The Function And Potential Therapeutic Value Of SDPR In KRAS-mutant Lung Cancer

Background and ObjectionLung cancer is one of the most common malignant tumors,and its mortality ranks first among all malignant tumors.In lung cancer,KRAS mutation frequency accounts for about 20%.Due to the particularity of its functional domain and the existence of various mutant isomers,KRAS lacks specific targeting drugs.In addition,most of the common target genes in lung cancer are located in the upstream and downstream signal pathways or alternative pathway of KRAS.KRAS mutation will abnormally activate its downstream signal pathways and alternative pathways,thus mediating resistance of a variety of targeted drug.Therefore,the treatment of KRAS mutant lung cancer is difficult and the prognosis is very poor.It is particularly important to find biomarkers and potential therapeutic targets that do not depend on KRAS signal pathway and can effectively evaluate the prognosis and efficacy of patients.MethodsThe KRASG12D mutant transgenic mice based on Cre/loxp system were constructed,and Cre recombinant adeno-associated virus was used to trigger the expression of KRASG12D mutant gene to promote lung tumorigenesis.The differentially expressed gene was screened by analyzing the gene expression profile data of KRAS mutant lung cancer dataset in GEO database.Real-time quantitative polymerase chain reaction(qRT-PCR),immunohistochemical staining(IHC)and western blot were used to detect the expression of SDPR in human lung cancer cell lines,lung adenocarcinoma tissue microarray and tumor tissue samples of KRAS mutant transgenic mice.Meanwhile,the expression level of SDPR in non-small cell lung cancer and KRAS mutant subsets was analyzed by TCGA database,GEO database and GEPAI database,the prognostic value of SDPR was evaluated by Kaplan-Meier survival analysis and Cox regression analysis.Also,GSEA dataset and transcription factor database were used to predict SDPR-binding transcription factors and miRNAs.In addition,the correlation among SDPR,immune checkpoint molecules and tumor infiltration pattern was analyzed by GSEA dataset and TIMER online website.ResultsWe successfully activated the expression of KRASG12D gene in the transgenic mouse model,and the lung tissue of mice formed primary tumor.We screened out that SDPR is a down-regulated differentially expressed gene in different KRAS mutant lung cancer datasets.And we found SDPR expression was significantly down-regulated in KRAS mutant lung cancer cells,transgenic mouse lung cancer tissues and human lung adenocarcinoma microarray tissues.Survival analysis and Cox regression analysis showed that the low expression of SDPR was an independent predictor of survival in patients with lung cancer,especially in patients with KRAS mutant subsets.Based on the analysis of GEO dataset and the prediction website of transcription factor,we found DACH1 and WT-1 may be transcription factors upstream of SDPR,miR-1,miR-204,miR-144,miR-106 and miR-363 may regulate the expression of SDPR.In addition,in non-small cell lung cancer,the expression level of SDPR was negatively correlated with the expression of immune checkpoint molecules(PD-L1,TNFRSF18,TNFRSF9,TDO2).The immune infiltration pattern of tumor varies with the expression level or copy number variation(CNV)of SDPR.ConclusionWe found that SDPR was significantly down-regulated in KRAS mutant lung cancer which was verified in KRAS mutant transgenic mice.In addition,we elucidated the potential regulatory network of SDPR in KRAS mutant lung cancer,revealed the relationship between SDPR expression level and immune infiltration,and provided an independent prognostic factor and potential target for KRAS mutant NSCLC.We discussed the prognostic value,regulatory network and immunomodulatory function of SDPR in KRAS mutant lung cancer.We will further explore whether SDPR and its upstream and downstream signal pathways are involved in the therapeutic resistance mediated by KRAS mutation and evaluate whether it can provide a new therapeutic direction for KRAS mutant lung cancer.