HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer. (28th January 2021)

• Record Type: Journal Article
• Authors: Wan, Peter Kok-Ting; Leung, Thomas Ho-Yin; Siu, Michelle Kwan-Yee; Mo, Xue-Tang; Tang, Hermit Wai-Man; Chan, Karen Kar-Loen; Cheung, Annie Nga-Yin; Ngan, Hextan Yuen-Sheung
• Is Part Of: Cancer letters. Volume 497(2021)
• Page Start: 14
• Page End: 27
• Publication Date: 2021-01-28
• Subjects: Nurr1 -- HPV -- Cancer aggressiveness -- Self-renewal -- Radioresistance -- Cervical cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.09.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment. Highlights: Nurr1 is upregulated in HPV-positive cervical cancer and primary tumor-derived spheroids. Nurr1 promotes proliferation, invasion, self-renewal and radioresistance. Nurr1 independently activates MEK/ERK and PI3K/Akt/mTOR signaling. Trametinib and dactolisib abrogate Nurr1-mediated tumorigenesis.