title: CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation.
abstract: Cullin 4A (CUL4A) encodes a core subunit of an E3 ubiquitin ligase that targets proteins for ubiquitin-mediated degradation, and aberrant expression of the CUL4A is found in many tumor types. However, its roles and clinicopathologic significance in pituitary adenomas are not clear. The aim of this study was to investigate the possible role of CUL4A in pituitary tumorigenesis. Immunohistochemistry was used to examine CUL4A expression in human normal pituitaries and pituitary tumors with respect to various clinicopathologic factors in pituitary adenomas. Cell proliferation was assessed by MTT and colony formation, and migration and invasion were analyzed by Transwell and Matrigel assays after CUL4A overexpression or knockdown in pituitary tumor cells. Overexpression of CUL4A was frequently observed in pituitary adenomas compared with normal adenohypophysial tissue and significantly associated with tumor progressiveness and invasion. CUL4A overexpression in GH3 adenoma cells increased colony numbers, cell viability and cell invasion and silencing CUL4A in AtT20 adenoma cells decreased cell proliferation, migration and invasion. Mechanistically, CUL4A could modulate the expression of p53, p21, and p27 in pituitary tumor cells. In addition, high levels of CUL4A expression also significantly inversely correlated with the p53 protein level in human pituitary adenomas. Our results indicate that CUL4A enhances pituitary cell proliferation, migration and invasion and may thus contribute to pituitary tumor development and progression.
authors.affiliation: Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Xu
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
authors.forename: Guangxin
authors.initials: G
authors.lastname: Ma
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
mesh_terms: D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D013006:Growth Hormone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D011388:Prolactin / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone