Comprehensive Analysis of Alternative Polyadenylation Events Associated with the Tumor Immune Microenvironment in Colon Adenocarcinoma.

Objective: Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood. Methods: We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established. Results: A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells. Conclusion: Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM.

Overexpression of PRKCH promotes tumorigenesis in patients with glioma and influences glioma stem cell properties.

BACKGROUND: PRKCH is a member of the PKC family with the potential to regulate cell proliferation and differentiation. Glioma is the most common primary tumor of the central nervous system, with a high recurrence rate and poor prognosis. Recent studies have demonstrated that PRKCH can promote the proliferation of glioma cells. The purpose of this study was to investigate the promoting effect and possible mechanism of PRKCH on glioma development. METHODS: Tumor tissue and paracancerous tissue were collected from 160 glioma patients treated at the General Hospital of Northern Theater Command. The expression level of PRKCH was detected by immunohistochemistry and immunoblotting. Univariate/multivariate analysis and log-rank analysis, as well as prognosis and survival analysis, were performed using SPSS26 software. The PRKCH overexpression model was constructed in vitro to study the effect of PRKCH expression on the characteristics of glioma stem cells. RESULTS: The expression of PRKCH in glioma tissues was higher than that in adjacent tissues. PRKCH expression level is an independent prognostic factor in glioma patients, promoting poor prognosis and shorter survival in glioma patients. Furthermore, overexpression of PRKCH in glioma stem cells significantly increased stem cell properties and enhanced cell viability. Downregulation of PRKCH significantly inhibited the progression of glioma stem cells. CONCLUSION: PRKCH promotes the development of gliomas and may be a therapeutic target for gliomas.

The expression of epidermal growth factor receptor 1 and human epidermal growth factor receptor 2 based on tumor location affect survival in gastric cancer.

To investigate the different expression of epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 2 (HER2) in gastric cancer based on tumor locations and its impact on patients survival.Gastric cancer is heterogeneous disease, recent years have established a molecular classification and described distribution of molecular subtypes in stomach. However, the difference of EGFR and HER-2 expression among tumor location is still unknown.Between January 2010 and August 2014, 2477 consecutive patients with gastric cancer were treated in our surgery department. The tumor locations were classified into 4 groups: cardia, fundus, corpus, and antrum. Based on tumor locations, the clinicopathologic characteristics, EGFR and HER-2 expression, and follow-up data were analyzed by univariant analysis and Kaplan-Meier analysis retrospectively.There were difference of gender, age, Borrmann type, pathological type, differentiation, T-stage, tumor size, gastrectomy method, and complications among the locations. The positive rate of EGFR expression in fundus was 18.18%, which was lower than cardia (46.21%), corpus (43.62%), and antrum (48.83%) (P < .001). The 5-year survival rate in EGFR positive patients was 50.8%, which was significantly lower than EGFR negative patients (64.0%, P = .021). The positive rate of HER-2 expression in cardia was 48.15%, which was significantly higher than fundus (37.5%), corpus (35.45%), and antrum (38.54%) (P = .009), but HER-2 expression did not correlate with 5-year survive (P = .548).Our results suggest that there exist difference of EGFR and HER-2 expression based on tumor locations, and the distribution of EGFR impact on patients survival. Emphasizing the role of EGFR and HER-2 in the context of location contribute to make appropriate treatment strategy and improve prognosis of gastric cancer.