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Tumor Biology

, Volume 36, Issue 3, pp 1721–1729

First Online: 18 December 2014Received: 04 August 2014Accepted: 23 October 2014

Abstract

In non-small cell lung cancer NSCLC, both USP7 expression and p53 gene status were reported to be an indicator of poor prognosis in adenocarcinoma patients; however, its roles and mechanisms in lung squamous cell carcinoma and large cell carcinoma need to be clarified. The USP7 expression was examined in NSCLC tumors excluding adenocarcinoma, their corresponding non-tumorous tissues, and NSCLC cells. Then, the prognostic role of USP7 was analyzed in 110 NSCLC samples excluding the adenocarcinoma. Finally, the roles and mechanisms of USP7 in the proliferation, metastasis, and invasion of a NSCLC cell were assessed using a specific vshRNA. The USP7 expression was higher in NSCLC tissues compared to non-tumorous samples, accordingly, the high level of USP7 was detected in NSCLC cell lines compared with HBE cell. After the USP7 downregulation, the H460 cells exhibited decreased metastasis-invasion in vitro and in vivo. The preliminary mechanism study indicated overexpression of USP7 might regulate the p53-MDM2 pathway by inducing the MDM2 de-ubiquitination and subsequent stabilization, which resulted in the upregulation of the Bad phosphorylation. Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability. Clinically, USP7 overexpression significantly correlated with malignant phenotype. Furthermore, the 5-year overall survival in patients with USP7 was higher than that of USP7. Multivariate analysis showed USP7 overexpression was an independent prognostic marker for these cancers. USP7 overexpression may regulate the survival and invasive properties of squamous cell carcinoma and large cell carcinoma cells, and may serve as a molecular target.

KeywordsLung cancer USP7 Prognosis Apoptosis AbbreviationsNSCLCNon-small cell lung cancer

qRT-PCRQuantitative real-time polymerase chain reaction

MDM2Murine double minute

HSV1Herpes simplex virus type 1

EBNA1Epstein-Barr nuclear antigen 1

DMEMDulbecco Modified Eagle medium

TNMTumor-lymph node-metastasis

OSOverall survival

TMATissue microarray

EMTEpithelial-mesenchymal transition

Guang-Yin Zhao and Zong-Wu Lin contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1007-s13277-014-2773-4 contains supplementary material, which is available to authorized users.

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Autor: Guang-Yin Zhao - Zong-Wu Lin - Chun-Lai Lu - Jie Gu - Yun-Feng Yuan - Feng-Kai Xu - Rong-Hua Liu - Di Ge - Jian-Yong Ding

Fuente: https://link.springer.com/article/10.1007/s13277-014-2773-4







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