Wang Ping, Zhou Yi, Mei Qi, Zhao Jing, Huang Liu, Fu Qiang
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Department of Oncology, Huanggang Central Hospital, Huanggang, Hubei, 438000, China.
Oncotarget. 2017 Apr 24;8(35):58611-58624. doi: 10.18632/oncotarget.17381. eCollection 2017 Aug 29.
Colorectal cancer (CRC) represents one of the most prevalent malignancies and the third leading cause of cancer death worldwide. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate to inorganic phosphate, therefore participates in the energy metabolism. Proteomic studies have demonstrated the up-regulated expression of PPA1 in various tumors, however, its expression pattern in CRC hasn't been reported. In the current study, we used RT-qCR, Western Blot and immunohistochemical (IHC) staining to explore the expression of PPA1 in 113 paired colon cancer tissues and adjacent normal tissues, which revealed that PPA1 was correlated with lymph node metastasis. The prognostic value of PPA1 was confirmed by Kaplan-Meier survival analysis and Cox regression analysis. We further purified PPA1 and obtained the phosphor-JNK1 protein and performed enzymatic studies, which identified that PPA1 can directly dephosphorylate pJNK1, while showed no catalytic activity towards pERK or p-p38 proteins. Moreover, overexpression of PPA1 enhanced cell viability through JNK-p53 signaling pathways, and it may also prevent cell apoptosis by inhibiting Bcl-2 and Caspase-3 cleavage. To our knowledge, this is the first study demonstrated the expression and clinical significance of PPA1 in colon cancer, which also provided evidence that figuring out PPA1 specific inhibitors can be invaluable in the future chemotherapy development towards colon cancer.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，也是癌症死亡的第三大主要原因。无机焦磷酸酶（PPA1）是一种催化焦磷酸水解为无机磷酸的酶，因此参与能量代谢。蛋白质组学研究表明PPA1在各种肿瘤中表达上调，然而，其在结直肠癌中的表达模式尚未见报道。在本研究中，我们使用逆转录定量聚合酶链反应（RT-qCR）、蛋白质免疫印迹法（Western Blot）和免疫组织化学（IHC）染色来探究PPA1在113对结肠癌组织和相邻正常组织中的表达，结果显示PPA1与淋巴结转移相关。通过Kaplan-Meier生存分析和Cox回归分析证实了PPA1的预后价值。我们进一步纯化了PPA1并获得了磷酸化JNK1蛋白并进行了酶学研究，结果确定PPA1可以直接使pJNK1去磷酸化，而对pERK或p-p38蛋白没有催化活性。此外，PPA1的过表达通过JNK-p53信号通路增强了细胞活力，并且它还可能通过抑制Bcl-2和Caspase-3的裂解来防止细胞凋亡。据我们所知，这是第一项证明PPA1在结肠癌中的表达及其临床意义的研究，该研究还提供了证据，表明开发PPA1特异性抑制剂在未来结肠癌化疗发展中可能具有重要价值。
