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Abstract

Volume 25, Issue 2 (March 2023) 25, 198–207; 10.4103/aja202240

Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity

Jian Huang1, Wang Liu2, Bi-Yun Lin1, Jean C Li2, Jane Lu2, Ben-Yi Li2

1 Center for Pathological Diagnosis and Research, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
2 Department of Urology, The University of Kansas Medical Center, Kansas City, KS 66160, USA

Correspondence: Dr. BY Li (bli@kumc.edu) or Dr. J Huang (18665763598@163.com)

Received: 28 February 2022; Accepted: 02 June 2022; published online: 12 August 2022

Abstract

Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.

Keywords: cell cycle regulation; disease progression; mitogen-activated protein kinase-8-interacting protein 2; patient survival; prostate cancer

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Asian Journal of Andrology CN 31-1795/R ISSN 1008-682X  Copyright © 2023  Shanghai Materia Medica, Chinese Academy of Sciences.  All rights reserved.