Abstract
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.
Highlights
Non-small cell lung cancer (NSCLC) is the most common tumor type (~85%) in lung cancer which has a high mortality in the worldwide[1]
The expression of PPA1 in lung carcinoma patients To explore the clinical significance of PPA1 in lung carcinoma, we performed the immunohistochemical analysis to detect the expression of PPA1 with a PPA1-specific antibody in frozen primary lung carcinoma samples (n = 185, contained 62 adenocarcinoma, 93 SCC, 9 adeno acathnoma and 21 SCLC) and normal lung tissues (n = 10) (Fig. 1a)
Developing novel molecular prognosis biomarkers for predicting the prognosis and identifying the high-risk subgroup of non-small cell lung cancer (NSCLC) patients at early stage who might benefit from comprehensive therapy is urgently needed
Summary
Non-small cell lung cancer (NSCLC) is the most common tumor type (~85%) in lung cancer which has a high mortality in the worldwide[1]. As typically diagnosed at a distant stage, the 5-year survival rate of NSCLC patients are less than 15%2. Recent advances in multimodality therapy improve the clinical outcome[3], patients with NSCLC still have a high rate of relapse and will die because of cancer recurrence[4,5]. It is urgent to develop novel molecular prognosis biomarkers for predicting the prognosis and identifying the high-risk subgroup of NSCLC patients with early stage who might benefit from comprehensive therapy. PPA1 has been demonstrated to regulate neurite growth via a JNK dephosphorylation manner in mouse neuroblastoma cells[8], as well as it was proved to induce type I collagen synthesis and stimulate calcification by osteoblasts[9]. Researches indicated that PPA1 expression and activity increasing in rat and mouse livers are correlated with aging[10,11]
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