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CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation

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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.

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Acknowledgments

This work was supported by National Natural Science Foundation of China No. 81172528, 31271461, Doctoral Fund of Ministry of Education of China No. 20110131110035, Natural Science Foundation of Shandong Province No. ZR2011HM034 and Taishan Scholar Program of Shandong Province (GW).

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None of the authors has any conflict of interest associated with the present work.

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Authors and Affiliations

  1. 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

    Yangyang Xu, Yunshan Wang, Guangxin Ma & Guangwei Wei

  2. International Biotechnology R&D Center, Shandong University School of Ocean, 180 Wenhua Xi Road, Weihai, 264209, Shandong, China

    Yunshan Wang

  3. Department of Respiratory Medicine, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China

    Qin Wang

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  1. Yangyang Xu
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  2. Yunshan Wang
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  3. Guangxin Ma
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  4. Qin Wang
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  5. Guangwei Wei
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Correspondence to Guangwei Wei.

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Yangyang Xu and Yunshan Wang are joint first authors.

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Xu, Y., Wang, Y., Ma, G. et al. CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation. J Neurooncol 116, 625–632 (2014). https://doi.org/10.1007/s11060-013-1349-2

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  • DOI: https://doi.org/10.1007/s11060-013-1349-2

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