口腔疾病防治2025，Vol.33Issue(5)：345-358,14.DOI:10.12016/j.issn.2096-1456.202440461
基于缺氧相关基因的头颈部鳞状细胞癌分子分类及STC2的临床意义
Molecular classification of head and neck squamous cell carcinoma based on hypoxia-related genes and clinical significance of STC2
摘要
Abstract
Objective To construct a molecular classification system for head and neck squamous cell carcinoma(HNSCC)utilizing hypoxia-related gene(HAG)expression profiles,and to comprehensively examine the clinicopathologi-cal significance and biological functions of the hypoxia gene stanniocalcin 2(STC2)in HNSCC.Methods Transcrip-tomic data and clinical information of 546 HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)data-base,and based on the expression profiles of 200 HRGs,HNSCC was classified subclasses using non-negative matrix factorization(NMF).HNSCC was classified into three subclasses(C1,C2,and C3),and the molecular characteristics and prognostic differences of the subclasses were assessed by comparing the tumor mutation load,functional enrichment analysis,drug sensitivity,and clinical features among the subclasses.LASSO-Cox regression was used to screen progno-sis-related genes and construct prognostic models.Using oral squamous cell carcinoma(OSCC)-related data in the TC-GA database,we analyzed the expression differences of STC2 in OSCC and control samples,and detected the mRNA and protein expression of STC2 in oral squamous carcinoma samples using qRT-PCR and immunohistochemistry.We knocked down STC2 in CAL-27 cells and verified the knockdown efficiency by qRT-PCR and Western blot.CCK-8 assay and cell scratch assay were used to assess the effect of STC2 on cell proliferation and migration ability.Results Based on HRGs expression profiles,HNSCC was categorized into three subclasses(C1,C2,and C3).Subclass C1 had moderate hypoxic activity and good prognosis;subclass C2 had the highest hypoxic activity,poor prognosis,and poor sensitivity to CTLA-4 inhibitors(P＜0.05);subclass C3 had the lowest hypoxic activity and moderate prognosis,and STC2 belonged to subclass C3.The frequency of cyclin-dependent kinase inhibitor 2A(CDKN2A),phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),and tumor protein p53(TP 53)mutations was higher in HNSCC.C1 genomic gain and deletion burden were significantly higher than C3 subclass(P＜0.05)and C2 genomic gain than C3 subclass(P＜0.05).The C2 subclass was significantly enriched in hypoxia-associated pathways,such as glycine metabolism and base excision repair(P＜0.05).The C1,C2,and C3 subclasses were significantly positively cor-related in terms of sex(male)(Cramer's V=0.15),radiation exposure(Cramer's V=0.12),medication(Cramer's V=0.18),and pathological grading(G1/G2)(Cramer's V=0.25)(P＜0.05).Nine prognosis-related genes were screened by LASSO-Cox regression,among which high expression of STC2 was positively correlated with poorer overall survival(OS)in HNSCC patients(P＜0.01).Bioinformatics analysis showed that STC2 mRNA expression was higher in OSCC than in normal controls(P＜0.05).qRT-PCR and immunohistochemistry confirmed that both mRNA and protein expression of STC2 were significantly upregulated in OSCC tissues and cells(P＜0.01).In vitro experiments showed that STC2 ex-pression was knocked down to approximately 80%in CAL-27 cells(P＜0.001),and the STC2 knockdown group had a reduced value-added rate(P＜0.001)and a reduced percentage of scratch closure(P＜0.05)compared with the control group.Conclusion We successfully constructed a molecular typing system for HNSCC based on the expression pro-files of HRGs and categorized HNSCC into three subclasses with significant prognostic differences,among which the C2 subclass had the highest hypoxic activity and the poorest prognosis.STC2 was highly expressed in HNSCC and suggest-ed a poor prognosis,demonstrating that it may be a potential target for HNSCC treatment.关键词
头颈部鳞状细胞癌/口腔鳞状细胞癌/缺氧相关基因/癌症基因组图谱/生物信息学分析/斯钙素2/预后标记/预后模型/肿瘤微环境/免疫治疗Key words
head and neck squamous cell carcinoma/oral squamous cell carcinoma/hypoxia-associated genes/The Cancer Genome Atlas/bioinformatics analysis/stanniocalcin 2/prognostic marker/prognostic model/tumor mi-croenvironment/immunotherapy分类
口腔医学引用本文复制引用
朱嘉宁,王天天,张瑞,宋红权..基于缺氧相关基因的头颈部鳞状细胞癌分子分类及STC2的临床意义[J].口腔疾病防治,2025,33(5):345-358,14.基金项目
黑龙江省自然科学基金项目(LH2022H0569) （LH2022H0569）
黑龙江省博士后科研启动基金(LBH-Q21143) This study was supported by the grants from Natural Science Foundation of Heilongjiang Province of China(No.LH2022H0569) （LBH-Q21143）
Postdoctoral Scientific Research Developmental Fund of Heilongjiang Province of China(No.LBH-Q21143). （No.LBH-Q21143）
