carcinoma. Oncol Rep. 18:825–832. 2007.

28. 

Cano A, Pérez-Moreno MA, Rodrigo I, et al: The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI

29. 

Park SY, Jang KY, Kim YN, et al: Expression and prognostic significance of serum response factor in cholangiocarcinoma. Korean J Pathol. 43:517–522. 2009. View Article : Google Scholar

30. 

Kim KR, Bae JS, Choi HN, et al: The role of serum response factor in hepatocellular carcinoma: An association with matrix metalloproteinase. Oncol Rep. 26:1567–1572. 2011.PubMed/NCBI

31. 

Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: an update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar : PubMed/NCBI

32. 

Kajiyama H, Shibata K, Terauchi M, et al: Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 31:277–283. 2007.

33. 

Yang AD, Fan F, Camp ER, et al: Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 12:4147–4153. 2006. View Article : Google Scholar : PubMed/NCBI

34. 

Rho JK, Choi YJ, Lee JK, et al: Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 63:219–226. 2009. View Article : Google Scholar : PubMed/NCBI

35. 

Van Malenstein H, Dekervel J, Verslype C, et al: Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 329:74–83. 2013.PubMed/NCBI

36. 

Huang XY, Ke AW, Shi GM, et al: αB-crystallin complexes with 14-3-3ζ to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology. 57:2235–2247. 2013.

37. 

Nagai T, Arao T, Furuta K, et al: Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther. 10:169–177. 2011. View Article : Google Scholar

38. 

Yu W, Feng S, Dakhova O, et al: FGFR-4 Arg388 enhances prostate cancer progression via extracellular signal-related kinase and serum response factor signaling. Clin Cancer Res. 17:4355–4366. 2011.

39. 

Prencipe M, Madden SF, O’Neill A, et al: Identification of transcription factors associated with castration-resistance: is the serum responsive factor a potential therapeutic target? Prostate. 73:743–753. 2013. View Article : Google Scholar : PubMed/NCBI

40. 

Pérez-Saborido B, de los Galanes SJ, Menéu-Díaz JC, et al: Tumor recurrence after liver transplantation for hepatocellular carcinoma: recurrence pathway and prognostic factors. Transplant Proc. 39:2304–2307. 2007.PubMed/NCBI

41. 

Medjkane S, Perez-Sanchez C, Gaggioli C, Sahai E and Treisman R: Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis. Nat Cell Biol. 11:257–268. 2009. View Article : Google Scholar : PubMed/NCBI

42. 

Bai S, Nasser MW, Wang B, et al: MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem. 284:32015–32027. 2009. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Bae JS, Noh SJ, Kim KM, Jang KY, Chung MJ, Kim DG and Moon WS: Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma . Int J Oncol 44: 129-136, 2014.
APA
Bae, J.S., Noh, S.J., Kim, K.M., Jang, K.Y., Chung, M.J., Kim, D.G., & Moon, W.S. (2014). Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma . International Journal of Oncology, 44, 129-136. https://doi.org/10.3892/ijo.2013.2154
MLA
Bae, J. S., Noh, S. J., Kim, K. M., Jang, K. Y., Chung, M. J., Kim, D. G., Moon, W. S."Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma ". International Journal of Oncology 44.1 (2014): 129-136.
Chicago
Bae, J. S., Noh, S. J., Kim, K. M., Jang, K. Y., Chung, M. J., Kim, D. G., Moon, W. S."Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma ". International Journal of Oncology 44, no. 1 (2014): 129-136. https://doi.org/10.3892/ijo.2013.2154
Copy and paste a formatted citation
x
Spandidos Publications style
Bae JS, Noh SJ, Kim KM, Jang KY, Chung MJ, Kim DG and Moon WS: Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma . Int J Oncol 44: 129-136, 2014.
APA
Bae, J.S., Noh, S.J., Kim, K.M., Jang, K.Y., Chung, M.J., Kim, D.G., & Moon, W.S. (2014). Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma . International Journal of Oncology, 44, 129-136. https://doi.org/10.3892/ijo.2013.2154
MLA
Bae, J. S., Noh, S. J., Kim, K. M., Jang, K. Y., Chung, M. J., Kim, D. G., Moon, W. S."Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma ". International Journal of Oncology 44.1 (2014): 129-136.
Chicago
Bae, J. S., Noh, S. J., Kim, K. M., Jang, K. Y., Chung, M. J., Kim, D. G., Moon, W. S."Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma ". International Journal of Oncology 44, no. 1 (2014): 129-136. https://doi.org/10.3892/ijo.2013.2154
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