let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis

Journal of Translational Medicine

Ka Fai To⁴  Alfred SL Cheng³  Jun Yu⁵  Kin Mang Lau¹  Yi Pan¹  Weiqin Yang³  Yujuan Dong²  Raymond WM Lung¹  Joanna HM Tong¹  Wei Kang⁴ 

[1] Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People¿s Republic of China;Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People¿s Republic of China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, People¿s Republic of China;Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People¿s Republic of China;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People¿s Republic of China

关键词: Tumor suppressor;    Gastric cancer;    AKT2;    let-7g;    let-7b;   

Others  :  1147697
DOI  :  10.1186/s12967-014-0281-3

 received in 2014-06-06, accepted in 2014-09-24,  发布年份 2014

【 摘 要 】

Background

Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis.

Methods

The expression of let-7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT-PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches.

Results

let-7b/g was found down-regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3¿UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor-suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g.

Conclusion

In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer.

【 授权许可】

   
2014 Kang et al.; licensee BioMed Central Ltd.

【 图 表 】

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