Duan Huijie, Lei Zhong, Xu Fei, Pan Tao, Lu Demin, Ding Peili, Zhu Chunpeng, Pan Chi, Zhang Suzhan
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, School of Medicine, Cancer Institute, Zhejiang University, Hangzhou, China.
Front Oncol. 2019 Aug 23;9:790. doi: 10.3389/fonc.2019.00790. eCollection 2019.
mutation is originally associated with the progression of Parkinson's disease. In recent years, has been reported as a tumor suppressor gene in various cancers, including lung cancer. However, the biological functions and potential molecular mechanisms of PARK2 in non-small cell lung cancer (NSCLC) are still unclear. The level of PARK2 expression in 32 tissue samples of NSCLC and matched non-tumor lung tissues was detected by Western blot, and 64 specimens of NSCLC tissues were detected by immunohistochemistry. H1299 and H460 cell lines were used to overexpression models, and H460 cell line was also used to knockdown model. Using cell viability, colony formation, cell cycle, apoptosis, migration, and invasion assay, the biological functions of PARK2 were evaluated and the potential molecular mechanism of PARK2 was investigated . Meanwhile, 22 nude mice were employed for studies. Western blot analysis revealed a decrease of PARK2 protein expression in human NSCLC samples. Immunohistochemistry also identified a vastly reduced expression of PARK2 in NSCLC (72%) and low PARK2 expression was significantly associated with tumor histological grade, lymph node metastasis and advanced TNM stage. Overexpression of suppressed cell proliferation, colony formation, migration, and invasion, arrested cell cycle progression in the G1 phase, and induced apoptosis in human non-small cell lines H1299 and H460 . Meanwhile, knockdown of had the opposite biological functions. In addition, PARK2 significantly decreased the tumor volumes in subcutaneous xenograft model and reduced the incidence of metastatic tumors in the transfer model. Exploration of the molecular mechanism of PARK2 in NSCLC showed that PARK2 negatively regulated the EGFR/AKT/mTOR signaling pathway. was an important tumor suppressor in NSCLC, which might inhibit cancer growth and metastases through the down regulation of the EGFR/AKT/mTOR signaling pathway.
突变最初与帕金森病的进展相关。近年来，已报道其在包括肺癌在内的多种癌症中作为肿瘤抑制基因。然而，PARK2在非小细胞肺癌（NSCLC）中的生物学功能和潜在分子机制仍不清楚。通过蛋白质印迹法检测了32例NSCLC组织样本及配对的非肿瘤肺组织中PARK2的表达水平，并通过免疫组织化学检测了64例NSCLC组织标本。使用H1299和H460细胞系构建过表达模型，同时使用H460细胞系构建敲低模型。通过细胞活力、集落形成、细胞周期、凋亡、迁移和侵袭实验，评估了PARK2的生物学功能并研究了其潜在分子机制。同时，使用22只裸鼠进行体内研究。蛋白质印迹分析显示人NSCLC样本中PARK2蛋白表达降低。免疫组织化学也证实NSCLC中PARK2表达大幅降低（72%），且PARK2低表达与肿瘤组织学分级、淋巴结转移及晚期TNM分期显著相关。PARK2过表达抑制了人非小细胞系H1299和H460的细胞增殖、集落形成、迁移和侵袭，使细胞周期停滞于G1期，并诱导细胞凋亡。同时，PARK2敲低具有相反的生物学功能。此外，PARK2在皮下异种移植模型中显著减小了肿瘤体积，并在转移模型中降低了转移瘤的发生率。对PARK2在NSCLC中的分子机制研究表明，PARK2负向调节EGFR/AKT/mTOR信号通路。PARK2是NSCLC中的重要肿瘤抑制因子，可能通过下调EGFR/AKT/mTOR信号通路抑制癌症生长和转移。
