PKCι Is a Promising Prognosis Biomarker and Therapeutic Target for Pancreatic Cancer.

BACKGROUND: As the highest prevalent pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) ranks the 7th lethal malignancy worldwide. The late diagnosis, chemotherapeutic resistance, and high associated mortality make PDAC a dilemma facing the oncologists. Protein kinase C (PKC) enzymes have been shown to be important in different cancer progression. METHODS: To understand the pattern of PKC enzymes in PDAC, we examined all PKC family member genes expression in PDAC and matched normal tissues. The critical role of PKCι was further investigated in different PDAC cells using cellular and molecular technology. RESULTS: We found that PRKCI (PKCι) was the most significantly overexpressed PKCs in pancreatic cancer. However, little is known about its role and regulation of oncogenic signaling pathways in pancreatic cancer. In this study, we confirmed the overexpression of PKCι in PDAC, and this high expression was associated with poor prognosis of patients. We proved that knockdown of PKCι by small interfering RNA or shRNA significantly inhibited pancreatic cancer cell growth and migration or invasion. Conversely, PKCι overexpression promoted pancreatic cancer cell growth and migration. Moreover, bioinformatical and technical studies informed the participation of PKCι in regression of apoptosis in PDAC cells, which may be related to the regulation of both PI3K/AKT and Wnt/ß-catenin pathways. CONCLUSIONS: Therefore, our results are adding more insight into the importance of PKCι in pancreatic cancer. PKCι induces pancreatic cancer progression through activation of PI3K/AKT and Wnt/ß-catenin signaling pathways, which may provide a promising therapeutic target for pancreatic cancer.

Centromere protein F promotes progression of hepatocellular carcinoma through ERK and cell cycle-associated pathways.

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. The centromere proteins (CENPs) are critical for the mitosis-related protein complex and are involved in kinetochore assembly and spindle checkpoint signaling during mitosis. However, the clinical significance of CENPs in the recurrence and progression of HCC remains poorly understood. Here, we examined the expression of all CENPs and their association with recurrence and survival of HCC patients using the global gene expression profile dataset established in our laboratory. The effect of silencing CENPF on cell viability, migration, and epithelial-mesenchymal transition (EMT) were detected using CCK-8, transwell, and western blot, respectively. RT-qPCR and western blot were performed to confirm the silencing of CENPF and the relationship between STAT5A and CENPF, while tumorigenesis was tested using the HCC Huh7 xenograft mouse model. Most of the CENPs is overexpressed in HCC, and overexpression of CENPF was significantly associated with the poor survival of HCC patients. CENPF promoted HCC cell lines migration and EMT progression. Knockdown CENPF inhibited cell growth activity against human HCC cells in vitro and xenograft tumors in vivo. Bioinformatics analysis revealed that CENPF genes are enriched in the cell cycle. Silencing CENPF arrested cell cycle at the G2/M phase and inhibited Cyclin B1 and Cyclin E1 expressions. Meanwhile, silencing CENPF prohibited phosphorylation of ERK and the expression of NEK2. Additionally, we found that STAT5A down-regulated CENPF expression and inhibited cancer cell growth viability. In conclusion, our data suggested that CENPF could be potentially developed into a theranostic biomarker to tackle HCC progression.

Pan-Cancer Study on Protein Kinase C Family as a Potential Biomarker for the Tumors Immune Landscape and the Response to Immunotherapy.

The protein kinase C (PKC) family has been described with its role in some cancers, either as a promoter or suppressor. PKC signaling also regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha (PPARalpha). However, the role of different PKC enzymes in tumor immunity remains poorly defined. This study aims to investigate the correlation between PKC genes and tumor immunity, in addition to studying the probability of their use as predictive biomarkers for tumor immunity and immunotherapeutic response. The ssGSEA and the ESTIMATE methods were used to assess 28 tumor-infiltrating lymphocytes (TILs) and the immune component of each cancer, then correlated with PKC levels. Prediction of PKC levels-dependent immunotherapeutic response was based on human leukocytic antigen (HLA) gene enrichment scores and programmed cell death 1 ligand (PD-L1) expression. Univariate and multivariate Cox analysis was performed to evaluate the prognostic role of PKC genes in cancers. Methylation level and CNAs could drive the expression levels of some PKC members, especially PRKCI, whose CNGs are predicted to elevate their level in many cancer types. The most crucial finding in this study was that PKC isoenzymes are robust biomarkers for the tumor immune status, PRKCB, PRKCH, and PRKCQ as stimulators, while PRKCI and PRKCZ as inhibitors in most cancers. Also, PKC family gene levels can be used as predictors for the response to immunotherapies, especially HLAs dependent and PD-L1 blockade-dependent ones. In addition to its prognostic function, all PKC family enzymes are promising tumor immunity biomarkers and can help select suitable immune therapy in different cancers.