Integrated Clinical and Prognostic Analysis of the m6A RNA Methylation Regulator YTHDF3 in Pan-Cancer and its Correlation with Cancer Cell Proliferation

Leiqun Cao; Bingjie Zeng; Yulan Wang; Xianzhao Wang; Yueyang Qin; Congcong Zhang; Mengyi Wu; Jiayi Wang; Xiao Zhang; Lifang Ma

doi:10.7150/jca.78403

Integrated Clinical and Prognostic Analysis of the m⁶A RNA Methylation Regulator YTHDF3 in Pan-Cancer and its Correlation with Cancer Cell Proliferation

J Cancer. 2022 Nov 21;13(15):3623-3639. doi: 10.7150/jca.78403. eCollection 2022.

Authors

Leiqun Cao^{1

2}, Bingjie Zeng², Yulan Wang², Xianzhao Wang², Yueyang Qin², Congcong Zhang^{1

2}, Mengyi Wu³, Jiayi Wang^{2

4}, Xiao Zhang⁴, Lifang Ma^{2

4}

Affiliations

¹ Anhui University of Science and Technology School of Medicine, Huainan, Anhui, 232001, China.
² Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
³ Shanghai University of Traditional Chineses Medicine, Shanghai, 201203, China.
⁴ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.

Abstract

Background: N6-methyladenosine (m⁶A) is the most abundant and extensive chemical modification of mammalian RNA molecules. Although numerous studies have investigated m⁶A methylation-related genes, to the best of our knowledge, none have examined the expression patterns of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) across cancers. Methods: Using various publicly available datasets, we searched for a potential carcinogenic role of YTHDF3 in 33 tumor types. Furthermore, the clinicopathological parameters, clinical prognostic value, enrichment analysis, mutations, microsatellite instability (MSI), tumor mutation burden (TMB), levels of infiltrating cells, and related immune checkpoint genes were included. Finally, we performed a validation analysis using existing clinical samples and proliferation-related functional experiments. Results: YTHDF3 is highly expressed in most cancer types and associated with patient prognosis in certain tumors. The ROC analysis suggested that YTHDF3 has high diagnostic value in 13 types of cancer. Furthermore, we found that the genes associated with YTHDF3 were enriched for translation initiation and mRNA metabolic processes. The results of the GSEA enrichment suggest that YTHDF3 may be associated with different pathways in cells in various tumor types. We further analyzed the correlations between YTHDF3 expression and MSI, TMB, and immune checkpoint genes. YTHDF3 also possibly exerts important antitumor immunotherapy effects. Additionally, the results of the immune analysis using TIMER showed that high YTHDF3 expression levels in pan-cancer tissues were related to an immunosuppressive microenvironment. Finally, we experimentally demonstrated that both overexpression and downregulation of YTHDF3 can affect cancer cell proliferation rates. Conclusion: YTHDF3 is a promising biomarker for cancer diagnosis. This study provides the first comprehensive pan-cancer report on YTHDF3 and increases our understanding of its oncogenic role in different tumors.

Keywords: Cancer; Immunosuppressive microenvironment; Methylation; Prognosis; YTHDF3.