Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic adenocarcinoma and stomach adenocarcinoma: An integrative pan-cancer analysis

Background: Thrombospondin-2 (THBS2) is a versatile glycoprotein that regulates numerous biological functions, including the apoptosis-proliferation balance in endothelial cells, and it has been linked to tumor angiogenesis. However, the role of THBS2 in human cancer remains unknown. This study aimed to determine THBS2 expression in pan-cancer, understand whether THBS2 is associated with its prognosis, and to identify possible roles of THBS2 in tumor immunity and the extracellular matrix (ECM). Methods: Data about THBS2 expression in cancers and normal tissues were downloaded from the Genotype-Tissue Expression (GTEx) and UCSC Xena and analyzed using the ONCOMINE database, Perl programming language, and the Gene Expression Profiling and Interactive Analyses vision 2 (GEPIA2) web server. Survival prognosis was analyzed using the survival, survminer, and forestplot packages in R v. 4.0.3 and the limma package in R . Immune and matrix components were also analyzed using R v. 4.0.3. Most importantly, we partially validated the role and mechanism of THBS2 in pancreatic and gastric cancers in vitro using PANC1 and BGC-823 cell lines. Results: Thrombospondin-2 was significantly overexpressed in 17 of the 33 investigated cancers, and linked to a poor prognosis in pan-cancer survival analysis, especially in adrenocortical (ACC), kidney renal papillary cell (KIRP), and stomach (STAD) carcinomas, kidney chromophobe (KICH), and pancreatic adenocarcinoma (PAAD). Immune infiltration and THBS2 expression were also related. The expression of THBS2 has been linked to immune scores, stromal scores, and immune checkpoint markers in various cancers. The PPI network revealed that THBS2 is associated with multiple extracellular matrix proteins and immune proteins. Knockdown of THBS2 decreased the expression of CD47 and MMP-2 as well as the proliferation, migration, and invasion of PANC1 and BGC-823 cells in vitro . Conclusions: Our findings suggested that THBS2 could be a prognostic biomarker that acts as a bridge between the ECM and immune infiltration in various types of cancers, and that it promoted the progression of numerous types of cancers, especially PAAD and STAD.