Luo Dehong, Liu Daishun, Shi Wen, Jiang Huimin, Liu Wei, Zhang Xiaoyuan, Bao Yonghua, Yang Wancai, Wang Xiaojun, Zhang Chaoyang, Wang Hui, Yuan Liying, Chen Yanpei, Qu Tianyin, Ou Dong, Shen Wenzhi, Yang Shuang
The Third Affiliated Hospital of Zunyi Medical University/ First People's Hospital of Zunyi, Zunyi, 563200, China.
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Oncogenesis. 2019 Sep 24;8(10):53. doi: 10.1038/s41389-019-0162-y.
Inorganic pyrophosphatase (PPA1) promotes tumor progression in several tumor types. However, the underlying mechanism remains elusive. Here, we disclosed that PPA1 expression is markedly upregulated in lung carcinoma tissue versus normal lung tissue. We also found that the non-small cell lung cancer (NSCLC) cell lines show increased PPA1 expression levels versus normal lung cell line control. Moreover, the knockdown of PPA1 promotes cell apoptosis and inhibits cell proliferation. Whereas, the ectopic expression of PPA1 reduces cell apoptosis and enhances cell proliferation. Most interestingly, the expression of mutant PPA1 (D117A) significantly abolishes PPA1-mediated effect on cell apoptosis and proliferation. The underlying mechanism demonstrated that TP53 expression deficiency or JNK inhibitor treatment could abolish PPA1-mediated NSCLC progression. In summary, the aforementioned findings in this study suggest a new pathway the PPA1 mediates NSCLC progression either via TP53 or JNK. Most important, the pyrophosphatase activity is indispensible for PPA1-mediated NSCLC progression. This may provide a promising target for NSCLC therapy.
无机焦磷酸酶（PPA1）在多种肿瘤类型中促进肿瘤进展。然而，其潜在机制仍不清楚。在此，我们发现与正常肺组织相比，肺癌组织中PPA1表达明显上调。我们还发现，与正常肺细胞系对照相比，非小细胞肺癌（NSCLC）细胞系中PPA1表达水平增加。此外，敲低PPA1可促进细胞凋亡并抑制细胞增殖。而PPA1的异位表达可减少细胞凋亡并增强细胞增殖。最有趣的是，突变型PPA1（D117A）的表达显著消除了PPA1介导的对细胞凋亡和增殖的影响。潜在机制表明，TP53表达缺陷或JNK抑制剂处理可消除PPA1介导的NSCLC进展。总之，本研究中的上述发现提示了一条新途径，即PPA1通过TP53或JNK介导NSCLC进展。最重要的是，焦磷酸酶活性对于PPA1介导的NSCLC进展是不可或缺的。这可能为NSCLC治疗提供一个有前景的靶点。
