Title: Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Abstract

Abstract Objectives N6‐methyladenosine (m6A) is a ubiquitous epigenetic RNA modification that plays a pivotal role in tumour development and metastasis. In this study, we aimed to investigate the expression profiling, clinical significance, biological function and the regulation of m6A‐related genes in hepatoblastoma (HB). Materials and Methods The mRNA and protein expression levels of m6A‐related genes were analysed using Gene Expression Omnibus (GEO) and tissue microarray (TMA) cohort. Kaplan‐Meier analysis was performed to evaluate the prognostic value of m6A‐related genes in HB. Knockdown of m6A‐related genes was conducted to analyse its function on cell proliferation, migration and invasion. Furthermore, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signalling pathway. Results We found that most m6A‐related genes were significantly upregulated in HB tumour tissues. High levels of methyltransferase‐like 3 (METTL3, P  = .013), YTHDF2 ( P  = .037) and FTO ( P  = .032) indicated poor clinical outcomes, and the upregulation of METTL3 was an independent prognostic factor in HB patients. Functional assays showed that knockdown of METTL3 could dramatically suppress the proliferation, migration and invasion of HB cells. In addition, METTL3 was identified to be a direct target of microRNA‐186 (miR‐186). Consistently, miR‐186 was low expressed in HBmore » tumour tissues. Moreover, overexpression of miR‐186 significantly inhibited cell aggressive phenotype both in vitro and in vivo, while the inhibitory effect could be reversed by METTL3 overexpression. Mechanism study indicated that miR‐186/METTL3 axis contributed to the progression of HB via the Wnt/β‐catenin signalling pathway. Conclusions M6A‐related genes were frequently dysregulated in HB. miR‐186/METTL3/Wnt/β‐catenin axis might serve as novel therapeutic targets and prognostic biomarkers in HB.« less

Authors:

Cui, Xichun ^[1]; Wang, Zhifang ^[2]; Li, Jianhao ^[3]; Zhu, Jianming ^[3]; Ren, Zhigang ^[3]; Zhang, Dandan ^[4]; Zhao, Wei ^[1]; Fan, Yingzhong ^[1]; Zhang, Da ^[1]; Sun, Ranran  ^[3]

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+ Show Author Affiliations

1. Pediatric Surgery Department The First Affiliated Hospital of Zhengzhou University Zhengzhou China
2. Endocrinology Department The First Affiliated Hospital of Zhengzhou University Zhengzhou China
3. Precision Medicine Center The First Affiliated Hospital of Zhengzhou University Zhengzhou China
4. Pathology Department The First Affiliated Hospital of Zhengzhou University Zhengzhou China

Publication Date:

Wed Jan 22 00:00:00 EST 2020

Sponsoring Org.:

USDOE

OSTI Identifier:

1593197

Alternate Identifier(s):

OSTI ID: 1593199

Resource Type:

Published Article

Journal Name:

Cell Proliferation

Additional Journal Information:

Journal Name: Cell Proliferation Journal Volume: 53 Journal Issue: 3; Journal ID: ISSN 0960-7722

Publisher:

Wiley-Blackwell

Country of Publication:

United Kingdom

Language:

English