SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling.
SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling.
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SNORA74B 基因沉默通过诱导 PHLPP 和抑制 Akt/mTOR 信号传导来抑制胆囊癌细胞。
DOI：
10.18632/oncotarget.15301
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Han K
中科院分区：
文献类型：
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作者：
Qin Y;Meng L;Fu Y;Quan Z;Ma M;Weng M;Zhang Z;Gao C;Shi X;Han K
小核仁rna （snoRNAs）与许多癌症的发展有关。因此，我们使用表达微阵列分析和定量实时PCR （qRT-PCR）验证了胆囊癌（GBC）组织和匹配的邻近非肿瘤组织中snoRNAs的差异表达。Western blot分析显示，GBC中SNORA74B水平高于非肿瘤组织。SNORA74B表达与GBC患者的局部侵袭、TNM分期、CA19-9水平和Ki67表达呈正相关，而与内源性Akt抑制剂PHLPP表达负相关。此外，SNORA74B表达对总生存期（OS）和无病生存期（DFS）具有预后影响。功能研究表明，使用sh-SNORA74B沉默GBC细胞中的SNORA74B可抑制细胞增殖，诱导G1阻滞，促进细胞凋亡。初步分子研究发现，SNORA74B沉默抑制AKT/mTOR信号通路的激活，同时增加PHLPP的表达。使用shRNA去除PHLPP可消除sh-SNORA74B对GBC细胞增殖的抑制作用，表明沉默SNORA74B的抗肿瘤作用是由PHLPP介导的。这些发现明确了SNORA74B在GBC细胞增殖、细胞周期和凋亡中的重要作用，并提示其可能作为GBC治疗的新靶点。
Small nucleolar RNAs (snoRNAs) have been implicated in the development of many cancers. We therefore examined the differential expression of snoRNAs between gallbladder cancer (GBC) tissues and matched adjacent non-tumor tissues using expression microarray analysis with confirmation by quantitative real-time PCR (qRT-PCR). Western blot analysis showed that SNORA74B levels were higher in GBC than non-tumor tissues. SNORA74B expression was positively associated with local invasion, advanced TNM stage, CA19-9 level, and Ki67 expression in patients with GBC, while it was negatively associated with expression of PHLPP, an endogenous Akt inhibitor. Moreover, SNORA74B expression was prognostic for overall survival (OS) and disease-free survival (DFS). Functional studies revealed that silencing SNORA74B in GBC cells using sh-SNORA74B suppressed cell proliferation, induced G1 arrest, and promoted apoptosis. Preliminary molecular investigation revealed that SNORA74B silencing inhibited activation of the AKT/mTOR signaling pathway, while increasing PHLPP expression. PHLPP depletion using shRNA abrogated sh-SNORA74B suppression of GBC cell proliferation, indicating that the antitumor effects of SNORA74B silencing were mediated by PHLPP. These findings define the important role of SNORA74B in cell proliferation, cell cycle, and apoptosis of GBC, and suggest that it may serve as a novel target for GBC treatment.