Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer

Abstract

Background Reversible N 6 -methyladenosine (m 6 A) modifications in messenger RNAs can be categorized under the field of “RNA epigenetics.” However, the potential role of m 6 A-related genes in gastric cancer (GC) prognosis has not been systematically researched. Aims This study was aimed at providing insights into the prognostic role of m 6 A-related gene expression, at both mRNA and protein levels. Methods Kaplan–Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m 6 A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored. Results Among nine m 6 A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients. Conclusions Aberrant expression of demethylase genes, FTO and ALKBH1 , has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis. Electronic supplementary material The online version of this article (10.1007/s10620-018-5452-2) contains supplementary material, which is available to authorized users.

FTO-mediated cytoplasmic m6Amdemethylation adjusts stem-like properties in colorectal cancer cell

“…First, we show that FTO expression in colon cancer cells is finely regulated at the post-transcriptional level, though the precise underlying mechanism remains to be determined. This observation is in agreement with a recent report in gastric tissue [38] and stresses the importance of quantifying gene expression at the protein level for diagnostic purpose. Second, as will be discussed below, FTO activity and substrate specificity may vary with its subcellular distribution.…”

“…Decreased expression is achieved post transcriptionally, since quantitative PCR (qPCR) analysis of FTO mRNA levels showed no significant differences between CTC lines and primary/metastatic patient derived lines ( Figure 3b ). A similar disconnect in FTO mRNA/protein was reported in gastric tumors [38].…”

N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications

“…Therefore, YTHDF1 may be a marker of HCC. In GC, the abnormal expression of FTO has significant prognostic value; hence, FTO may play important roles in GC progression and metastasis [58]. Similarly to the report of Li, Xu et al [59] concluded that FTO expression might play an important role in promoting the occurrence of GC and might be an important molecular marker for the diagnosis and prognosis of this disease.…”

Identification of a m6A RNA methylation regulators-based signature for predicting the prognosis of esophageal adenocarcinoma

“…1b). Interestingly, FTO has been reported to be highly expressed in ESCC and other malignant tumors such as melanoma and gastric cancer, implying its distinct role in EAC [28,40,41]. In the correlation analysis, KIAA1429 was found to present the strongest correlation with YTHDF3.…”