N6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1.

Duo Wang,Yue Jin,Ce Li,Jiawen Xiao,Kezuo Hou,Bowen Yang,Wenqing Lu,Xiujuan Qu,Yizhe Wang,Xiaofang Che,Jianfei Qi,Yunpeng Liu

doi:10.3389/fonc.2021.681280

Abstract

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

Highlights

Gastric cancer (GC) is the fifth most prevalent malignant cancer and the third leading cause of tumor-related mortality worldwide [1]
The results of multivariate Cox regression analysis showed that the high expression of fat mass and obesity-associated protein (FTO) (HR=1.82, P=0.010, 95% CI: 1.15-2.87), lymph node metastasis (HR=1.32, P
By systematically analyzing all 33 known m6A regulators, we identified that FTO acted as a key prognostic risk factor in gastric cancer (GC)

Summary

Introduction

Gastric cancer (GC) is the fifth most prevalent malignant cancer and the third leading cause of tumor-related mortality worldwide [1]. Significant progress has been made over the past few decades, overall survival (OS) of GC is still poor. The rate of five-year survival for patients diagnosed with distant-metastasis disease remains less than 5% [2]. It is vital to diagnose those patients with advanced GC as early as possible. A great deal of biomarkers have been developed to predict treatment efficacy, few could be used for clinical application. It remains essential to identify more specific biomarkers to improve early diagnosis of GC

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Results

Conclusion