title: Inactivation of tumor suppressor gene HIC1 in gastric cancer is reversed via small activating RNAs.
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.
authors.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.
authors.forename: Shengli
authors.initials: S
authors.lastname: Pan
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xuehua
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.forename: Jianian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianfang
authors.initials: J
authors.lastname: Li
authors.forename: Qu
authors.initials: Q
authors.lastname: Cai
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yingyan
authors.initials: Y
authors.lastname: Yu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D005753:Gastric Mucosa / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058727:RNA, Small Untranslated / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D015533:Transcriptional Activation
chemical_list: C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D058727:RNA, Small Untranslated
keywords: Gastric cancer; HIC1; RNA activation; RNA interference; RNA-induced gene activation; RNAa; RNAi; SNP; Single nucleotide polymorphism; Tumor-suppressor gene; double-stranded RNA; dsRNA; hypermethylated in cancer 1