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

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 HB 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.

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

“…As the most common pediatric liver cancer, hepatoblastoma (HB) has also been reported to have aberrant m 6 A modification [60,81]. Liu et al found that METTL3 was significantly upregulated in HB, inducing enhanced m 6 A modification across the whole transcriptome.…”

SPATS2, negatively regulated by miR-145-5p, promotes hepatocellular carcinoma progression through regulating cell cycle

“…Emerging evidence has widely confirmed the critical role of miRNAs in tumorigenesis. MiRNAs could promote carcinogenesis through targeting tumor suppressor genes or inhibit tumor development by suppressing oncogenes [12][13][14][15][16] . MiR-145-5p has been characterized as a tumor suppressor in gastric cancer 17 , colorectal cancer 18 , breast cancer 19 , and bladder cancer 20 .…”

The prognostic value of METTL3 in cancer patients: a meta-analysis

“…METTL3 was considered to be a methyltransferase, part of the methyltransferase complex, and was responsible for the m6A modi cation [27,53].METTL3 was involved in many signal pathways such as PI3K / Akt [31,[54][55][56][57][58], MAPK [22] ,Wnt /beta-Catenin [47,59,60] and p38 / ERK [61]pathways,which were all associated with tumor deterioration. In addition, METTL3 could in uence the development of tumor by regulating some transcription factors or important oncogenes.Studies had found that METTL3 could positively regulate the expression of oncogene EZH2 [24,25,62].It promoted the expression of MYC as well as increased stability of protein by regulating the m6A methylation of MYC mRNA to lead to carcinogenesis in PCA and gastric cancer, promote the occurrence of OSCC tumor and affect the growth and invasion of BCA cells [40,[63][64][65][66].When METTL3 was silenced, it inhibited the activity of the Wnt pathway by reducing the m6A methylation level of LEF1 mRNA and reducing protein expression [59,67].…”

“…The studies were screened according to the following procedure [19,[39][40][41][42][43][44][45][46][47][48] (Fig. 1).At rst We retrieved a total of 349 articles from the online database.After preliminary screening and duplicate checking, 253 articles were retained.Through reading the title and abstract of the articles, the articles were further screened.Studies of 207 related to METTL3 expression and cancer prognosis were excluded according to exclusion criteria.…”