BUB1-deficiency suppresses kidney renal clear cell carcinoma progression via the PI3K/Akt pathway: A bioinformatics-oriented validating study

Abstract

Although great advances have been reached in the diagnosis, treatment and prognosis of kidney renal clear cell carcinoma (KIRC), the advancement of therapeutic strategies for KIRC in clinical practices have been seriously limited due to its unknown molecular mechanisms. To resolve this issue, through analyzing the datasets from the online UCSC database, a novel BUB1 gene was found to be elevated in the cancerous tissues compared to their normal tissues of KIRC, and and KIRC patients with high-expressed BUB1 tended to have a worse prognosis. The subsequent experiments validated that BUB1 protein was located in both nucleus and cytoplasm of KIRC cells, and the expression levels of BUB1 gene were significantly elevated in KIRC tissues and cells, in contrast to their normal counterparts. Loss-of-function experiments verified that knockdown of BUB1 suppressed cell proliferation, mobility, epithelial-mesenchymal transition (EMT) and tumor growth, whereas induced apoptotic cell death in the KIRC cells in vitro and in vivo. In addition, bioinformatics analysis predicted that the differentially-expressed genes (DEGs) in the BUB1-deficient cohorts were enriched in the cell division-related PI3K/Akt signal pathway, and we evidenced that silencing of BUB1 was capable of inactivating the downstream PI3K/Akt signal pathway. Of note, deficiency of BUB1-induced suppressing effects on the malignant phenotypes in KIRC cells were all reversed by co-treating cells with PI3K/Akt pathway activator 740Y-P. Furthermore, it was found that the expression status of BUB1 gene were related with epigenetic modifications, immune infiltration and immunotherapy responses in KIRC. Collectively, silencing of BUB1 inhibited the progression of KIRC through inactivating the downstream PI3K/Akt signal pathway, and BUB1 gene could be potentially used as biomarkers for the diagnosis and treatment of KIRC in clinic.