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./nMethods: 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./nResults: 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./nConclusion: 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.

中文翻译：

---

LncRNA CSMD1-1通过激活MYC信号传导促进肝细胞癌的发展。

新兴证据表明，长的非编码RNA（lncRNA）在包括肝细胞癌（HCC）在内的多种癌症的发生和发展中起着至关重要的作用，但是涉及肝癌发生的lncRNA的潜在分子机制尚未得到充分的探索。方法：在这项研究中，我们使用定制的微阵列分析了127对HCC和非肿瘤肝组织（Discovery Cohort）中lncRNA的表达。然后，在验证队列（n = 260）和两个外部验证队列（n = 92和n = 124）中分别通过qRT-PCR和COX回归分析验证了lncCSMD1-1的表达和临床意义。体外和体内进行了测定以探索lncCSMD1-1对HCC细胞的生物学作用。通过RNA下拉和RNA免疫沉淀鉴定了lncCSMD1-1与MYC的相互作用。/ n结果：通过微阵列，我们发现了一个高度上调的lncRNA，即lncCSMD1-1，这与发现队列中的肿瘤进展和不良预后相关，并得到了验证。在另外3个HCC队列中。一致地，lncCSMD1-1的异位表达在体外和体内显着促进HCC细胞的细胞增殖，迁移，侵袭，肿瘤生长和转移实验。HCC细胞的基因表达谱分析和基因集富集分析表明，MYC靶基因集在过表达lncCSMD1-1的HCC细胞中显着富集，并且发现lncCSMD1-1与HCC细胞核中的MYC蛋白直接结合，从而导致在MYC蛋白升高中。从机制上讲，lncCSMD1-1与MYC蛋白相互作用以阻断其泛素-蛋白酶体降解途径，从而激活其下游靶基因。/n结论： lncCSMD1-1在HCC中被上调，并通过激活MYC信号通路促进HCC的进程。这些结果提供了证据，lncCSMD1-1可以作为HCC的新的预后标志物和潜在的治疗靶点。