Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported.MethodsqRT-PCR, western blotting and immunohistochemistry were used to detect METTL13’s expression in tissues. The effects of METTL13 on ccRCC cells’ growth and metastasis were determined by both functional experiments and animal experiments. Weighted gene co-expression network analysis (WGCNA) was performed to annotate METTL13’s functions and co-immunoprecipitation (co-IP) was used to determine the interaction between METTL13 and c-Myc.ResultsMETTL13 was underexpressed in ccRCC tissues compared to normal kidney tissues and its low expression predicted poor prognosis for ccRCC patients. The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells’ proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT). The in vivo experiment demonstrated the inhibitory effect that METTL13 had on ccRCC cells’ growth and metastasis. Bioinformatic analyses showed various biological functions and pathways METTL13 was involved in. In ccRCC cells, we observed that METTL13 could negatively regulate PI3K/AKT/mTOR/HIF-1α pathway and that it combined to c-Myc and inhibited c-Myc protein expression.ConclusionsIn general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients. Meanwhile, METTL13 can inhibit growth and metastasis of ccRCC cells with participation in multiple potential molecular mechanisms. Therefore, we suggest METTL13 can be a new diagnostic and therapeutic target for ccRCC in the future.
Highlights
Clear cell renal cell carcinoma is the most common and aggressive type of renal malignancy
Low expression of Methyltransferase like 13 (METTL13) is associated with poor outcome of ccRCCDespite the oncogenic role of METTL13 in most of human cancers, The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) dataset showed that METTL13 was underexpressed at transcriptional level in Clear cell renal cell carcinoma (ccRCC) tissues (Fig. 1a, b)
By using the website UALCAN, we detected that METTL13 expression levels were significantly and negatively correlated to tumor grades and to cancer stages of ccRCC (Fig. 1c, d)
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported. A study indicated that METTL13 inhibits apoptosis of lung, breast and liver cancer cells and miR-16 can repress the expression of METTL13 by binding to its 3′-untranslated region [8]. In 2016, researchers detected high expression levels of METTL13 in the plasma of patients with breast, ovarian and lung cancer [9], following which it was identified as a recurrence predictor for breast cancer [10]. Studies targeted at METTL13 are still very scarce and unintegrated with uncertainty of its roles in various cancers; its expression and biological functions in ccRCC remain unknown, which are worth further exploration
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