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

Kang W, Tong JH, Lung RW, Dong Y, Yang W, Pan Y, Lau KM, Yu J, Cheng AS, To KF - J Transl Med (2014)

Bottom Line: Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches. 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. kfto@cuhk.edu.hk.

ABSTRACT

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.

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Related in: MedlinePlus

let-7b/g is down-regulated in in gastric cancer and correlates with poor survival. (A) The expression of let-7b/g in 9 gastric cancer cell lines compared with normal gastric epithelium tissue (AM7996). (B) let-7b/g showed a decreased expression in primary gastric tumors compared with paired adjacent non-tumours tissues (n = 76; let-7b, P = 0.013; let-7g, P = 0.003). (C) Downregulation of let-7b/g predicted poorer survival in clinical gastric cancer patients (let-7b, P = 0.001; let-7g, P = 0.051).
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Fig1: let-7b/g is down-regulated in in gastric cancer and correlates with poor survival. (A) The expression of let-7b/g in 9 gastric cancer cell lines compared with normal gastric epithelium tissue (AM7996). (B) let-7b/g showed a decreased expression in primary gastric tumors compared with paired adjacent non-tumours tissues (n = 76; let-7b, P = 0.013; let-7g, P = 0.003). (C) Downregulation of let-7b/g predicted poorer survival in clinical gastric cancer patients (let-7b, P = 0.001; let-7g, P = 0.051).

Mentions: The expression of let-7b/g was measured in gastric cancer cell lines and normal stomach epithelium tissue by miRNA qRT-PCR. let-7b and let-7g were observed down-regulated in 6 and 7 gastric cancer cell lines respectively compared with normal gastric epithelial sample (Figure 1A). In a total of 76 paired primary RNA samples, the expression of let-7b and let-7g showed a decreased level in tumors compared with the corresponding non-tumorous gastric mucosal samples (let-7b, P = 0.013; let-7g, P = 0.003; Figure 1B).Figure 1


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

Kang W, Tong JH, Lung RW, Dong Y, Yang W, Pan Y, Lau KM, Yu J, Cheng AS, To KF - J Transl Med (2014)

let-7b/g is down-regulated in in gastric cancer and correlates with poor survival. (A) The expression of let-7b/g in 9 gastric cancer cell lines compared with normal gastric epithelium tissue (AM7996). (B) let-7b/g showed a decreased expression in primary gastric tumors compared with paired adjacent non-tumours tissues (n = 76; let-7b, P = 0.013; let-7g, P = 0.003). (C) Downregulation of let-7b/g predicted poorer survival in clinical gastric cancer patients (let-7b, P = 0.001; let-7g, P = 0.051).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4196013&req=5

Fig1: let-7b/g is down-regulated in in gastric cancer and correlates with poor survival. (A) The expression of let-7b/g in 9 gastric cancer cell lines compared with normal gastric epithelium tissue (AM7996). (B) let-7b/g showed a decreased expression in primary gastric tumors compared with paired adjacent non-tumours tissues (n = 76; let-7b, P = 0.013; let-7g, P = 0.003). (C) Downregulation of let-7b/g predicted poorer survival in clinical gastric cancer patients (let-7b, P = 0.001; let-7g, P = 0.051).
Mentions: The expression of let-7b/g was measured in gastric cancer cell lines and normal stomach epithelium tissue by miRNA qRT-PCR. let-7b and let-7g were observed down-regulated in 6 and 7 gastric cancer cell lines respectively compared with normal gastric epithelial sample (Figure 1A). In a total of 76 paired primary RNA samples, the expression of let-7b and let-7g showed a decreased level in tumors compared with the corresponding non-tumorous gastric mucosal samples (let-7b, P = 0.013; let-7g, P = 0.003; Figure 1B).Figure 1

Bottom Line: Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches. 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. kfto@cuhk.edu.hk.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus