PARK2 Suppresses Proliferation and Tumorigenicity in Non-small Cell Lung Cancer
PARK2 Suppresses Proliferation and Tumorigenicity in Non-small Cell Lung Cancer
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PARK2 抑制非小细胞肺癌的增殖和致瘤性
DOI：
10.3389/fonc.2019.00790
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发表时间：
2019-08-23
影响因子：
4.7
通讯作者：
Zhang, Suzhan
中科院分区：
文献类型：
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作者：
Duan, Huijie;Lei, Zhong;Zhang, Suzhan
目的：PARK2突变最初与帕金森病的进展有关。近年来，PARK2被报道为多种癌症（包括肺癌）的肿瘤抑制基因。然而，PARK2在非小细胞肺癌（NSCLC）中的生物学功能和潜在的分子机制尚不清楚。方法：采用Western blot法检测32例非小细胞肺癌组织样本及匹配的非肿瘤肺组织中PARK2的表达水平，采用免疫组化法检测64例非小细胞肺癌组织样本中PARK2的表达水平。用H1299和H460细胞株建立PARK2过表达模型，用H460细胞株建立PARK2敲低模型。通过细胞活力、集落形成、细胞周期、细胞凋亡、迁移和侵袭等实验，评估了PARK2的生物学功能，并探讨了PARK2在体外的潜在分子机制。同时，选取22只裸鼠进行体内实验。结果：Western blot分析显示，人NSCLC样品中PARK2蛋白表达降低。免疫组织化学还发现，在NSCLC中，PARK2的表达大幅降低（72%），并且PARK2的低表达与肿瘤组织学分级、淋巴结转移和TNM分期显著相关。在体外实验中，人类非小细胞系H1299和H460中，过表达PARK2抑制细胞增殖、集落形成、迁移和侵袭，阻止细胞周期在G1期的进展，并诱导细胞凋亡。同时，敲低PARK2具有相反的生物学功能。此外，PARK2显著降低皮下异种移植瘤模型中的肿瘤体积，降低转移瘤的发生率。对PARK2在NSCLC中的分子机制的探索表明，PARK2负调控EGFR/AKT/mTOR信号通路。结论：PARK2是NSCLC中重要的抑癌因子，可能通过下调EGFR/AKT/mTOR信号通路抑制肿瘤生长和转移。
Aims: PARK2 mutation is originally associated with the progression of Parkinson's disease. In recent years, PARK2 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. Methods: 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 PARK2 overexpression models, and H460 cell line was also used to PARK2 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 in vitro. Meanwhile, 22 nude mice were employed for in vivo studies. Results: 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 PARK2 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 in vitro. Meanwhile, knockdown of PARK2 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. Conclusions: PARK2 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.