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

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.

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.

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.

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.