Identification of prognostic and metastasis-related alternative splicing signatures in hepatocellular carcinoma
Identification of prognostic and metastasis-related alternative splicing signatures in hepatocellular carcinoma
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肝细胞癌中预后和转移相关的选择性剪接特征的鉴定
DOI：
10.1042/bsr20201001
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发表时间：
2020-07-15
影响因子：
4
通讯作者：
Huang, Zongqiang
中科院分区：
文献类型：
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作者：
Huang, Runzhi;Yan, Gaili;Huang, Zongqiang
摘要肝细胞癌（HCC）是消化系统最常见的恶性肿瘤，是世界范围内癌症死亡的主要原因之一。其高转移率和高复发率导致肝癌患者生存率低。然而，肝癌转移的机制仍不清楚。选择性剪接事件（ASEs）在肿瘤的发生、发展和转移中起着重要作用。我们下载了肝癌标本的RNA测序和7种ASEs的数据，以探讨ASEs在肝癌发生和转移中的作用机制。这些数据来自癌症基因组图谱（TCGA）和TCGASpliceSeq数据库。单变量考克斯回归分析用于确定总共3197个总体生存相关ASE（OS-SE）。基于Lasso回归筛选出的5个OS-SE，构建了曲线下面积为0.765的预测模型。模型具有较好的可靠性，风险评分也被证明是一个独立的预测。在390个候选SF中，Y-box蛋白3（YBX 3）与OS和转移显著相关。在177个ASEs中，ATP结合盒亚家族A成员6（ABCA 6）-43162-AT和PLIN 5 -46808-AT被鉴定为与OS、骨转移相关并且与SF共表达。通过基因组变异分析（Gene Set Variation Analysis，GSVA）和单变量回归分析，初步确定初级胆汁酸合成为生存相关（KEGG）途径，与ABCA 6 -43162-AT和PLIN 5 -46808-AT相关。最后，我们提出ABCA 6 -43162-AT和PLIN 5 -46808-AT可能通过初级胆汁酸生物合成途径在异常YBX 3的调控下参与HCC的不良预后和转移。
Abstract As the most common neoplasm in digestive system, hepatocellular carcinoma (HCC) is one of the most important leading cause of cancer deaths worldwide. Its high-frequency metastasis and relapse rate lead to the poor survival of HCC patients. However, the mechanism of HCC metastasis is still unclear. Alternative splicing events (ASEs) have a great effect in cancer development, progression and metastasis. We downloaded RNA sequencing and seven types of ASEs data of HCC samples, in order to explore the mechanism of ASEs underlying tumorigenesis and metastasis of HCC. The data were taken from the The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. Univariate Cox regression analysis was used to determine a total of 3197 overall survival-related ASEs (OS-SEs). And based on five OS-SEs screened by Lasso regression, we constructed a prediction model with the Area Under Curve of 0.765. With a good reliability of the model, the risk score was also proved to be an independent predictor. Among identified 390 candidate SFs, Y-box protein 3 (YBX3) was significantly correlated with OS and metastasis. Among 177 ASEs, ATP-binding cassette subfamily A member 6 (ABCA6)-43162-AT and PLIN5-46808-AT were identified both associated with OS, bone metastasis and co-expressed with SFs. Then we identified primary bile acid biosynthesis as survival-related (KEGG) pathway by Gene Set Variation Analysis (GSVA) and univariate regression analysis, which was correlated with ABCA6-43162-AT and PLIN5-46808-AT. Finally, we proposed that ABCA6-43162-AT and PLIN5-46808-AT may contribute to HCC poor prognosis and metastasis under the regulation of aberrant YBX3 through the pathway of primary bile acid biosynthesis.