RESUMO
Introduction: Cell cycle-associated cyclin-dependent kinases (ccCDKs) are essential regulators known to control cell division and facilitate tumorigenesis and progression. However, there is currently no comprehensive study of distinct ccCDKs in prostate cancer (PCa). The purpose of this study was to determine the value of ccCDK expression in predicting the prognosis of patients with PCa and to identify the gene functions of ccCDK in PCa. Methods: The UALCAN databases were analyzed to examine the expression of CDKs in prostate cancer. The Human Protein Atlas was used to verify the expression of CDKs online. Then, we assessed the prognostic values of CDKs using GEPIA. GeneMANIA and Metascape analyses were used to predict biological functions. We analyzed the mutation of CDKs by cBioPortal. The TIMER database was used to evaluate the correlation of CDKs and immune infiltration. The expression of CDKs in tissue was examined through quantitative real-time polymerase chain reaction. After that, we focused on CDK3 and identified the expression of CDK3 by immunohistochemistry and western blot. The functions of CDK3 in C4-2 cell proliferation were determined by CCK-8 assays. C4-2 cells were tested for their ability to invade and migrate through transwell and wound healing assays. Results: The results showed that CDK1/3/4/5/6/16 was expressed at relatively higher levels in PCa tissues than in normal tissues. Patients with low expression of CDK1/3/5/16 exhibited significantly better disease-free survival than those with high expression. ccCDKs were enriched in the IL-18 signaling pathway and correlated with the infiltration of immune cells in PCa. Moreover, our cohort study data verified that there were significantly higher expression of CDK1/3/5/16 in PCa tissues compared to benign prostate hyperplasia tissues, and CDK3 was remarkably associated with a shorter progression-free survival for biochemical recurrence in PCa patients. CDK3 was positively expressed in PCa cells and tissues, and functional experiments demonstrated that silencing CDK3 inhibited PCa cell proliferation, migration, and invasion. Conclusions: Our study provides new evidence of ccCDKS in promoting PCa progression and implies that CDK3 may serve as an oncogene in PCa and may be valuable in the prognosis of biochemical recurrence in PCa patients.
RESUMO
Background: Abnormal regulation of the NOTCH signaling pathway in prostate cancer (PCa) can promote tumorigenesis, progression, and T cell exhaustion. However, there has not been a comprehensive analysis of NOTCH family genes (NOTCHs) as potential therapeutic targets and prognostic biomarkers for PCa patients. Methods: NOTCHs expressions in various types of cancer tissues and normal adjacent tissues in the TIMER and UALCAN database were screened. Immunohistochemistry (IHC) and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were applied to validate the expression pattern of NOTCHs in clinical samples. The relationships of NOTCHs expression and clinicopathologic parameters or disease-free survival (DFS) were evaluated via GEPIA2 and UALCAN. A proteins network was built using STRING and GeneMANIA. Additionally, NOTCHs mutation status was analyzed by cBioportal. Finally, we used GDSC and TIMER to investigate NOTCH signaling-related drugs and immune cell infiltration. Results: The transcriptional levels of NOTCH1 and NOTCH4 in PCa tissues were significantly lower than in normal tissues, which was further validated in clinical patients' tissue samples. Furthermore, NOTCH1, NOTCH3, and NOTCH4 expressions in PCa were associated with worse DFS. Interestingly, there was a significant positive correlation between NOTCHs and androgen receptor (AR), but not with AR-related genes (KLK3 and TMPRSS2). Finally, we found that NOTCHs expressions were remarkably associated with infiltration of B cells, CD8+/CD4+ T cells, macrophages, neutrophils, and dendritic cells, which indicated that NOTCHs mutation status might be a potential therapeutic target for -tinib antineoplastic drugs. Conclusions: The expression and mutation of NOTCH1-4 in PCa were associated with disease progression, prognosis, immune cell infiltration, and drug sensitivity.
