Identification and Characterization of Alcohol-related Hepatocellular Carcinoma Prognostic Subtypes based on an Integrative N6-methyladenosine methylation Model

Abstract

Background: Alcohol consumption increases the risk of hepatocellular carcinoma (HCC), and associated with a high mortality rate and poor prognosis. N6-methyladenosine (m6A) methylations play key roles in tumorigenesis and progression. However, our current knowledge about m6A in alcohol-related HCC (A-HCC) remains elucidated. Herein, the authors construct an integrative m6A model based on A-HCC subtyping and mechanism exploration workflow. Methods: Based on the m6A expressions of A-HCC and in vivo experiment, different prognosis risk A-HCC subtypes are identified. Meanwhile, multiple interdependent indicators of prognosis including patient survival rate, clinical pathological prognosis and immunotherapy sensitivity. Results: The m6A model includes LRPPRC, YTHDF2, KIAA14219, and RBM15B, classified A-HCC patients into high/low-risk subtypes. The high-risk subtype compared to the low-risk subtype showed phenotypic malignancy, poor prognosis, immunosuppression, and activation of tumorigenesis and proliferation-related pathways, including the E2F target, DNA repair, and mTORC1 signalling pathways. The expression of Immunosuppressive cytokines DNMT1/EZH2 was up-regulated in A-HCC patients, and teniposide may be a potential therapeutic drug for A-HCC. Conclusion: Our model redefined A-HCC prognosis risk, identified potential m6As linking tumour progress and immune regulations and selected possible therapy target, thus promoting understanding and clinical applications about A-HCC.

Biological function analysis of ARHGAP39 as an independent prognostic biomarker in hepatocellular carcinoma

“…There is increasing evidence that the m 6 A modification has a significant impact on cancers, including HCC, through various mechanisms [65]. It has been reported that METTL3, YTHDF1, HNRNPA2B1, HNRNPC, and RBM15B are overexpressed in HCC, and most of them can lead to a poor prognosis [66][67][68][69], which is similar to our results. In addition, METTL3 promotes the process of HCC by regulating the m 6 A levels of USP7 [70]; the increased expression of YTHDF1 enhances the proliferation of HCC cells, which can be achieved by the connection of circMAP2K4 with HSA-Mir-139-5p [71].…”

Insight into the structure, physiological function, and role in cancer of m6A readers—YTH domain-containing proteins

“…In recent years, a number of cohort studies from TCGA patient samples and other online databases illustrated the expression level of YTH family and its association with the clinical characteristics of some cancer types [ 86 – 97 ]. We summarized the association and clinical characteristics between YTH family members and various tumors in Table 2 .…”

Unveiling the m6A Methylation Regulator Links between Prostate Cancer and Periodontitis by Transcriptomic Analysis

“…Finally, the statistics of the filtered datasets are shown in Table 1. The 23 m6A RNA methylation-related genes were acquired from the previous related research [24][25][26][27], including 8 readers, 13 writers, and 2 erasers (Table 2).…”