Abstract
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.
Highlights
Renal cell carcinoma (RCC) is currently the 9th most common cancer in men and 14th most common in women worldwide [1]
We aimed to study the role of METTL3 in renal cell carcinoma (RCC) carcinogenesis and development
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
Summary
Renal cell carcinoma (RCC) is currently the 9th most common cancer in men and 14th most common in women worldwide [1]. The mortality of RCC has continuously increased by approximately 1.5-5.9% every year [2]. About 25% of patients are diagnosed with locally advanced or metastatic disease at first. 20-40% patients of local RCC with history of surgical resection will develop metastatic RCC subsequently [3, www.impactjournals.com/oncotarget. RCC is unique in that it is relatively resistant to radiotherapy and does not respond to standard chemotherapy [5, 6]. Though cytokine therapy and molecular targeting therapy have been applied for RCC, the therapeutic effects of these are limited with a short interval [7]. The overall survival of RCC remains poor. The detailed molecular mechanism underlying the RCC carcinogenesis requires to be fully clarified [8]
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