ABSTRACT
Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC. Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan-Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression. Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-ß, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation. Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.
ABSTRACT
We investigated the role of the competing endogenous RNA (ceRNA) network in the development and progression of pancreatic adenocarcinoma (PAAD). We analyzed the expression profiles of PAAD and normal pancreatic tissues from multiple GEO databases and identified 457 differentially expressed circular RNAs (DEcircRNAs), 19 microRNAs (DEmiRNAs) and 1993 mRNAs (DEmRNAs). We constructed a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs that regulates the NF-kappa B, PI3K-Akt, and Wnt signaling pathways. We then identified and validated five hub genes, CXCR4, HIF1A, ZEB1, SDC1 and TWIST1, which are overexpressed in PAAD tissues. The expression of CXCR4, HIF1A, ZEB1, and SDC1 in PAAD was regulated by circ-UBAP2 and hsa-miR-494. The expression of CXCR4 and ZEB1 correlated with the levels of M2 macrophages, T-regulatory cells (Tregs) and exhausted T cells in the PAAD tissues. The expression of CXCR4 and ZEB1 positively correlated with the expression of CTLA-4 and PD-1. This suggests that CXCR4 and ZEB1 proteins inhibit antigen presentation and promote immune escape mechanisms in PAAD cells. In summary, our data suggest that the circUBAP2-mediated ceRNA network modulates PAAD by regulating the infiltration and function of immune cells.
