title: An alternative POLDIP3 transcript promotes hepatocellular carcinoma progression.
abstract: 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-β), which lacks exon 3 and 29 amine acids, in clinical hepatocellular carcinoma (HCC) tissues. The roles of POLDIP3-β 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-β 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-β 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.
authors.affiliation: Department of Medical Genetics, Second Military Medical University, No. 800 Xiang-Yin Road, Shanghai 200433, China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, Second Military Medical University, No. 800 Xiang-Yin Road, Shanghai 200433, China. Electronic address: jihangyuan@smmu.edu.cn.
authors.forename: Ji-Hang
authors.initials: JH
authors.lastname: Yuan
authors.affiliation: Department of Medical Genetics, Second Military Medical University, No. 800 Xiang-Yin Road, Shanghai 200433, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, Second Military Medical University, No. 800 Xiang-Yin Road, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Medical Genetics, Second Military Medical University, No. 800 Xiang-Yin Road, Shanghai 200433, China. Electronic address: shsun@vip.sina.com.
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; C495327:POLDIP3 protein, human; D016601:RNA-Binding Proteins
keywords: Alternative splicing; Hepatocellular carcinoma; Migration; Proliferation