IGF2BP2 Regulates MALAT1 by Serving as an N6-Methyladenosine Reader to Promote NSCLC Proliferation.

Le Han,Wenjuan Chen,Chen Huang,Zhenghong Chen,Yili Zhang,Guangyan Lei

doi:10.3389/fmolb.2021.780089

Abstract

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is an important posttranscriptional regulatory for stability and m6A modification. Here, we investigated the role of IGF2BP2 in non–small-cell lung cancer (NSCLC) proliferation. TCGA database was used to predict the expression and clinical significance of IGF2BP2 in normal and NSCLC samples. The expression of IGF2BP2 was further validated in NSCLC samples from surgery. Then we performed the functional study in NSCLC cell lines through overexpressing and knocking down IGF2BP2 in NSCLC cell lines in vitro and in vivo. The mechanism of interaction between IGF2BP2 and lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in NSCLC proliferation was determined by RIP assay. We demonstrated that IGF2BP2 is highly expressed in NSCLC and positively associated with poor overall survival (OS) and disease-free survival (DFS). We identified that lncRNA MALAT1 is a target of IGF2BP2 in NSCLC. IGF2BP2 promotes MALAT1 stability in an m6A-dependent mechanism, thus promoting its downstream target autophagy-related (ATG)12 expression and NSCLC proliferation.

Highlights

Lung cancer is one of the most diagnosed cancers with high morbidity and mortality in most countries (Bray et al, 2018)
Because insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) usually functions as a key regulator of IncRNAs, we speculate whether lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) can be regulated by IGF2BP2
We showed that high expression of IGF2BP2 in Non–small-cell lung cancer (NSCLC) is correlated with unsatisfied overall survival (OS) and disease-free survival (DFS). lncRNA MALAT1 is a direct target of IGF2BP2 in NSCLC

Summary

Introduction

Lung cancer is one of the most diagnosed cancers with high morbidity and mortality in most countries (Bray et al, 2018). IGF2BP2 Promotes NSCLC Proliferation (Hirsch et al, 2017; Jones and Baldwin, 2018). IGF2BP2 is a distinct m6A reader that targets lots of mRNA transcripts, promoting the stability and storage of target mRNAs in carcinogenesis. IGF2BP2 promotes liver cancer proliferation in an N6methyladenosine (m6A)-FEN1-dependent manner (Pu et al, 2020). METTL3 facilitates colorectal carcinoma progression in an m6A-IGF2BP2-dependent way (Li et al, 2019). Recent advances unveiled that IGF2BP2 is a major player in NSCLC progression. CircNDUFB2 inhibits NSCLC progression via destabilizing IGF2BPs and activating antitumor immunity (Li B. et al, 2021). It remains largely unclear how IGF2BP2 can regulate NSCLC progression

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