ARHGAP11A affects lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) progression by regulating FAM83A.

Background: Rho GTPase-activating protein 11A (ARHGAP11A) and family with sequence similarity 83, member A (FAM83A) play important roles in tumor development. However, the mutual regulatory relationship and mechanism of action between ARHGAP11A and FAM83A in lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) are still unclear. This study investigated the role of the ARHGAP11A-FAM83A regulatory network in LUAD/PAAD progression via bioinformatics and experimental analyses. Methods: In this study, 33 tumor-related sequencing datasets were downloaded from The Cancer Genome Atlas (TCGA) database, and relevant tumor tissues were collected to explore which tumors showed the highest correlation between ARHGAP11A and FAM83A. A Gene Set Enrichment Analysis (GSEA) was conducted to identify common enrichment pathways and the significantly different proteins of ARHGAP11A and FAM83A. The protein and gene expression of ARHGAP11A and FAM83A were also knocked down to explore the regulatory relationship and mechanism of ARHGAP11A and FAM83A in tumors. Univariate and multivariate Cox regression and receiver operating characteristic (ROC) curve analyses were conducted to establish and evaluate a prognostic model based on ARHGAP11A and FAM83A (risk model), and to explore the correlation of the model with patient clinical and pathological parameters. Finally, lactate and glucose content, Cell Counting Kit-8 (CCK-8), tablet cloning, flow cytometry cycles, apoptosis, and membrane potential experiments were performed to explore the roles of ARHGAP11A and FAM83A in tumor progression. Results: After a series of studies, we found a strong correlation between ARHGAP11A and FAM83A in LUAD and PAAD across 33 tumor types. In the collected tumor and adjacent cancer groups, the correlation between ARHGAP11A and FAM83A was significant and highly distributed in the LUAD and PAAD groups. Meanwhile, ARHGAP11A and FAM83A were significantly enriched in the MYC, MTORC1, and glycolysis-related pathways. A series of related and intersection analyses revealed that ARHGAP11A and FAM83A were highly correlated with lactate dehydrogenase A (LDHA). Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) experiments showed that the expression of ARHGAP11A had a significant effect on FAM83A and LDHA. Additionally, FAM83A also affected LDHA expression. The risk model played an important role in patient diagnosis and prognosis. Further, this risk model served as a superior independent prognostic factor compared with other clinical and pathological parameters. Finally, the knock down of ARHGAP11A and FAM83A significantly affected the glycolysis, proliferation, apoptosis resistance, cell-cycle progression, migration, invasion, and mitochondrial membrane potential of LUAD and PAAD cells. Conclusions: This study showed that ARHGAP11A affects the occurrence and development of LUAD and PAAD by regulating the expression of FAM83A. This study also provides a new perspective for later tumor treatment.