LncRNA CSMD1-1 promotes the progression of Hepatocellular Carcinoma by activating MYC signaling
LncRNA CSMD1-1 promotes the progression of Hepatocellular Carcinoma by activating MYC signaling
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LncRNA CSMD1-1通过激活MYC信号促进肝细胞癌的进展
DOI：
10.7150/thno.45989
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Wang, Hui-Yun
中科院分区：
文献类型：
--
作者：
Liu, Ji;Xu, Rui;Wang, Hui-Yun
新的证据表明，长链非编码RNA（lncRNA）在包括肝细胞癌（HCC）在内的多种癌症的发生和进展中发挥着关键作用，但lncRNA参与肝癌发生的潜在分子机制尚未得到充分探索。方法：在这项研究中，我们使用定制微阵列分析了 127 对 HCC 和非肿瘤肝组织（发现队列）中的 lncRNA 表达。然后，通过 qRT-PCR 和 COX 回归分析在一个验证队列 (n=260) 和两个外部验证队列（分别为 n=92 和 n=124）中验证 lncCSMD1-1 的表达和临床意义。进行体外和体内测定以探索lncCSMD1-1对HCC细胞的生物学效应。通过 RNA Pull-down 和 RNA 免疫沉淀鉴定了 lncCSMD1-1 与 MYC 的相互作用。还研究了 LncCSMD1-1 在 MYC 蛋白降解中的作用。结果：通过微阵列，我们在发现队列中发现了一种高度上调的 lncRNA lncCSMD1-1，它与肿瘤进展和不良预后相关，并在另外 3 个 HCC 队列中得到了验证。一致地，在体外和体内实验中，lncCSMD1-1的异位表达显着促进HCC细胞的细胞增殖、迁移、侵袭、肿瘤生长和转移。 HCC细胞基因表达谱及基因集富集分析表明，过表达lncCSMD1-1的HCC细胞中MYC靶基因集显着富集，且lncCSMD1-1直接与HCC细胞核中的MYC蛋白结合，导致MYC蛋白升高。从机制上讲，lncCSMD1-1 与 MYC 蛋白相互作用，阻断其泛素-蛋白酶体降解途径，从而激活其下游靶基因。结论：lncCSMD1-1在HCC中表达上调，并通过激活MYC信号通路促进HCC进展。这些结果证明lncCSMD1-1可能作为HCC的新型预后标志物和潜在治疗靶点。
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.