Pancreatic cancer is one of the most common malignancies of the digestive system, and progress in research related to its treatment has been slow. In recent decades, the discovery of m6A has increased our understanding of tumorigenesis regulation to a new level, helping us gain insight into the role of methylation and demethylation in tumor formation and progression . Many studies have demonstrated that m6A alternation is one of the key factors in cancer management . However, the role of m6A regulatory genes in pancreatic cancer remains unclear. Upon analysis of the different expressions or mutations of “readers”, “writers”, and “erasers” in different tissues, we found that the genes related to m6A regulation seem to be different in distant tumors. Therefore, in this study, we aimed to screen and uncover m6A regulatory factors closely related to clinicopathological significance and prognosis in pancreatic cancer. This study not only determined the value of m6A regulatory genes for pancreatic cancer prognosis but also proposed a novel therapeutic target for pancreatic cancer.
As a demethylase, ALKBH5 is involved in the mediation of methylation reversal. It has been reported that ALKBH5 is overexpressed in various cancers, including breast cancer , glioblastoma , ovarian cancer , and gastric cancer [25, 26]. Additionally, signaling associated with multiple cancers is dysregulated in PAAD development. We found that in patients with PAAD, a high ALKBH5 mRNA expression level was associated with the activation of AKT signaling pathways, which participate in important cellular pathological processes in PAAD development , suggesting that the mRNAs of molecules in the AKT pathway may be the m6a modification target mediated by ALKBH5 . Recently, a study has shown that ALKBH5 functions as an anti-tumor protein in pancreatic cancer progression ; in this paper, upregulated ALKBH5 sensitized pancreatic cancer to gemcitabine-chemotherapy, and knockdown of ALKBH5 decreased pancreatic cancer cell invasion, migration, proliferation, metastasis, and tumorigenesis. . As in the case of colorectal cancer , ALKBH5 showed obviously weaker mRNA expression in pancreatic cancer than in the normal tissue. However, in contrast to the case of rectal adenocarcinoma wherein high ALKBH5 expression in tumor tissues was clearly associated with worse OS, ALKBH5 expression in pancreatic cancer was found to be positively associated with OS in TCGA.
We also evaluated the effect of m6A regulatory gene alterations on the survival of patients with PAAD. In line with the characteristics of genetic alterations of m6A-related genes, the eraser gene ALKBH5 was the only gene among the ten regulators that was associated with the OS and DFS. This confirmed that “erasers” are the main regulators of m6A in PAAD. A better OS was observed in patients with eraser gene gain of function, making it clear that a decreased level of m6A plays a significant role in PAAD progression. However, we failed to obtain any significant results with regard to the relationship between the other nine m6A regulatory gene alterations and OS or DFS, possibly because of the limited number of patients. Direct detection of the m6A level and evaluation of its effect on PAAD survival in a new and larger cohort are needed to illustrate this contradictory phenomenon.
We also assessed the impact of m6A-related gene changes on prognosis, especially OS and DFS, in patients with PAAD. According to the genetic changes of m6A-related gene characteristics, only ALKBH5, an eraser gene, was associated with OS and DFS among the 10 regulatory genes. This confirms that erasers might be the predominant governors of m6A in PAAD. The patients with gained function of ALKBH5 achieved better OS, indicating that decreased m6A levels may play an important role in the progression of PAAD. However, we were unable to derive any significant results on the relationship between the other nine m6A regulatory gene changes and OS or DFS, possibly due to the limited number of patients. To account for this paradox, m6A levels need to be directly detected and their impact on PAAD survival should be evaluated in a new and larger cohort.
In conclusion, we screened alternations of ten m6A regulatory genes in the TCGA database of pancreatic cancer patients, and identified that ALKBH5 was the most valuable prognosis-related gene that may be associated with AKT signaling pathways. These findings revealed a novel molecular mechanism of PDAC tumorigenesis regulated by m6A modification and provided a new insight into the development of effective therapeutic strategies for the treatment of pancreatic cancer. Although we provided robust evidence for the prognostic value of the effect of ALKBH5 on pancreatic cancer, the underlying mechanism is not yet fully characterized. Thus, the effects of ALKBH5 clearly deserve further investigation.