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METTL13 inhibits progression of clear cell renal cell carcinoma with repression on PI3K/AKT/mTOR/HIF-1α pathway and

Zhuonan Liu¹, Tianshui Sun², Chiyuan Piao¹

¹Department of Urology, First Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, 110004, Liaoning Province, People's Republic of China.

Journal of Translational Medicine

|May 14, 2021

Abstract

Background:

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.

Methods:

qRT-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.

Results:

METTL13 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.

Conclusions:

In 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.

Insights

Methyltransferase like 13 (METTL13) is underexpressed in clear cell renal cell carcinoma (ccRCC), inhibiting tumor growth and metastasis. METTL13 represents a potential diagnostic and therapeutic target for ccRCC patients.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Clear cell renal cell carcinoma (ccRCC) is an aggressive malignancy.
The role of Methyltransferase like 13 (METTL13) in ccRCC is currently unknown.
METTL13 is implicated as an oncogene in various human cancers.

Purpose of the Study:

To investigate the expression and function of METTL13 in ccRCC.
To determine the prognostic value of METTL13 in ccRCC.
To elucidate the molecular mechanisms underlying METTL13's role in ccRCC.

Main Methods:

Quantitative reverse transcription PCR (qRT-PCR), western blotting, and immunohistochemistry were used to assess METTL13 expression.
In vitro and in vivo experiments evaluated the impact of METTL13 on ccRCC cell proliferation, migration, and metastasis.
Weighted gene co-expression network analysis (WGCNA) and co-immunoprecipitation (co-IP) were employed to identify METTL13-interacting proteins and pathways.

Main Results:

METTL13 was significantly underexpressed in ccRCC tissues compared to normal kidney tissues.
Low METTL13 expression correlated with poor prognosis in ccRCC patients.
METTL13 knockdown promoted ccRCC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), while overexpression inhibited these processes.
METTL13 negatively regulated the PI3K/AKT/mTOR/HIF-1α pathway and inhibited c-Myc protein expression.
In vivo studies confirmed METTL13's inhibitory effect on ccRCC tumor growth and metastasis.

Conclusions:

High METTL13 expression is associated with favorable prognosis in ccRCC.
METTL13 functions as a tumor suppressor in ccRCC by inhibiting cell growth and metastasis through multiple molecular mechanisms.
METTL13 holds promise as a novel diagnostic and therapeutic target for ccRCC.

Read full analysis

Keywords:

C-Myc Clear cell renal cell carcinoma Epithelial-mesenchymal transition HIF-1α Invasion METTL13 Migration Proliferation

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