Posttranscriptional Silencing HOTTIP By MiR-192 And MiR-204 Affects HCC Growth

Long non-coding RNA (lncRNA) HOTTIP is a vital oncogene in hepatocellular carcinoma (HCC), one of the deadliest cancers worldwide. However, the fine-regulation of HOTTIP at the post-transcriptional level and downstream molecular events caused by its deregulation remain poorly understood. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expressionvia the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays.Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients.In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonize endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo xenograft data also support the tumor suppressor role of both miRNAs. Besides the known target gene H0XA13, glutaminase (GLS) were identified as potential downstream targets of the miR-192/-204-HOTTIP axis in HCC.Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencing GLS, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS inhibition.These results elucidate that the miR-192/-204-HOTTIP axis mightbe an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications.