Liu Xuelei, Huang Shirui, Gu Xiaozhen, Yang Ziyi, Xiu Jiajun, Xu Xiaodan, Cao Yaxin, Wang Jingjing, Zhao Yunping, Peng Minggang, Tian Zhongxian, Hua Xiaohui, Wang Hui-Li, Huang Chuanshu
Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei, Anhui, PR China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, PR China.
J Biol Chem. 2025 Mar;301(3):108221. doi: 10.1016/j.jbc.2025.108221. Epub 2025 Jan 23.
Cigarette smoking (CS) is one of the greatest health concerns, which can cause lung cancer. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, has been well-documented for its carcinogenic activity in both epidemiological and laboratory studies. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and phosphatase and tensin homolog (PTEN) are two well-known phosphatase tumor suppressors that have been reported to be downregulated in human lung cancer tissues. However, the effect of NNK exposure on the expression of PHLPP1 and PTEN is unknown, and such effects may be early events leading to lung carcinogenesis. We explored this question in current studies and found that exposure of human bronchial epithelial BEP2D cells to NNK resulted in cell malignant transformation accompanied by a remarkable downregulation of PHLPP1 and PTEN. Such downregulation of PHLPP1 and PTEN was also consistently observed in vivo in Cigarette Smoking-exposed mouse lung tissues. Our studies further showed that overexpression of PHLPP1 or PTEN alleviated NNK-induced BEP2D cell transformation. Ectopic expression of PHLPP1 promoted PTEN protein expression, while PTEN overexpression did not affect PHLPP1 expression. Mechanistic studies showed that NNK was able to inhibit PP2A-C activity, which directly attenuated c-Jun phosphorylation at Ser63/73, and subsequently inhibited the PHLPP1 transcription and expression. Further, the downregulation of PHLPP1 led to a reduction of pten mRNA stability and expression through the HUR/Jun D/miR-613/NCL axis. Taken together, our studies advance the field of tobacco-induced lung cancer research by uncovering new mechanistic insights and identifying a novel molecular axis that could inform future therapeutic strategies. It also adds a new dimension by exploring the interaction between PHLPP1 and PTEN in the context of tobacco carcinogen exposure.
吸烟是最严重的健康问题之一，会导致肺癌。4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK）是一种烟草特有的亚硝胺，其致癌活性在流行病学和实验室研究中均有充分记录。PH结构域富含亮氨酸重复蛋白磷酸酶1（PHLPP1）和磷酸酶及张力蛋白同源物（PTEN）是两种著名的磷酸酶肿瘤抑制因子，据报道在人肺癌组织中表达下调。然而，NNK暴露对PHLPP1和PTEN表达的影响尚不清楚，这种影响可能是导致肺癌发生的早期事件。我们在当前研究中探讨了这个问题，发现将人支气管上皮BEP2D细胞暴露于NNK会导致细胞恶性转化，同时PHLPP1和PTEN显著下调。在暴露于吸烟的小鼠肺组织体内也一致观察到PHLPP1和PTEN的这种下调。我们的研究进一步表明，过表达PHLPP1或PTEN可减轻NNK诱导的BEP2D细胞转化。PHLPP1的异位表达促进了PTEN蛋白表达，而PTEN过表达不影响PHLPP1表达。机制研究表明，NNK能够抑制PP2A-C活性，直接减弱c-Jun在Ser63/73位点的磷酸化，随后抑制PHLPP1的转录和表达。此外，PHLPP1的下调通过HUR/Jun D/miR-613/NCL轴导致pten mRNA稳定性和表达降低。综上所述，我们的研究通过揭示新的机制见解和确定一个新的分子轴，为未来的治疗策略提供参考，推动了烟草诱导肺癌研究领域的发展。它还通过探索烟草致癌物暴露背景下PHLPP1和PTEN之间的相互作用增加了一个新的维度。
