YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression.

Hippo-Yes-associated protein 1 (YAP1) plays an important role in gastric cancer (GC) progression; however, its regulatory network remains unclear. In this study, we identified Copine III (CPNE3) was identified as a novel direct target gene regulated by the YAP1/TEADs transcription factor complex. The downregulation of CPNE3 inhibited proliferation and invasion, and increased the chemosensitivity of GC cells, whereas the overexpression of CPNE3 had the opposite biological effects. Mechanistically, CPNE3 binds to the YAP1 protein in the cytoplasm, inhibiting YAP1 ubiquitination and degradation mediated by the E3 ubiquitination ligase ß-transducin repeat-containing protein (ß-TRCP). Thereby activating the transcription of YAP1 downstream target genes, which creates a positive feedback cycle to facilitate GC progression. Immunohistochemical analysis demonstrated significant upregulation of CPNE3 in GC tissues. Survival and Cox regression analyses indicated that high CPNE3 expression was an independent prognostic marker for GC. This study elucidated the pivotal involvement of an aberrantly activated CPNE3/YAP1 positive feedback loop in the malignant progression of GC, thereby uncovering novel prognostic factors and therapeutic targets in GC.

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment.

BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. CONCLUSION: Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".

Pan-cancer analysis reveals potential of FAM110A as a prognostic and immunological biomarker in human cancer.

Background: Despite great success, immunotherapy still faces many challenges in practical applications. It was previously found that family with sequence similarity 110 member A (FAM110A) participate in the regulation of the cell cycle and plays an oncogenic role in pancreatic cancer. However, the prognostic value of FAM110A in pan-cancer and its involvement in immune response remain unclear. Methods: The Human Protein Atlas (HPA) database was used to detect the expression of FAM110A in human normal tissues, the Tumor Immune Estimation Resource (TIMER) and TIMER 2.0 databases were used to explore the association of FAM110A expression with immune checkpoint genes and immune infiltration, and the Gene Set Cancer Analysis (GSCA) database was used to explore the correlation between FAM110A expression and copy number variations (CNV) and methylation. The LinkedOmics database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Statistical analysis and visualization of data from the The Cancer Genome Atlas (TCGA) or the Genotype-Tissue Expression (GTEx) databases were performed using the R software (version 3.6.3). Clinical samples were validated using immunohistochemistry. Results: FAM110A expression was elevated in most tumor tissues compared with that in normal tissues. CNV and methylation were associated with abnormal FAM110A mRNA expression in tumor tissues. FAM110A affected prognosis and was associated with the expression of multiple immune checkpoint genes and abundance of tumor-infiltrating immune cells across multiple types of cancer, especially in liver hepatocellular carcinoma (LIHC). FAM110A-related genes were involved in multiple immune-related processes in LIHC. Conclusion: FAM110A participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in LIHC. FAM110A may serve as a prognostic and immunological biomarker for human cancer.