| Background:Cervical cancer is the second most common cancer as the leading cause of cancer death in women in developing countries.However,its pathogenesis remains unclear.Metabolic reprogramming refers to a series of metabolic changes characterized by the"Warburg effect"due to changes in the structure and function of some genes in tumor cells.A specific oncogenic mechanism of metabolic reprogramming is viral carcinogenesis mediated by several human oncogenic viruses that induce carcinogenesis,proliferation and evasion of cell death in a multistep process by targeting key cellular pathways and key proteins.In abnormal metabolic reprogramming,the significant intermediate metabolite is succinate,and the accumulation of succinate and the occurrence and development of tumors have been confirmed by previous studies.Objective:The current study is aimed to explore the relationship between succinylation modification caused by succinate accumulation and cervical carcinogenesis.Methods:The clinical study cohort consists of 126 cervical cancer samples and 42 matched paracancerous tissues.All subjects signed the informed consent forms,and the study is approved by the Ethics Committee of the Hospital.Lysine-succinylated-modified pan-antibody level was detected by immunohistochemical staining.The RNA-seq data of177 uterine cancer patients and 24 paracancerous tissues were downloaded from the TCGA database,with the clinical characteristics of the patients included age,height,weight,tissue score,pathological stage,follow-up time and final outcome,as well as complications of diabetes and hypertension.The data is used for model construction and validation.The non-negative matrix factorization(NMF)was used for cluster analysis,and the t-SNE algorithm was employed for dimensionality reduction analysis.Regression models,including generalized linear models and generalized mixed-effects models,were used to predict the survival prognosis of patients.Results:The levels of lysine succinylated pan-antibodies in the cytoplasm of 126 cervical cancer tissues and 42 paracancerous tissues were compared,and the results showed that high levels of lysine succinylated modifications were significantly enriched in cancer tissues(P=0.004).Paired analysis of 42 cases of cancer and adjacent tissues also confirmed the presence of hypersuccinylation in cervical cancer tissues(P=0.0014).The Pearson correlation coefficient between the succinylation score and age was R~2=-0.87,showing a strong negative correlation(P<0.001),and the Ki67 staining score and the succinylation modification level were positively correlated(R~2=0.69,P<0.001).More importantly,the overall survival analysis of cervical cancer patients with low,medium and high succinylation modification levels showed that the survival time of the high-level modification group was significantly worse(Log-rank test,P=0.048).The201 samples from the validation included 177 uterine cancers and 24 paracancerous tissues,which were divided into three categories:subtype 1,subtype 2 and subtype 3according to the expression of 20 succinylation-related genes.The expression of clinical features among the three subclasses was more significant.The risk score was calculated according to the Cox survival analysis regression model of the RNA-seq data of 20 succinylation-related genes and 3 pathological marker genes,and the results showed that the risk score was significantly different between different pathological stages(P=0.03),and was related to the age of the patient.Positive correlation(Pearson R~2=0.113,P=0.01).In addition,risk score(P=0.002)and pathological stage(P=0.001for stageⅢ,P=0.022 for stageⅣ)were strongly associated with patient prognosis in the validation model.Cox multivariate regression analysis showed that expression of SIRT2,SIRT6,SUCLG1,SDHC,SDHD and CD274(PDL1)were significantly associated with prognosis of cervical cancer.Conclusions:The level of lysine succinyl modification in cervical cancer tissue is higher than that in adjacent tissue;the lysine succinyl modification is related to the age of the patient and the high expression of Ki67;the prognosis of cervical cancer is poor in patients with high level of lysine succinyl modification;Dimensionality reduction and cluster analysis of succinylation-related genes can classify tumor tissue types into three subtypes,and there are significant clinical differences between each subtype;Based on the risk scores of succinylation-related genes,cervical cancer can be predicted patient prognosis. |
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