NME4 promotes cell malignant process by targeting SMAD2 in colorectal cancer

Nucleoside diphosphate kinase 4 (NME4) is aberrantly expressed in several cancer types. However, the function of NME4 in colorectal cancer (CRC) remains to be elucidated. Bioinformatic analysis and clinical sample collection revealed that NME4 was highly expressed in CRC tissues and positively correlated with stage and tumor size. Knockdown of NME4 expression inhibited the proliferation and migration of CRC cells and promoted apoptosis. Moreover, NME4 inhibition in vivo markedly suppressed the size and weight of tumors. Then, cDNA microarray and Ingenuity Pathway Analysis (IPA) analysis were applied to identify SMAD2 and mTOR signaling pathways as downstream targets of NME4. And it was confirmed that SMAD2 was significantly reduced in CRC tissues and significantly correlated with AJCC staging and positive numbers. Furthermore, overexpression of NME4 resulted in a substantial increase in SMAD2 expression. NME4 overexpression promoted cell proliferation and migration, whereas knockdown of SMAD2 greatly reversed its effects. Together, these results suggested that NME4 may act as a novel tumor-promoting factor that promotes CRC progression by regulating SMAD2 and mTOR signaling pathways.