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Inactivation of tumor suppressor gene HIC1 in gastric cancer is reversed via small activating RNAs
Authors:Shengli Pan  Zhiwei WangYinan Chen  Xuehua ChenJun Ji  Jianian ZhangJianfang Li  Qu CaiBingya Liu  Zhenggang ZhuYingyan Yu
Affiliation:Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Ruijin Hospital, Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University, School of Medicine, Ruijin er Road, No. 197, 200025 Shanghai, China
Abstract:HIC1 is a tumor suppressor gene that is down-expressed in different malignancies, in part, because of promoter hypermethylation. However, the biological function of HIC1 in gastric cancer remains unclear. It is known that small double-stranded RNAs can induce gene expression by targeting promoter sequences. In the present study, we examined the expression levels of HIC1 in gastric cancer tissue. Several pieces of small double-stranded RNAs were used for the activation of HIC1. Tissue microarray analysis of gastric cancer indicated that down-regulation of HIC1 in gastric cancer tissue was dramatic compared with the adjacent gastric mucosa. Gastric cancer cell lines also showed down-regulated HIC1 expression compared with a human immortalized gastric mucosa cell line. One out of four dsRNAs produced activation of HIC1 as assessed by real-time PCR and Western blotting. Use of a cell counting kit 8 and clonogenicity assays indicated that dsRNA-mediated re-expression of HIC1 inhibited cell proliferation and clonogenicity in gastric cancer. Reactivation of HIC1 suppressed cell migration and induced cell cycle arrest in the G0/G1 phase, as well as induced apoptosis. These results suggest that HIC1 is a potential target of gene therapy against gastric cancer, and that dsRNAs could function as a therapeutic option for up-regulating tumor suppressor genes in gastric cancer and other malignancies.
Keywords:HIC1, hypermethylated in cancer 1   dsRNA, double-stranded RNA   SNP, Single nucleotide polymorphism   RNAa, RNA-induced gene activation   RNAi, RNA interference
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