Aberrant expression of m6A mRNA methylation regulators in colorectal adenoma and adenocarcinoma

Dayu Kuai; Shengtao Zhu; Haiyun Shi; Ruichuang Yang; Tong Liu; Hui Liu; Li Min; Shutian Zhang

doi:10.1016/j.lfs.2021.119258

Aberrant expression of m⁶A mRNA methylation regulators in colorectal adenoma and adenocarcinoma

Life Sci. 2021 May 15:273:119258. doi: 10.1016/j.lfs.2021.119258. Epub 2021 Feb 23.

Authors

Dayu Kuai¹, Shengtao Zhu², Haiyun Shi², Ruichuang Yang³, Tong Liu⁴, Hui Liu⁴, Li Min⁵, Shutian Zhang⁶

Affiliations

¹ Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China; Department of Gastroenterology, Beijing Luhe Hospital, Capital Medical University, 101149, PR China.
² Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China.
³ Clinical Research Management Center, The Fifth Medical Center of PLA General Hospital, Beijing 100039, PR China.
⁴ Department of Pathology, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, PR China.
⁵ Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China. Electronic address: minli@ccmu.edu.cn.
⁶ Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China. Electronic address: zhangshutian@ccmu.edu.cn.

PMID: 33636176
DOI: 10.1016/j.lfs.2021.119258

Abstract

Background: As the most prevalent post-transcriptional mRNA modification in eukaryotes, N6-Methyladenosine (m⁶A) is closely linked to the occurrence and development of colorectal cancer (CRC). However, there is no systematic evaluation of the expression of m⁶A regulatory genes in CRC.

Methods: By analyzing the TCGA database, we identified METTL3, YTHDF1, IGF2BP1, IGF2BP3, EIF3B, HNRNPA2B1 as overexpressed m⁶A regulators in CRC. After verification by immunohistochemistry (IHC) in 10 CRC cases, YTHDF1, IGF2BP1, IGF2BP3, and EIF3B were identified as potential biomarkers in CRC. Further validation was done by IHC and qRT-PCR in two larger cohorts.

Results: We identified 6 up-regulated m⁶A regulatory genes in CRC in TCGA analysis, and verified that YTHDF1, IGF2BP1, IGF2BP3, and EIFB3 were all significantly differentially expressed between CRC and normal tissues by IHC (p < 0.0001). In another larger cohort, we further validated the overexpression of those genes in CRC as compared to both normal tissues (p < 0.0001) and adenoma tissues (p < 0.05). Detailed analysis suggested that detection of one of the three genes, YTHDF1, IGF2BP1 and IGF2BP3, and combined detection of EIF3B gene could be a good strategy for early diagnosis of both CRC and precancerous lesions. Furthermore, we found that the mRNA levels of YTHDF1, IGF2BP1, and IGF2BP3 were also significantly up-regulated in CRC but not adenoma as compared to normal tissues.

Conclusion: We evaluted the abnormal expression of m⁶A regulatory genes during CRC carcinogenesis, and identified four m⁶A genes (YTHDF1, IGF2BP1, IGF2BP3, and EIF3B) as potential biomarkers of both CRC and adenoma.

Keywords: Biomarkers; CRC; m(6)A regulators.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Adenoma / genetics
Adenoma / metabolism
Adenoma / pathology*
Adenosine / analogs & derivatives*
Adenosine / chemistry
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Case-Control Studies
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology*
DNA Methylation*
Eukaryotic Initiation Factor-3 / genetics
Eukaryotic Initiation Factor-3 / metabolism
Female
Follow-Up Studies
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Male
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Prognosis
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism
RNA, Messenger / chemistry*
RNA, Messenger / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

Biomarkers, Tumor
EIF3B protein, human
Eukaryotic Initiation Factor-3
IGF2BP1 protein, human
IGF2BP3 protein, human
Nerve Tissue Proteins
RNA Splicing Factors
RNA, Messenger
RNA-Binding Proteins
YTHDC1 protein, human
N-methyladenosine
Adenosine