An alternative POLDIP3 transcript promotes hepatocellular carcinoma progression
An alternative POLDIP3 transcript promotes hepatocellular carcinoma progression
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另一种 POLDIP3 转录物促进肝细胞癌进展
DOI：
10.1016/j.biopha.2017.01.139
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发表时间：
2017-05-01
影响因子：
7.5
通讯作者：
Sun, Shu-Han
中科院分区：
文献类型：
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作者：
Liu, Xiao-Ning;Yuan, Ji-Hang;Sun, Shu-Han
选择性剪接在许多病理生理过程中起着关键作用，剪接失调是癌症的标志。不同的同种型可能对癌症具有显著不同的影响。POLDIP3是核糖体蛋白S6激酶1的靶点，并调节DNA复制和mRNA翻译。在这项研究中，我们测量了临床肝细胞癌（HCC）组织中缺少外显子3和29氨基酸的另一种POLDIP3转录物（POLDIP3-β）的表达。通过Glo细胞活力测定、乙炔基脱氧尿苷掺入测定、集落形成测定、TUNEL测定、膜联蛋白V-碘化丙啶染色和流式细胞术、transwell测定、伤口愈合测定和体内异种移植物生长来评估POLDIP 3-B对HCC细胞增殖、凋亡和迁移的作用。我们的研究结果表明，与配对的相邻非癌肝组织相比，POLDIP3-β在HCC组织中显著上调。体外和体内功能实验结果表明，POLDIP 3-β的过表达显着增加肝癌细胞增殖，抑制肝癌细胞凋亡，增强肝癌细胞迁移，并促进异种移植物生长。而含有外显子3的正常POLDIP3的作用要弱得多。总之，我们的研究表明，POLDIP3的替代转录上调，并作为一个关键的癌基因在肝癌的功能。选择性靶向POLDIP3的这种亚型将是HCC的有希望的治疗策略。(C)2017 Elsevier Masson SAS。All rights reserved.
Alternative splicing plays critical roles in many pathophysiological processes and splicing dysregulation is a hallmark of cancer. The different isoforms may have significantly different effects on cancers. POLDIP3 is a target of ribosomal protein S6 kinase 1, and regulates DNA replication and mRNA translation. In this study, we measured the expression of an alternative POLDIP3 transcript (POLDIP3-beta), which lacks exon 3 and 29 amine acids, in clinical hepatocellular carcinoma (HCC) tissues. The roles of POLDIP3-b on HCC cell proliferation, apoptosis, and migration were assessed by Glo cell viability assays, Ethynyl deoxyuridine incorporation assays, colony formation assays, TUNEL assays, Annexin V-propidium iodide staining and flow cytometry, transwell assays, wound healing assays, and in vivo xenograft growth. Our results showed that POLDIP3-beta was significantly upregulated in HCC tissues compared with paired adjacent noncancerous hepatic tissues. In vitro and in vivo functional experiments results demonstrated that overexpression of POLDIP3-beta drastically increased HCC cell proliferation, inhibited HCC cell apoptosis, enhanced HCC cell migration, and promoted xenograft growth. While the effects of normal POLDIP3, which contains exon 3, were much weaker. In conclusion, our study demonstrated that an alternative transcript of POLDIP3 is upregulated and functions as a critical oncogene in HCC. Selectively targeting this isoform of POLDIP3 would be a promising therapeutic strategy for HCC. (C) 2017 Elsevier Masson SAS. All rights reserved.