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Correction: Liang, J., et al. Antisense Oligonucleotide Against Clusterin Regulates Human Hepatocellular Carcinoma Invasion Through Transcriptional Regulation of Matrix Metalloproteinase-2 and E-Cadherin. Int. J. Mol. Sci. 2012, 13, 10594-10607

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Antisense Oligonucleotide Against Clusterin Regulates Human Hepatocellular Carcinoma Invasion Through Transcriptional Regulation of Matrix Metalloproteinase-2 and E-Cadherin

DOI: 10.3390/ijms130810594

Keywords: hepatocellular carcinoma, metastasis, clusterin

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Abstract:

Secreted clusterin (sCLU) has been shown to be overexpressed in metastatic hepatocellular carcinoma (HCC) tissue, and its overexpression in HCC cells increases cell migration and the formation of liver metastatic tumor nodules in vivo. In this study, we tested the hypothesis that sCLU plays a role in the invasiveness of human HCC and may be associated with its metastatic spread. HCCLM3, a human hepatocellular carcinoma cell line, was transiently transfected with an antisense oligonucleotide (ASO) against sCLU (OGX-011). HepG2 liver hepatocellular cells were transiently transfected with the pc.DNA3.1-sCLU plasmid to overexpress sCLU, and subsequently evaluated for effects on invasion and the expression of molecules involved in invasion. We observed that suppression of the sCLU gene significantly reduced the invasive capability of the highly invasive HCCLM3 cells, and vice versa in the low invasive HepG2 cell line. The results revealed that knockdown of sCLU by OGX-011 resulted in a significant increase in the expression of E-cadherin and a decrease in matrix metalloproteinase-2 ( MMP-2) gene transcription. Overexpression of sCLU by transfection with pc.DNA3.1-sCLU significantly decreased the expression of E-cadherin and increased MMP-2 gene transcription. These data were further verified by reverse transcription-PCR and Western blot analysis. A significant reduction in MMP-2 expression and an increase in E-cadherin expression in sCLU-knockdown HCCLM3 cells were observed, as well as a significant increase in MMP-2 expression and a decrease in E-cadherin expression in HepG2 cells overexpressing sCLU. These data indicate a role for sCLU in augmenting MMP-2 transcription and decreasing E-cadherin expression. Our data show the involvement of sCLU in human HCC invasion, and demonstrate that silencing sCLU gene expression inhibits the invasion of human HCC cells by inhibiting MMP-2 expression and promoting E-cadherin expression. Thus, OGX-011 could be an effective therapeutic agent for HCC.

 References

[1]  Block, T.M.; Mehta, A.S.; Fimmel, C.J.; Jordan, R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003, 22, 5093–5097.
[2]  Okuda, K. Hepatocellular carcinoma. J. Hepatol 2000, 32, 225–237.
[3]  Parkin, D.M.; Pisani, P.; Ferlay, J. Global cancer statistics. CA A Cancer J. Clin 1999, 49, 33–64.
[4]  Nagao, T.; Inoue, S.; Yoshimi, F.; Sodeyama, M.; Omori, Y.; Mizuta, T.; Kawano, N.; Morioka, Y. Postoperative recurrence of hepatocellular carcinoma. Ann. Surg. 1990, 211, 28–33.
[5]  Yang, J.; Mani, S.A.; Donaher, J.L. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117, 927–939.
[6]  Hirohashi, S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am. J. Pathol 1998, 153, 333–339.
[7]  Sugimachi, K.; Taguchi, K.; Aishima, S. Altered expression of β-catenin without genetic mutation in intrahepatic cholangiocarcinoma. Mod. Pathol 2001, 14, 900–905.
[8]  Liu, L.; Zhu, X.D.; Wang, W.Q.; Shen, Y.; Qin, Y.; Ren, Z.G.; Sun, H.C.; Tang, Z.Y. Activation of β-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin. Canc. Res 2010, 16, 2740–2750.
[9]  Na, D.C.; Lee, J.E.; Yoo, J.E.; Oh, B.K.; Choi, G.H.; Park, Y.N. Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study. Exp. Mol. Pathol 2011, 90, 66–73.
[10]  Chen, D.; Zheng, X.; Jiao, X.; Gao, Y.; Zhang, K.; Liang, J. Transcriptional repressor snail and metastasis in hepatocellular carcinoma. Hepatogastroenterology 2012, 59, 1359–1365.
[11]  Jones, S.E.; Jomary, C. Clusterin. Int. J. Biochem. Cell. Biol 2002, 34, 427–431.
[12]  Wilson, M.R.; Easterbrook-Smith, S.B. Clusterin is a secreted mammalian chaperone. Trends Biochem. Sci 2000, 25, 95–98.
[13]  Blaschuk, O.; Burdzy, K.; Fritz, I.B. Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J. Biol. Chem 1983, 258, 7714–7720.
[14]  Redondo, M.; Villar, E.; Torres-Mu？oz, J.; Tellez, T.; Morell, M.; Petito, C.K. Overexpression of clusterin in human breast carcinoma. Am. J. Pathol 2000, 157, 393–399.
[15]  Xie, D.; Lau, S.H.; Sham, J.S.; Wu, Q.L.; Fang, Y.; Liang, L.Z.; Che, L.H.; Zeng, Y.X.; Guan, X.Y. Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma. Cancer 2005, 103, 277–283.
[16]  Chen, X.; Halberg, R.B.; Ehrhardt, W.M.; Torrealba, J.; Dove, W.F. Clusterin as a biomarker in murine and human intestinal neoplasia. Proc. Natl. Acad. Sci. USA 2003, 100, 530–9535.
[17]  Rodríguez-Pi？eiro, A.M.; García-Lorenzo, A.; Blanco-Prieto, S.; Alvarez-Chaver, P.; Rodríguez-Berrocal, F.J.; Cadena, M.P.; Martínez-Zorzano, V.S. Secreted clusterin in colon tumor cell models and its potential as diagnostic marker for colorectal cancer. Cancer Investig 2012, 30, 72–77.
[18]  Steinberg, J.; Oyasu, R.; Lang, S.; Sintich, S.; Rademaker, A.; Lee, C.; Kozlowski, J.M.; Sensibar, J.A. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin. Cancer Res 2010, 3, 1707–1711.
[19]  Miyake, H.; Gleave, M.E.; Arakawa, S.; Kamidono, S.; Hara, I. Introducing the clusterin gene into human renal cell carcinoma cells enhances their metastatic potential. J. Urol 2002, 167, 2203–2208.
[20]  Bi, J.; Guo, A.L.; Lai, Y.R.; Li, B.; Zhong, J.M.; Wu, H.Q.; Xie, Z.; He, Y.L.; Lv, Z.L.; Lau, S.H.; et al. Overexpression of clusterin correlates with tumor progression, metastasis in gastric cancer: a study on tissue microarrays. Neoplasma 2010, 57, 191–197.
[21]  Lau, S.H.; Sham, J.S.; Xie, D.; Tzang, C.H.; Tang, D.; Ma, N.; Hu, L.; Wang, Y.; Wen, J.M.; Xiao, G.; et al. Clusterin plays an important role in hepatocellular carcinoma metastasis. Oncogene 2006, 25, 1242–1250.
[22]  Kang, Y.K.; Hong, S.W.; Lee, H.; Kim, W.H. Overexpression of clusterin in human hepatocellular carcinoma. Hum. Pathol 2004, 35, 1340–1346.
[23]  Flanagan, L.; Whyte, L.; Chatterjee, N.; Tenniswood, M. Effects of clusterin over-expression on metastatic progression and therapy in breast cancer. BMC Cancer 2010, 22, 100–107.
[24]  Panico, F.; Rizzi, F.; Fabbri, L.M.; Bettuzzi, S.; Luppi, F. Clusterin (CLU) and lung cancer. Adv. Cancer Res 2009, 105, 63–76.
[25]  So, A.; Sinnemann, S.; Huntsman, D.; Fazli, L.; Gleave, M. Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo. Mol. Cancer Ther 2005, 4, 1837–1849.
[26]  Chou, T.Y.; Chen, W.C.; Lee, A.C.; Hung, S.M.; Shih, N.Y.; Chen, M.Y. Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway. Cell Signal 2009, 21, 704–711.
[27]  Pan, Q.; Bao, L.W.; Merajver, S.D. Tetrathiomolybdate inhibits angiogenesis and metastasis through suppression of the NF-κB signaling cascade. Mol. Cancer Res 2003, 1, 701–706.
[28]  Aalinkeel, R.; Nair, M.P.; Sufrin, G.; Mahajan, S.D.; Chadha, K.C.; Chawda, R.P.; Schwartz, S.A. Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res 2004, 64, 5311–5321.
[29]  Poon, R.T.; Fan, S.T.; Wong, J. Risk factors, prevention and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann. Surg 2000, 232, 10–24.
[30]  Soo, K.; O’Rourke, M.P.; Khoo, P.L. Twist function is required for the morphogenesis of the cephalic neural tube and the differentiation of the cranial neural crest cells in the mouse embryo. Dev. Biol. 2002, 247, 251–270.
[31]  Zhao, X.L.; Sun, T.; Che, N.; Sun, D.; Zhao, N.; Dong, X.Y.; Gu, Q.; Yao, Z.; Sun, B.C. Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1. Cell Mol. Med 2011, 15, 691–700.
[32]  Sawada, S.; Murakami, K.; Murata, J.; Tsukada, K.; Saiki, I. Accumulation of extracellular matrix in the liver induces high metastatic potential of hepatocellular carcinoma to the lung. Int. J. Oncol 2001, 1965–1970.
[33]  Thiery, J.P. Epithelial-mesenchymal transitions in tumor progression. Nat. Rev. Cancer 2002, 2, 2442–2454.
[34]  Huber, G.F.; Züllig, L.; Soltermann, A.; Roessle, M.; Graf, N.; Haerle, S.K.; Studer, G.; Jochum, W.; Moch, H.; Stoeckli, S.J. Down regulation of E-Cadherin (ECAD)—A predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx. BMC Cancer 2011, 11, 217:1–217:8.
[35]  Chen, X.; Wang, Y.; Xia, H.; Wang, Q.; Jiang, X.; Lin, Z.; Ma, Y.; Yang, Y.; Hu, M. Loss of E-cadherin promotes the growth, invasion and drug resistance of colorectal cancer cells and is associated with liver metastasis. Mol. Biol. Rep 2012, 39, 6707–6714.
[36]  Wells, A.; Yates, C.; Shepard, C.R. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin. Exp. Metastasis 2008, 25, 621–628.
[37]  Zhai, B.; Yan, H.X.; Liu, S.Q.; Chen, L.; Wu, M.C.; Wang, H.Y. Reduced expression of E-cadherin/catenin complex in hepatocellular carcinomas. World J. Gastroenterol 2008, 14, 5665–5673.

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