Downregulation of S100A4 expression by RNA interference suppresses cell growth and invasion in human colorectal cancer cells

Huang,Liyong; Xu,Ye; Cai,Guoxiang; Guan,Zuqing; Cai,Sanjun

doi:10.3892/or.2011.1598

Downregulation of S100A4 expression by RNA interference suppresses cell growth and invasion in human colorectal cancer cells

Authors:
- Liyong Huang
- Ye Xu
- Guoxiang Cai
- Zuqing Guan
- Sanjun Cai
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Affiliations: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, P.R. China
Published online on: December 20, 2011 https://doi.org/10.3892/or.2011.1598
Pages: 917-922
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

S100A4 protein, a member of the S100 superfamily of calcium-binding proteins, is frequently observed in various types of human cancers, including colorectal cancer (CRC). Our previous investigations have demonstrated that the overexpression of S100A4 is associated with lymph node metastasis and poor prognosis in CRC; however, its biological roles in CRC remain unclear. In the present study, we compared the expression of S100A4 at the mRNA and protein levels in six CRC cell lines, and found that the expression levels roughly coincided with their invasiveness. Using RNA interference, we suppressed S100A4 expression in SW620 CRC cells with highly invasive potential and S100A4 high expression. The specific knockdown of S100A4 strongly suppressed cell growth, migration and invasion activities. Furthermore, employing metastasis-related gene mRNA microarrays, we found four genes to be significantly dysregulated (more than 2-fold) after downregulation of S100A4, including three downregulated genes (MMP9, MMP10 and CDH11) and one upregulated gene (TIMP4). Our present results indicate that S100A4 may positively regulate tumor cell proliferation, invasion and metastasis associated with multiple molecules. Thus, the inhibition of S100A4 might be a potentially novel approach to treatment for CRC.

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1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
2	Huerta S: Recent advances in the molecular diagnosis and prognosis of colorectal cancer. Expert Rev Mol Diagn. 8:277–288. 2008. View Article : Google Scholar : PubMed/NCBI
3	Huang LY, Xu Y, Cai GX, Guan ZQ, Sheng WQ, Lu HF, Xie LQ, Lu HJ and Cai SJ: S100A4 overexpression underlies lymph node metastasis and poor prognosis in colorectal cancer. World J Gastroenterol. 17:69–78. 2011. View Article : Google Scholar : PubMed/NCBI
4	Marenholz I, Volz A, Ziegler A, Davies A, Ragoussis I, Korge BP and Mischke D: Genetic analysis of the epidermal differentiation complex (EDC) on human chromosome 1q21: chromosomal orientation, new markers, and a 6-Mb YAC contig. Genomics. 37:295–302. 1996. View Article : Google Scholar : PubMed/NCBI
5	Mazzucchelli L: Protein S100A4: too long overlooked by pathologists? Am J Pathol. 160:7–13. 2002. View Article : Google Scholar : PubMed/NCBI
6	Marenholz I, Heizmann CW and Fritz G: S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun. 322:1111–1122. 2004. View Article : Google Scholar : PubMed/NCBI
7	Barraclough R: Calcium-binding protein S100A4 in health and disease. Biochim Biophys Acta. 1448:190–199. 1998. View Article : Google Scholar : PubMed/NCBI
8	Micklem DR and Lorens JB: RNAi screening for therapeutic targets in human malignancies. Curr Pharm Biotechnol. 8:337–343. 2007. View Article : Google Scholar : PubMed/NCBI
9	Tuschl T and Borkhardt A: Small interfering RNAs: a revolutionary tool for the analysis of gene function and gene therapy. Mol Interv. 2:158–167. 2002. View Article : Google Scholar : PubMed/NCBI
10	Gentile A, Lazzari L, Benvenuti S, Trusolino L and Comoglio PM: Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71:3132–3141. 2011. View Article : Google Scholar : PubMed/NCBI
11	Huang Z, Huang S, Wang Q, Liang L, Ni S, Wang L, Sheng W, He X and Du X: MicroRNA-95 promotes cell proliferation and targets sorting Nexin 1 in human colorectal carcinoma. Cancer Res. 71:2582–2589. 2011. View Article : Google Scholar : PubMed/NCBI
12	Mortazavi F, Dubinett S and Rettig M: c-Crk proto-oncogene contributes to transcriptional repression of p120-catenin in non-small cell lung cancer cells. Clin Exp Metastasis. 28:391–404. 2011. View Article : Google Scholar : PubMed/NCBI
13	Mischke D, Korge BP, Marenholz I, Volz A and Ziegler A: Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (‘epidermal differentiation complex’) on human chromosome 1q21. J Invest Dermatol. 106:989–992. 1996.PubMed/NCBI
14	Vallely KM, Rustandi RR, Ellis KC, Varlamova O, Bresnick AR and Weber DJ: Solution structure of human Mts1 (S100A4) as determined by NMR spectroscopy. Biochemistry. 41:12670–12680. 2002. View Article : Google Scholar : PubMed/NCBI
15	Zou M, Al-Baradie RS, Al-Hindi H, Farid NR and Shi Y: S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. Br J Cancer. 93:1277–1284. 2005. View Article : Google Scholar : PubMed/NCBI
16	Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L and Barraclough R: Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Res. 60:1595–1603. 2000.PubMed/NCBI
17	Ai KX, Lu LY, Huang XY, Chen W and Zhang HZ: Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer. World J Gastroenterol. 14:1931–1935. 2008. View Article : Google Scholar : PubMed/NCBI
18	Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Fujita H, Nakata K, Ueda J, Sato N, Nagai E and Tanaka M: S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma. J Gastrointest Surg. 13:1852–1858. 2009. View Article : Google Scholar : PubMed/NCBI
19	Tsuna M, Kageyama S, Fukuoka J, Kitano H, Doki Y, Tezuka H and Yasuda H: Significance of S100A4 as a prognostic marker of lung squamous cell carcinoma. Anticancer Res. 29:2547–1554. 2009.PubMed/NCBI
20	Wang YY, Ye ZY, Zhao ZS, Tao HQ and Chu YQ: High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer. Ann Surg Oncol. 17:89–97. 2010. View Article : Google Scholar : PubMed/NCBI
21	Gongoll S, Peters G, Mengel M, Piso P, Klempnauer J, Kreipe H and von Wasielewski R: Prognostic significance of calcium-binding protein S100A4 in colorectal cancer. Gastroenterology. 123:1478–1484. 2002. View Article : Google Scholar : PubMed/NCBI
22	Boye K, Nesland JM, Sandstad B, Maelandsmo GM and Flatmark K: Nuclear S100A4 is a novel prognostic marker in colorectal cancer. Eur J Cancer. 46:2919–2925. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kwak JM, Lee HJ, Kim SH, Kim HK, Mok YJ, Park YT, Choi JS and Moon HY: Expression of protein S100A4 is a predictor of recurrence in colorectal cancer. World J Gastroenterol. 16:3897–3904. 2010. View Article : Google Scholar : PubMed/NCBI
24	Wang HY, Zhang JY, Cui JT, Tan XH, Li WM, Gu J and Lu YY: Expression status of S100A14 and S100A4 correlates with metastatic potential and clinical outcome in colorectal cancer after surgery. Oncol Rep. 23:45–52. 2010.PubMed/NCBI
25	Royston D and Jackson DG: Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol. 217:608–619. 2009. View Article : Google Scholar : PubMed/NCBI
26	Sundar SS and Ganesan TS: Role of lymphangiogenesis in cancer. J Clin Oncol. 25:4298–4307. 2007. View Article : Google Scholar : PubMed/NCBI
27	Brinckerhoff CE and Matrisian LM: Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol. 3:207–214. 2002. View Article : Google Scholar : PubMed/NCBI
28	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
29	Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin HB, Bhat KM, Sarfaraz S, Reagan-Shaw S, Spiegelman VS, Setaluri V and Mukhtar H: S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci USA. 103:14825–14830. 2006. View Article : Google Scholar
30	Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi T, Bosserhoff AK and Yasui W: Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene. 25:2546–2547. 2006. View Article : Google Scholar
31	Yen CY, Chen CH, Chang CH, Tseng HF, Liu SY, Chuang LY, Wen CH and Chang HW: Matrix metalloproteinases (MMP) 1 and MMP10 but not MMP12 are potential oral cancer markers. Biomarkers. 14:244–249. 2009. View Article : Google Scholar : PubMed/NCBI
32	Brew K and Nagase H: The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 1803:55–71. 2010. View Article : Google Scholar : PubMed/NCBI
33	Riddick AC, Shukla CJ, Pennington CJ, Bass R, Nuttall RK, Hogan A, Sethia KK, Ellis V, Collins AT, Maitland NJ, Ball RY and Edwards DR: Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer. 92:2171–2180. 2005. View Article : Google Scholar : PubMed/NCBI
34	Okazaki M, Takeshita S, Kawai S, Kikuno R, Tsujimura A, Kudo A and Amann E: Molecular cloning and characterization of OB-cadherin, a new member of cadherin family expressed in osteoblasts. J Biol Chem. 269:12092–12098. 1994.PubMed/NCBI
35	Brieger J, Duesterhoeft A, Brochhausen C, Gosepath J, Kirkpatrick CJ and Mann WJ: Recurrence of pleomorphic adenoma of the parotid gland - predictive value of cadherin-11 and fascin. APMIS. 116:1050–1057. 2008. View Article : Google Scholar : PubMed/NCBI
36	Li Z, Zhou Z and Donahue HJ: Alterations in Cx43 and OB-cadherin affect breast cancer cell metastatic potential. Clin Exp Metastasis. 25:265–272. 2008. View Article : Google Scholar : PubMed/NCBI
37	Tamura D, Hiraga T, Myoui A, Yoshikawa H and Yoneda T: Cadherin-11-mediated interactions with bone marrow stromal/osteoblastic cells support selective colonization of breast cancer cells in bone. Int J Oncol. 33:17–24. 2008.PubMed/NCBI
38	Chu K, Cheng CJ, Ye X, Lee YC, Zurita AJ, Chen DT, Yu-Lee LY, Zhang S, Yeh ET, Hu MC, Logothetis CJ and Lin SH: Cadherin-11 promotes the metastasis of prostate cancer cells to bone. Mol Cancer Res. 6:1259–1267. 2008. View Article : Google Scholar : PubMed/NCBI