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HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer
Cancer Letters ( IF 9.1 ) Pub Date : 2020-09-30 , DOI: 10.1016/j.canlet.2020.09.025
Peter Kok-Ting Wan , Thomas Ho-Yin Leung , Michelle Kwan-Yee Siu , Xuetang Mo , Hermit Wai-Man Tang , Karen Kar-Loen Chan , Annie Nga-Yin Cheung , Hextan Yuen-Sheung Ngan

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.



中文翻译:

HPV诱导的Nurr1通过ERK和AKT信号传导促进宫颈癌的癌症侵袭性,自我更新和抗辐射性

人乳头瘤病毒(HPV)是宫颈癌的病因。然而,对HPV介导的致癌作用的机制仍知之甚少。在这里,我们显示核受体相关1蛋白(Nurr1)在原发性子宫颈癌组织的球状细胞和HPV阳性细胞系中上调,而Nurr1上调与癌症等级相关。Nurr1促进细胞增殖,迁移,侵袭和锚定非依赖性细胞生长。除了其对癌症的攻击性的效果,Nurr1的增强了细胞的自我更新能力在体外体内,强调了Nurr1在维持癌症干细胞样细胞(CSLC)的干性中的重要性。从机理上讲,Nurr1独立激活了MEK / ERK和PI3K / Akt / mTOR信号级联。MEK抑制剂曲美替尼(GSK)和PI3K / mTOR双重抑制剂dactolisib(BEZ)已显示出通过上调p21和p27表达以及抑制MMP9和KLF4表达来消除Nurr1增强的肿瘤发生。我们提供了进一步的证据,证明BEZ(而不是GSK)可以消除Nurr1增强的抗辐射性,表明其在临床环境中对CSCS放射增敏的潜在价值。这项研究强调了Nurr1的空前作用,并阐明了Nurr1促进肿瘤进展和放射抵抗的机制,为宫颈癌的治疗提供了新的治疗策略。

更新日期:2020-10-30
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