Prognostic Evaluation for Oral Squamous Cell Carcinoma: A Novel Method Based on m⁶A Methylation Regulators

Abstract

Objective

This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma (OSCC) based on the expression of heterogeneous nuclear ribonucleoprotein C (HNRNPC), YTH domain-binding protein 2 (YTHDF2), and methyltransferase 14 (METTL14).

Methods

We obtained the RNA sequence and clinical information of OSCC patients from The Cancer Genome Atlas database. An optical method was established by the least absolute shrinkage and selection operator Cox regression algorithm, which was used to calculate the risk score of every sample. In addition, all samples (n=239) were classified into high-risk (n=119) and low-risk (n=120) groups, and the overall survival (OS) time and clinical characteristics were compared between groups. Moreover, bioinformatics analysis was carried out. Gene set enrichment analysis was performed to investigate the signaling pathways of HNRNPC, YTHDF2, and METTL14.

Results

The two groups showed significantly different OS time, tumor grades, tumor stages, and pathologic T stages (P<0.05). The receiver operating characteristic analysis identified that our method was effective and it was more accurate than use of age, gender, tumor grade, tumor stage, pathologic T stage, and pathologic N stage in OSCC prognostic prediction. Gene set enrichment analysis revealed that HNRNPC, YTHDF2, and METTL14 were mainly associated with ubiquitin-mediated proteolysis, cell cycle, RNA degradation, and spliceosome signaling pathways.

Conclusion

The method based on the expression of HNRNPC, YTHDF2, and METTL14 can predict the prognosis of patients with OSCC independently, and its prognostic value is better than that of clinicopathological characteristic indicators.

Keywords

oral squamous cell carcinoma / m⁶A methylation regulators / RNA modification / prognostic prediction / The Cancer Genome Atlas

References

[1] BrayF, FerlayJ, SoerjomataramI, et al.. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424

[2] BloebaumM, PoortL, BöckmannR, et al.. Survival after curative surgical treatment for primary oral squamous cell carcinoma. J Craniomaxillofac Surg, 2014, 42(8): 1572-1576

[3] FullerCD, WangSJ, ThomasCR, et al.. Conditional survival in head and neck squamous cell carcinoma: results from the SEER dataset 1973–1998. Cancer, 2007, 109(7): 1331-1343

[4] ArduinoPG, CarrozzoM, ChiecchioA, et al.. Clinical and histopathologic independent prognostic factors in oral squamous cell carcinoma: A retrospective study of 334 cases. J Oral Maxillofac Surg, 2008, 66(8): 1570-1579

[5] HeC. Grand challenge commentary: RNA epigenetics. Nat Chem Biol, 2010, 6(11): 863-865

[6] KeS, Pandya-JonesA, SaitoY, et al.. m⁶A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev, 2017, 31(10): 990-1006

[7] LiuN, PanT. N6-methyladenosine-encoded epitranscriptomics. Nat Struct Mol Biol, 2016, 23(2): 98-102

[8] YangY, HsuPJ, ChenYS, et al.. Dynamic transcriptomic m⁶A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res, 2018, 28(6): 616-624

[9] CuiQ, ShiH, YeP, et al.. m⁶A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep, 2017, 18(11): 2622-2634

[10] ChaiRC, WuF, WangQX, et al.. m⁶A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas. Aging, 2019, 11(4): 1204-1225

[11] PanY, MaP, LiuY, et al.. Multiple functions of m⁶A RNA methylation in cancer. J Hematol Oncol, 2018, 11(1): 48-58

[12] DaiDJ, WangHY, ZhuLY, et al.. N6-methyladenosine links RNA metabolism to cancer progression. Cell Death Dis, 2018, 9(2): 124-136

[13] XuL, YuC, DuXJ. Bioinformatics analysis of m⁶A methylation regulators’ influence on survival prognosis of patients with oral squamous cell carcinoma. Acta Med Univ Sci Technol Huazhong, 2020, 49(4): 443-449

[14] ZhaoW, CuiY, LiuL, et al.. METTL3 facilitates oral squamous cell carcinoma Tumorigenesis by enhancing c-Myc stability via YTHDF1-mediated m⁶A modification. Mol Ther Nucleic Acids, 2020, 20(6): 1-12

[15] LiuL, WuY, LiQ, et al.. METTL3 Promotes Tumorigenesis and Metastasis through BMI1 m⁶A Methylation in Oral Squamous Cell Carcinoma. Mol Ther, 2020, 28(10): 2177-2190

[16] HuangGZ, WuQQ, ZhengZN, et al.. m⁶A-related bioinformatics analysis reveals that HNRNPC facilitates progression of OSCC via EMT. Aging, 2020, 12(12): 11667-11684

[17] MooreSR, JohnsonNW, PierceAM, et al.. The epidemiology of mouth cancer: a review of global incidence. Oral Dis, 2000, 6(2): 65-74

[18] ChenJX, SunYC, XuX, et al.. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle, 2017, 16(23): 2259-2271

[19] ZhongL, LiaoD, ZhangM, et al.. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett, 2019, 442: 252-261

[20] ParisJ, MorganM, CamposJ, et al.. Targeting the RNA m⁶A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Cell Stem Cell, 2019, 25(1): 137-148

[21] WuYS, ZhaoWW, LiuY, et al.. Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response. EMBO J, 2018, 37(23): e99017

[22] WengHY, HuangHL, WuHZ, et al.. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m⁶A Modification. Cell Stem Cell, 2018, 22(2): 191-205

[23] MaJZ, YangF, ZhouC, et al.. METTL14 suppresses the metastatic potential of HCC by modulating m⁶A-dependent primary miRNA processing. Hepatology, 2017, 65(2): 529-543

[24] NakayamaKI, NakayamaK. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer, 2006, 6(5): 369-381

[25] KastanMB, BartekJ. Cell-cycle checkpoints and cancer. Nature, 2004, 432(11): 316-323

[26] KopsGJ, WeaverBA, ClevelandDW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer, 2005, 5(12): 773-785

[27] DavidCJ, ManleyJL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev, 2010, 24(21): 2343-2364

[28] ShiY. Mechanistic insights into precursor messenger RNA splicing by the spliceosome. Nat Rev Mol Cell Biol, 2017, 18(9): 655-670