SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling

Abstract

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.

TTF1‑NP induces protective autophagy during apoptosis by inhibiting the Akt/mTOR pathway and activating JNK in human liver cancer cells

“…mTOR is activated by Akt and negatively regulates autophagy (28). Extensive research has indicated that inhibiting the Akt/mTOR pathway contributes to autophagy in cancer cells (29,30). In our study, TTF1-NP inhibited the Akt/mTOR pathway and decreased p-Akt (Ser473) and p-mTOR (Ser2448) levels in a dose-dependent manner.…”

Analysis of Expression Pattern of snoRNAs in Different Cancer Types with Machine Learning Algorithms

“…The next identified tumor subtype is UCEC. Tumor-associated snoRNAs, such as ACA56 [60], HBII-336 [61], SNORD19 [41], and U19 [56,62], have been screened out using four quantitative parameters for UCEC identification. Among these four parameters, U19 is a relatively unique parameter with expression level higher than 119, indicating its potential role in tumor subtyping.…”

“…Among these four parameters, U19 is a relatively unique parameter with expression level higher than 119, indicating its potential role in tumor subtyping. According to recent publications [56,62], snoRNA U19 (SNORA74), as an H/ACA box snoRNA, contributes to the regulation of the famous AKT/mTOR signaling pathway. The expression level of such gene has been screened out and functionally confirmed to participate in multiple tumor subtypes including UCEC and gallbladder cancer [62].…”

Guide snoRNAs: Drivers or Passengers in Human Disease?

“…Expression of two other snoRNAs, snoRA47 and ACA11, are also high in hepatocellular carcinoma tissues compared to normal tissues [49,50]. snoRA74 (U19), responsible for modifying the two most conserved Ψs on 28S rRNA, 3741 and 3743 is found to be up-regulated in gallbladder cancer [51]. These positions are conserved from bacteria (protein only modification) to humans [1,38,41].…”