LncRNA CSMD1-1 promotes the progression of Hepatocellular Carcinoma by activating MYC signaling

Abstract

Emerging evidence suggests that long non-coding RNAs (lncRNA) play critical roles in the development and progression of diverse cancers including hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of lncRNAs that are involved in hepatocarcinogenesis have not been fully explored. Methods: In this study, we profiled lncRNA expression in 127 pairs of HCC and nontumor liver tissues (a Discovery Cohort) using a custom microarray. The expression and clinical significance of lncCSMD1-1 were then validated with qRT-PCR and COX regression analysis in a Validation Cohort (n=260) and two External Validation Cohorts (n=92 and n=124, respectively). In vitro and in vivo assays were performed to explore the biological effects of lncCSMD1-1 on HCC cells. The interaction of lncCSMD1-1 with MYC was identified by RNA pull-down and RNA immunoprecipitation. The role of LncCSMD1-1 in the degradation of MYC protein was also investigated. Results: With microarray, we identified a highly upregulated lncRNA, lncCSMD1-1, which was associated with tumor progression and poor prognosis in the Discovery Cohort, and validated in another 3 HCC cohorts. Consistently, ectopic expression of lncCSMD1-1 notably promotes cell proliferation, migration, invasion, tumor growth and metastasis of HCC cells in in vitro and in vivo experiments. Gene expression profiling on HCC cells and gene sets enrichment analysis indicated that the MYC target gene set was significantly enriched in HCC cells overexpressing lncCSMD1-1, and lncCSMD1-1 was found to directly bind to MYC protein in the nucleus of HCC cells, which resulted in the elevation of MYC protein. Mechanistically, lncCSMD1-1 interacted with MYC protein to block its ubiquitin-proteasome degradation pathway, leading to activation of its downstream target genes. Conclusion: lncCSMD1-1 is upregulated in HCC and promotes progression of HCC by activating the MYC signaling pathway. These results provide the evidence that lncCSMD1-1 may serve as a novel prognostic marker and potential therapeutic target for HCC.

LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network

“…Long non-coding RNAs (lncRNAs) refer to non-coding RNAs consisting of >200 nucleotides. Increasing studies have reported lncRNAs play vital roles in cancer cell proliferation, metastasis and chemoresistance 14 - 17 . Moreover, the lncRNAs tend to exhibit higher tissue-specific expressions than protein coding genes 18 - 20 .…”

Epigenetic Mechanisms of LncRNAs Binding to Protein in Carcinogenesis

“…In liver cancer, two lncRNAs GHET1 and CSMD1-1 stabilize activating transcription factor 1 (ATF1) mRNA expression or c-Myc protein respectively, by binding to its protein to regulate cancer cell migration and invasion [ 50 , 51 ]. Involvement of the EZH2 protein in the migration and invasion processes of cancer has also been highlighted with various lncRNAs.…”

Long Non-Coding RNA TRIM52-AS1 Promotes Growth and Metastasis via miR-218-5p/ROBO1 in Hepatocellular Carcinoma

“…At the same time, lncCSMD1-1 interacted with MYC protein to block its ubiquitin-proteasome degradation pathway, thereby activating its downstream target gene. 17 Research by Xu et al found that the expression of lncRNA H19 was negatively correlated with sorafenib sensitivity in HCC cells. Inhibition of lncRNA H19 could increase the sensitivity of sorafenib by inhibiting the epithelial-mesenchymal transition (EMT) of HCC cells.…”