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.

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

“…In the search for markers of PA aggressiveness, many biological molecules have been investigated, including growth factors and their receptors, angiogenic factors, matrix metalloproteinases, miRNAs, and many others, but none of them has gained wide acceptance and use (9,17,18,19,47). Ki-67 LIO3% has been proposed by the 2004 WHO classification as a marker of atypical adenomas, along with the presence of mitoses and p53 nuclear labeling, although its effectiveness is far from being universally accepted (3,6,9,12,13,15,17,19).…”

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

“…Multiple molecular dysfunctions are associated with GBM formation and growth, such as EGFR, TGF-b1, VEGF, p53, pRb, p21, p27, p16, p19, and telomerase [20][21][22][23][24][25][26]. Considerable effort has been made to determine the underlying mechanisms of gliomagenesis, but an effective therapy has not been established and patients diagnosed with GBM have a median survival of only 12-15 months [27,28]. In the present manuscript, we identified KDM5B as a candidate target gene for glioma growth.…”

Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells

“…27 Mechanistically, CUL4A modulates the expression of p53, p27, and Bcl-2 in pituitary tumor cells. 10,11 Similarly, we found that knockdown of CUL4A downregulated the expression of MMP-2 and upregulated the expression of p27 and p53 in OS cells, suggesting that CUL4A might be involved in the development of OS cells via regulation of the expression of p27, p53, and MMP-2.…”

“…[10][11][12] In addition, CUL4A induces tumorigenesis of skin cancer by inhibition of DNA repair and accelerating S phase entry, 13 and results in inactivation of RASSF1A and promoting cell cycle progression, 14 suggesting that CUL4A may play a critical role in regulation of some biological processes. 15 Up to now, few studies report the link between CUL4A expression and OS.…”