Molecular Characteristics And Biological Functions Of Hypoxic Microenvironment In Hepatocellular Carcinoma

Objects: Hypoxia is an important feature of the tumor microenvironment and is closely associated with cell proliferation,metastasis,tumor immune response,and drug resistance.All these factors can further promote tumor progression and lead to a poor prognosis.However,in hepatocellular carcinoma(HCC),the potential role of hypoxia of the tumor microenvironment(TME),drug sensitivity,and immunotherapy remains unclear.Methods: Initially,Unsupervised clustering distinguishes different hypoxic phenotypes in HCC.Find hypoxia-related signature genes in HCC,and construct a hypoxia-related score model,Hypoxia＿DEGs＿Score,to quantify hypoxia status and predict prognosis.The prognosis prediction of the scoring model was validated by datasets from four independent sources.A significant correlation between the characteristic gene C12orf75 in the model and Hypoxia＿DEGs＿Score was found by correlation analysis,and the effect of C12orf75 on HCC proliferation,invasion and metastasis was explored by interfering with the expression of C12orf75 by si RNA.The model reveals the impact of somatic mutation,copy number variation,DNA methylation,N6-methyladenosine modification,and TME on the occurrence and development of HCC under hypoxia.In addition,we also performed the association analysis of Hypoxia＿DEGs＿Score with immunotherapy efficacy and drug response and verified the validity of the drug-related research.Results: We performed a systematic,comprehensive analysis of the effects of hypoxia on multiple HCC cohorts based on the hypoxia signature.The Hypoxia＿DEGs＿Score predictive model was constructed,and that has an excellent survival prediction value.The signature gene C12orf75 in the model not only showed a significant positive correlation with Hypoxia＿DEGs＿Score,but also could serve as a prognostic predictor of HCC.And interfering with the expression of C12orf75 can inhibit the proliferation,migration and invasion of HCC.In hypoxic HCC,somatic mutation,copy number variation,and DNA methylation are closely related to hypoxia alternation and are involved in tumorigenesis,progression,metastasis,and drug resistance.In HCC,aggravated hypoxic stress will be accompanied by an immune exclusion state and increased infiltration of immunosuppressive cells,implying poor efficacy of immunotherapy.In the validation of the IMvigor210 and GSE78220 cohorts,patients with high Hypoxia＿DEGs＿Score were found to have worse therapeutic outcomes and prognoses.Through correlation analysis of drug response with Hypoxia＿DEGs＿Score and hypoxia drug response experiments,we found that patients with higher Hypoxia＿DEGs＿Score may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/m TOR pathways.Conclusions: The impact of hypoxic stress on tumor biology,tumorigenesis,and progression was revealed from genomics,transcriptomic,and epigenetic levels.Hypoxia＿DEGs＿Score can predict the prognosis of HCC patients and has an excellent predictive capability on the alteration of TME,the efficacy of immunotherapy,and the response of drugs.Therefore,Hypoxia＿DEGs＿Score helps develop personalized immunotherapy regimens for HCC patients to improve prognosis.