The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma

We aimed to study the role of METTL3 in renal cell carcinoma (RCC) carcinogenesis and development. Immunohistochemistry was performed in clinical tissue microarray. Expression level of METTL3 in RCC tissues and cell lines was evaluated by quantitative real-time PCR (qRT-PCR) and western blot. Then, the effects of METTL3 on proliferation, migration, invasion and cell cycle were studied in RCC cells. Additionally, in vivo study was carried out in nude mice. Negative METTL3 expression was associated with larger tumor size (P=0.010) and higher histological grade (P=0.021). Moreover, RCC patients with positive METTL3 expression had an obvious longer survival time (P=0.039). METTL3 mRNA and protein expression was lower in RCC samples compared with adjacent non-tumor samples, and lower in RCC cell lines (CAKI-1, CAKI-2 and ACHN) compared with HK-2. Afterwards, knockdown of METTL3 could obviously promote cell proliferation, migration and invasion function, and induce G0/G1 arrest. In contrast, up-regulation of METTL3 could inhibit such functions and reduce G0/G1 arrest. Additionally, up-regulation of METTL3 significantly suppressed tumor growth in vivo. Furthermore, significant changes in epithelial-to-mesenchymal transition (EMT) and PI3K-Akt-mTOR pathways were observed. Overall, our findings demonstrated that METTL3 might have a carcinostasis role in cell proliferation, migration, invasion function and cell cycle of RCC, indicating METTL3 may act as a novel marker for tumorigenesis, development and survival of RCC.

Oncotarget. 2017 Oct 10*** epublish ***

Xiao Li, Jingyuan Tang, Wen Huang, Feng Wang, Pu Li, Chao Qin, Zhiqiang Qin, Qing Zou, Jifu Wei, Lixin Hua, Haiwei Yang, Zengjun Wang

State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China., Research Division of Clinical Pharmacology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China., Department of Urology, Affiliated Cancer Hospital of Jiangsu Province of Nanjing Medical University, Nanjing 210009, China.