A Coiled-Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine-Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway
A Coiled-Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine-Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway
复制标题
含有 50 个剪接变体的卷曲螺旋结构域受富含丝氨酸/精氨酸的剪接因子 3 调节，并通过 Ras 信号通路促进小鼠肝细胞癌。
DOI：
10.1002/hep.30147
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发表时间：
2019-01-01
期刊：
影响因子：
13.5
通讯作者：
Yun, Jing-Ping
中科院分区：
文献类型：
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作者：
Wang, Hong;Zhang, Chris Zhiyi;Yun, Jing-Ping
对选择性剪接的解除管制有助于癌症的恶性进展。对于肝细胞癌（HCC）中重要的选择性剪接事件知之甚少。高通量测序显示，在50%的HCC病例中，含有50 (CCDC50) pre-mRNA的线圈结构域被异常剪接。采用BaseScope检测CCDC50S（一种截短的致癌剪接变体）在HCC组织中的表达。与良性肝脏肿瘤及其他几种实体肿瘤相比，HCC中CCDC50S mRNA表达上调，具有诊断潜力（敏感性0.711，特异性0.793）。HCC中CCDC50S mRNA的高表达与肿瘤分化差、肿瘤淋巴结转移（TNM）晚期、预后不良有显著相关。CCDC50S的过表达通过激活Ras/叉头盒蛋白O4 （Foxo4）信号通路发挥致瘤活性，促进HCC的生长和转移。抑制丝裂原活化蛋白激酶(MEK)/细胞外信号调节激酶（ERK）磷酸化或Foxo4的过表达均可显著减弱ccdc50s介导的表型。此外，富含丝氨酸和精氨酸的剪接因子3 （SRSF3）直接与CCDC50S mRNA结合，维持其在细胞质中的稳定性。SRSF3的胞质滞留是由乙型肝炎病毒编码的X蛋白（HBx）和14-3-3 β相互作用介导的。异位HBx表达诱导胞浆内SRSF3和CCDC50S的表达。结论：我们的研究提供了令人信服的证据，表明HBx/SRSF3/14-3-3 β复合物可上调CCDC50S，并通过Ras/Foxo4信号通路促进HCC的癌性进展。这些数据表明，CCDC50S可能作为HCC的诊断和预后生物标志物，可能是一个有希望的治疗靶点。
Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High-throughput sequencing revealed that coiled-coil domain containing 50 (CCDC50) pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with benign liver tumors and several other types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity, 0.711; specificity, 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced tumor node metastasis (TNM) stage, and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis by activation of Ras/forkhead box protein O4 (Foxo4) signaling. Either suppression of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine- and arginine-rich splicing factor 3 (SRSF3) directly bound to CCDC50S mRNA to maintain its stability in the cytoplasm. The cytosolic retention of SRSF3 was mediated by the interaction of hepatitis B virus-encoded X protein (HBx) and 14-3-3 beta. Ectopic HBx expression induced expression of cytosolic SRSF3 and CCDC50S. Conclusion: Our study provided compelling evidence that up-regulation of CCDC50S was modulated by HBx/SRSF3/14-3-3 beta complex and enhanced oncogenic progression of HCC through the Ras/Foxo4 signaling pathway. These data suggest that CCDC50S may serve as a diagnostic and prognostic biomarker and probably a promising therapeutic target in HCC.