An ion channel-based prognostic model identified TRPV2 and GJB3 as immunotherapy determinants in pancreatic cancer.

Background: Less than 10% of people who have pancreatic ductal adenocarcinoma (PDAC) will survive the malignancy for five years. The ion channel genes-related biomarker and predictive model were needed for exploitation. Methods: Differentially expressed ion channel genes (DEICGs) were detected in PDAC patients. GO and KEGG enrichment analysis was conducted on DEICGs. The prognostic genes were found using Cox regression analysis. After that, a risk model was created and examined. A nomogram was created based on independent predictive analysis. The molecular functions of two risk groups were explored. Immune checkpoint molecule expression was compared in two risk groups. We evaluated the possible cancer immunotherapy response in two risk groups using the TIDE method. We further examined how TRPV2 functions in PDAC as a potent oncogene and regulates the activity of macrophages by in vitro validation, including CCK8, EdU, and Transwell assays. Results: A total of twenty-four DEICGs were found. Next, we discovered that two DEICGs (TRPV2 and GJB3) were connected to PDAC patients' overall survival (OS). The risk model was created and validated, and a nomogram was used to forecast the overall survival of PDAC patients. The high-risk group considerably accumulated oncogenic pathways. Furthermore, we discovered a correlation between the expression of critical immunological checkpoints and the risk score. Furthermore, patients in the high-risk category had a lower chance of benefiting from immune therapy. The HPA database confirmed that TRPV2 is expressed as a protein. Lastly, TRPV2 controls macrophage activity and acts as a potent oncogene in PDAC. Conclusion: Altogether, this study suggested that two ion channel genes, TRPV2 and GJB3, were potential biomarkers for the prognosis of PDAC and immunotherapy targets, and the research will be crucial for creating novel PDAC treatment targets and predictive molecular indicators.

Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma.

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-ß-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

Exosome-derived ENO1 regulates integrin α6ß4 expression and promotes hepatocellular carcinoma growth and metastasis.

Alpha-enolase (ENO1) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). Although the role of ENO1 as a glycolytic enzyme in HCC cells has been well characterized, little is known about the other roles of ENO1, especially exosome-derived ENO1, in regulating HCC progression. Here, we demonstrated that ENO1 is frequently upregulated in HCC cells or tissues, with even higher expression in highly metastatic HCC cells or metastatic tissues as well as in exosomes derived from highly metastatic sources. Moreover, ENO1 expression is associated with the tumor-node-metastasis (TNM) stage, differentiation grade and poor prognosis in HCC patients. Surprisingly, ENO1 can be transferred between HCC cells via exosome-mediated crosstalk, exhibiting an effect similar to that of ENO1 overexpression in HCC cells, which promoted the growth and metastasis of HCC cells with low ENO1 expression by upregulating integrin α6ß4 expression and activating the FAK/Src-p38MAPK pathway. In summary, our data suggest that exosome-derived ENO1 is essential to promoting HCC growth, metastasis, and further patient deterioration. The findings from this study implicate a novel biomarker for the clinical evaluation of HCC progression, especially the prediction of HCC metastatic risk.

CBX2 Regulates Proliferation and Apoptosis via the Phosphorylation of YAP in Hepatocellular Carcinoma.

Chromobox 2 (CBX2), a chromobox family protein, is a crucial component of the polycomb group complex: polycomb repressive complex 1 (PRC1). Research on CBX2 as an oncogene has been published in recent years. However, the connection between CBX2 and hepatocellular carcinoma (HCC) has not been studied. In this article, based on the results of immunohistochemical (IHC) staining of HCC and adjacent liver tissue microarrays, we found that high CBX2 expression is associated with poor prognosis in HCC patients. The results of a CCK8 assay, a clonogenic survival assay and a nude mouse tumorigenicity assay showed that knockdown of CBX2 inhibited the proliferation of HCC cells. According to the results of Annexin V-FITC/propidium iodide (PI) staining-based fluorescence activated cell sorting (FACS) analysis, knockdown of CBX2 increased HCC cell apoptosis. Furthermore, the RNA-seq results revealed that knockdown of CBX2 inhibited the expression of WTIP, which is an inhibitor of the Hippo pathway. We used western blotting to validate the mechanism and discovered that knockdown of CBX2 increased the phosphorylation of YAP, which explains why knockdown of CBX2 inhibits proliferation and increases apoptosis in HCC cells. In conclusion, CBX2 could be a potential target for HCC anticancer treatment.

SIRT5 Promotes Hepatocellular Carcinoma Progression by Regulating Mitochondrial Apoptosis.

SIRT5 belongs to a family of NAD+-dependent lysine deacetylases called sirtuins. Although accumulating evidence indicates SIRT5 upregulation in cancers, including liver cancer, the detailed roles and mechanisms remain to be revealed. Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths among men worldwide, and finding effective targets for HCC treatment and prevention is urgently needed. In the present study, we confirmed that mitochondrial sirtuins, particularly SIRT5, are more highly expressed in HCC cell lines than in normal liver cell lines. Moreover, SIRT5 knockdown suppresses HCC cell proliferation and SIRT5 overexpression promotes HCC cell proliferation. Furthermore, we verified that SIRT5 knockdown increases HCC cell apoptosis via the mitochondrial pathway. By co-IP and western blotting, we illustrated that SIRT5 deacetylates cytochrome c thus regulating HCC cell apoptosis. Taken together, our findings suggest that SIRT5 may function as a prognostic factor and drug target for HCC treatment.