Construction and clinical evaluation of N6-methyladenosine risk signature of YTHDC2, IGF2BP2, and HNRNPC in head and neck squamous cell carcinoma

doi:10.7518/hxkq.2022.06.012

Abstract

Abstract:

Objective This work aimed to construct N6-methyladenosine (m⁶A) regulator-based prognostic signature and evaluate the prognostic value and the intervention on tumor immune microenvironment of this m⁶A risk signature. Methods Using transcriptome and clinical data of head and neck squamous cell carcinoma (HNSCC) from The Cancer Genome Atlas (TCGA), we profiled m⁶A regulators and constructed an m⁶A risk signature. The relationship between m⁶A modulation and immune function was studied by differential gene expression, cell type enrichment, and correlation analyses. Results Fifteen m⁶A regulators had aberrant expression in HNSCC. A three-gene m⁶A prognostic signature (i.e., YTHDC2, IGF2BP2, and HNRNPC) was constructed and identified as an independent prognostic indicator for HNSCC. The m⁶A regulator signature-based high-risk group revealed pro-tumoral immune microenvironment due to the dysregulation of immune-related gene expression, abnormal enrichment of multiple immunocytes, and production of immunoregulatory factors. Conclusion This comprehensive analysis of m⁶A regulators and tumor immune landscape in HNSCC revealed that the m⁶A signature of YTHDC2, IGF2BP2, and HNRNPC could serve as a promising biomarker for monitoring HNSCC development and may be a potential target for tumor therapy in the future.

Key words: head and neck squamous cell carcinoma, N6-methyladenosine, prognostic risk signature, tumor immune microenvironment, bioinformatic analysis

CLC Number:

Q 786

Yue Qiangwei, Xu Le, Zhang Dongsheng.. Construction and clinical evaluation of N6-methyladenosine risk signature of YTHDC2, IGF2BP2, and HNRNPC in head and neck squamous cell carcinoma[J]. West China Journal of Stomatology, 2022, 40(6): 704-709.

Figures/Tables 4

References 24

1	Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015, 136(5): E359-E386.
2	Cramer JD, Burtness B, Le QT, et al. The changing therapeutic landscape of head and neck cancer[J]. Nat Rev Clin Oncol, 2019, 16(11): 669-683.
3	Huang H, Weng H, Chen J. m6A modification in Coding and Non-coding RNAs: roles and therapeutic implications in cancer[J]. Cancer Cell, 2020, 37(3): 270-288.
4	Liu J, Li K, Cai J, et al. Landscape and regulation of m6A and m6Am methylome across human and mouse tissues[J]. Mol Cell, 2020, 77(2): 426-440.e6.
5	Zhao X, Cui L. Development and validation of a m6A RNA methylation regulators-based signature for predic-ting the prognosis of head and neck squamous cell carcinoma[J]. Am J Cancer Res, 2019, 9(10): 2156-2169.
6	Terlizzi M, Casolaro V, Pinto A, et al. Inflammasome: cancer's friend or foe[J]. Pharmacol Ther, 2014, 143(1): 24-33.
7	Zhang B, Wu Q, Li B, et al. m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer[J]. Mol Cancer, 2020, 19(1): 53.
8	Han D, Liu J, Chen C, et al. Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells[J]. Nature, 2019, 566(7743): 270-274.
9	Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape[J]. Genome Biol, 2017, 18(1): 220.
10	Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer[J]. Nat Rev Cancer, 2018, 18(5): 269-282.
11	Li Y, Xiao J, Bai J, et al. Molecular characterization and clinical relevance of m6A regulators across 33 cancer types[J]. Mol Cancer, 2019, 18(1): 137.
12	Shriwas O, Priyadarshini M, Samal SK, et al. DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NA-NOG[J]. Apoptosis, 2020, 25(3/4): 233-246.
13	Zhao W, Cui Y, Liu L, et al. METTL3 facilitates oral squamous cell carcinoma tumorigenesis by enhancing c-Myc stability via YTHDF1-mediated m6A modification[J]. Mol Ther Nucleic Acids, 2020, 20: 1-12.
14	Ban Y, Tan P, Cai J, et al. LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma[J]. Mol Oncol, 2020, 14(6): 1282-1296.
15	Tanabe A, Konno J, Tanikawa K, et al. Transcriptional machinery of TNF-α-inducible YTH domain containing 2 (YTHDC2) gene[J]. Gene, 2014, 535(1): 24-32.
16	Fanale D, Iovanna JL, Calvo EL, et al. Germline copy number variation in the YTHDC2 gene: does it have a role in finding a novel potential molecular target involved in pancreatic adenocarcinoma susceptibility[J]. Expert Opin Ther Targets, 2014, 18(8): 841-850.
17	Cui Q, Shi H, Ye P, et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells[J]. Cell Rep, 2017, 18(11): 2622-2634.
18	Cheng M, Sheng L, Gao Q, et al. The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network[J]. Oncogene, 2019, 38(19): 3667-3680.
19	Wu Y, Zhao W, Liu Y, et al. Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response[J]. EMBO J, 2018, 37(23): e99017.
20	Fischl H, Neve J, Wang Z, et al. hnRNPC regulates cancer-specific alternative cleavage and polyadenylation profiles[J]. Nucleic Acids Res, 2019, 47(14): 7580-7591.
21	Li T, Hu PS, Zuo Z, et al. METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma[J]. Mol Cancer, 2019, 18(1): 112.
22	Liu J, Zhang X, Chen K, et al. CCR7 Chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis[J]. Immunity, 2019, 50(3): 600-615.
23	Winkler R, Gillis E, Lasman L, et al. m6A modification controls the innate immune response to infection by targeting type I interferons[J]. Nat Immunol, 2019, 20(2): 173-182.
24	Wang H, Hu X, Huang M, et al. Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation[J]. Nat Commun, 2019, 10(1): 1898.

临床特征		风险分组		P值
临床特征		低风险	高风险	P值
年龄/岁	≤65	121	135	0.611
	>65	65	65
性别	女性	59	44	0.031*
	男性	127	156
临床分期	Ⅰ期	17	5	0.047*
	Ⅱ期	22	26
	Ⅲ期	34	38
	Ⅳ期	113	131
病理分级	1级	34	15	0.002***
	2级	118	128
	3级	33	57
	4级	1	0

[1]	Liu Lei, Xiang Zhongzheng, Li Yi, Guo Wei, Yang Kai, Wang Jun, Sun Zhijun, Ren Guoxin, Zhang Jianguo, Sun Moyi, Ran Wei, Huang Guilin, Tang Zhangui, Li Longjiang. The immune checkpoint inhibitors treatment of head and neck squamous cell carcinoma: an expert consensus [J]. West China Journal of Stomatology, 2022, 40(6): 619-628.
[2]	Yang Lisa,Shi Congyu,Liang Yuhao,Liu Tong,Hou Xiaoru,Tian Xudong,Wang Xiaoyi. Bioinformatics analysis of programmed cell death ligand 1 co-expression genes and their regulatory network in head and neck squamous cell carcinoma [J]. West China Journal of Stomatology, 2019, 37(5): 516-520.
[3]	Guang-xue Cui,Xiaolei Gao,Xinhua Liang. Invasion and metastasis mechanism of human papillomavirus in head and neck squamous cell carcinomas [J]. West China Journal of Stomatology, 2018, 36(5): 544-551.
[4]	Guangxue Cui, Xiaolei Gao, Xinhua Liang. Role of human papillomavirus in head and neck squamous cell carcinomas [J]. West China Journal of Stomatology, 2017, 35(2): 187-191.