Pan-cancer analysis of the prognosis and immunological role of AKAP12: A potential biomarker for resistance to anti-VEGF inhibitors

The primary or acquired resistance to anti-VEGF inhibitors remains a common problem in cancer treatment. Therefore, identifying potential biomarkers enables a better understanding of the precise mechanism. Through the GEO database, three profiles associated with bevacizumab (BV) resistance to ovarian cancer, glioma, and non-small-cell lung carcinoma, respectively, were collected for the screening process, and two genes were found. A-kinase anchor protein 12 (AKAP12), one of these two genes, correlates with tumorigenesis of some cancers. However, the role of AKAP12 in pan-cancer remains poorly defined. The present study first systematically analyzed the association of AKAP12 with anti-VEGF inhibitors' sensitivity, clinical prognosis, DNA methylation, protein phosphorylation, and immune cell infiltration across various cancers via bioinformatic tools. We found that AKAP12 was upregulated in anti-VEGF therapy-resistant cancers, including ovarian cancer (OV), glioblastoma (GBM), lung cancer, and colorectal cancer (CRC). A high AKAP12 expression revealed dismal prognoses in OV, GBM, and CRC patients receiving anti-VEGF inhibitors. Moreover, AKAP12 expression was negatively correlated with cancer sensitivity towards anti-VEGF therapy. Clinical prognosis analysis showed that AKAP12 expression predicted worse prognoses of various cancer types encompassing colon adenocarcinoma (COAD), OV, GBM, and lung squamous cell carcinoma (LUSC). Gene mutation status may be a critical cause for the involvement of AKAP12 in resistance. Furthermore, lower expression of AKAP12 was detected in nearly all cancer types, and hypermethylation may explain its decreased expression. A decreased phosphorylation of T1760 was observed in breast cancer, clear-cell renal cell carcinoma, and lung adenocarcinoma. For the immunologic significance, AKAP12 was positively related to the abundance of pro-tumor cancer-associated fibroblasts (CAFs) in various types of cancer. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that "cell junction organization " and "MAPK pathway " participated in the effect of AKAP12. Importantly, we discovered that AKAP12 expression was greatly associated with metastasis of lung adenocarcinoma as well as differential and angiogenesis of retinoblastoma through investigating the single-cell sequencing data. Our study showed that the dual role of AKAP12 in various cancers and AKAP12 could serve as a biomarker of anti-VEGF resistance in OV, GBM, LUSC, and COAD.