title: CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition.
abstract: CUL4A, a member of the CULLIN family, functions as a scaffold protein for an E3 ubiquitin ligase. It was reported that the CUL4A gene showed amplification in some human primary hepatocellular carcinomas (HCC). However, the exact role of CUL4A in HCC remains unknown. Here, we aimed to investigate the expression and function of CUL4A in HCC development. Through immunohistochemistry study, we showed increased CUL4A expression in HCC tissues. Statistical analysis disclosed an inverse correlation between CUL4A expression and tumor differentiation grade, and patient survival, but a positive correlation with hepatocyte proliferation as well as lymphatic and venous invasion. CUL4A expression in HCC tissues was associated with HBeAg status in patients and upregulated by HBV in HCC cell lines. Further functional assay showed that CUL4A overexpression significantly promoted growth of H22 tumor homografts in BALB/c mice. Consistently, CUL4A knockdown inhibited the proliferation of established HCC cells, accompanied by S-phase reduction and Cyclin A and Cyclin B1 repression. Furthermore, CUL4A siRNA ameliorated the motility of HCC cell lines with altered expression of epithelial-mesenchymal transition (EMT)-associated molecules. Taken together, our findings indicate that CUL4A plays a pivotal role in HCC progression and may serve as a potential marker for clinical diagnosis and target for therapy.
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.|Blood Group Reference &Research Laboratory, Shandong Blood Center, Jinan 250014, PR China.
authors.forename: Yingfang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, PR China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Blood Group Reference &Research Laboratory, Shandong Blood Center, Jinan 250014, PR China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan 250012, PR China.
authors.forename: Xueen
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Gao
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liang
mesh_terms: D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: C534699:CCNB1 protein, human; C114234:CUL4A protein, human; D044842:Cullin Proteins; D019925:Cyclin A; D056744:Cyclin B1; D034741:RNA, Small Interfering