The Role And Clinical Significance Of C9orf46 In Lung Adenocarcinoma

Objective:The Global Cancer Report released in 2020 shows that the incidence rate of lung cancer is ranked as second after breast cancer and its mortality rate is ranked as first among all cancers.In-depth study of the pathogenesis of lung cancer may find new therapeutic targets and diagnostic markers,which will benefit to invent early interfering therapy to improve the survival of patients.C9orf46 gene is located on chromosome 9p24.1 and encodes the protein C9orf46 consisted with 147 amino acids,which is widely expressed in human and mouse normal tissues,functions as a plasminogen receptor,and modulates plasmin proteolytic function in tissues.The expression level of C9orf46 can be used to effectively predict cervical lymph node metastasis of oral squamous cell carcinoma,but its role in lung adenocarcinoma has not been reported.This study was aimed to explore the role and clinical significance of C9orf46 in lung adenocarcinoma.Methods:1.The lung adenocarcinoma dataset as obtained from The Cancer Genome Atlas(TCGA),and the differences in C9orf46 expression between normal lung tissues(59 cases)and lung adenocarcinoma tissues(515cases)in the datasets as analyzed,and then the lung adenocarcinoma tissues were analyzed.Lung adenocarcinoma tissues were grouped according to clinical stage and compared one by one to determine whether the expression level of C9orf46 was related to clinical stage.2.The relationship between the expression level of C9orf46 and the overall survival(OS)and first progression(FP)survival of patients with lung adenocarcinoma was analyzed by Kaplan-Meier Plotter.3.The correlation between C9orf46 expression level and clinical characteristics was analyzed by X~2test.4.After knocking down the expression of C9orf46 in A549 and H1993 lung adenocarcinoma cells,the effect of the expression level of C9orf46 on the proliferation and colony formation of A549and H1993 cells was detected by cell counting and clony formation assay.5.After knocking down the expression of C9orf46 in A549 and H1993 lung adenocarcinoma cells,the effect on cell invasion and migration ability was detected by Transwell assay.6.After knocking down the expression of C9orf46in A549 and H1993 lung adenocarcinoma cells,the expression levels of autophagic markers LC3B and p62/SQSTM 1 were detected by Western blot to examine the effect of knockdown of C9orf46 on autophagy in A549 and H1993cells.7.GSEA software was used to discover the signaling pathways related to C9orf46,which was verified by experiments with cultured cells.Results:1.The expression of C9orf46 in lung adenocarcinoma tissue was significantly increased(P<0.01),but there was no significant difference between the clinical stages(P>0.05).2.Kaplan-Meier Plotter was used to analyze the effect of C9orf46 expression on the overall survival and first progression survival of patients with lung adenocarcinoma.The results showed that high expression of C9orf46 was negatively correlated to the survival of patients(P<0.01),but was not an independent indicator of overall survival or first progression of lung adenocarcinoma patients.3.Through the analysis of 515cases of Analysis of lung adenocarcinomas in the TCGA database showed that high expression of C9orf46 was associated with the percentage of predicted forced expiratory volume in 1 second after inhalation of bronchodilator.4.Knockdown of C9orf46 inhibited the proliferation and colony formation of A549 and H1993 cells.5.Knockdown of C9orf46 reduced the ability of A549and H1993 cells to invade and migrate.6.Knockdown of C9orf46 enhanced autophagy in A549 and H1993 cells.7.The results of GSEA and cell experiments showed that C9orf46 could promote the ERK/m TORC1 and the AKT/m TORC1 signaling pathways.Conclusions:The expression of C9orf46 in lung adenocarcinoma tissue was significantly increased,and it’s high expression is associated to unfavorable survivals of lung adenocarcinoma patients.The high expression of C9orf46 is related to the forced expiratory volume in the first second after inhalation of bronchodilator.C9orf46 can promote A549 and H1993 cell proliferation,plate colony formation,invasion and migration ability and inhibit autophagy by regulating AKT/m TORC1 and ERK/m TORC1 signal transduction.