title: Dual knockdown of N-ras and epiregulin synergistically suppressed the growth of human hepatoma cells.
abstract: Hepatocellular carcinoma (HCC) is a major challenge because of its resistance to conventional cytotoxic chemotherapy and radiotherapy. Multi-targeted therapy might be a new option for HCC treatment. Our previous study showed that N-ras gene was activated in HCC and was inhibited by RNA interference. In the present study, we investigated the alternation of gene expression by microarray in N-Ras-siRNA-treated HepG2 cells. The results revealed that the EREG gene, encoding epiregulin, was dramatically up-regulated in response to silence of N-ras. We speculated that the up-regulation of epiregulin was involved in the compensatory mechanism of N-ras knockdown for cell growth. Therefore, we evaluated whether dual silence of N-ras and epiregulin display a greater suppression of cell growth. The results confirmed that dual knockdown of N-ras and epiregulin synergistically inhibited cell growth. Our results also showed that dual knockdown of N-ras and epiregulin significantly induced cell arrest at G0/G1 phase. Furthermore, Western blot assay showed that dual knockdown of N-ras and epiregulin markedly reduced the phosphorylations of ERK1/2, Akt and Rb, and inhibited the expression of cyclin D1. Our findings imply that multi-targeted silence of oncogenes might be an effective treatment for HCC.
authors: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors: Meng
authors: M
authors: Zhao
authors: Hong-wei
authors: HW
authors: He
authors: Huan-xing
authors: HX
authors: Sun
authors: Kai-huan
authors: KH
authors: Ren
authors: Rong-guang
authors: RG
authors: Shao
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000235:genetics*; D066260:Epiregulin; D016193:G1 Phase / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C530104:CCND1 protein, human; C587880:EREG protein, human; D066260:Epiregulin; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)