Abstract
BackgroundRecent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. However, the specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear.MethodsThe GEPIA web tool was used to find the clinical relevance of ITGA2 in cancer, and this significance was verified using Western blotting analysis of paired patient tissues and immunohistochemistry of the pancreatic cancer tissue. Functional assays, such as the MTS assay, colony formation assay, and transwell assay, were used to determine the biological role of ITGA2 in human cancer. The relationship between ITGA2 and programmed death-ligand 1 (PD-L1) was examined using Western blot analysis, RT-qPCR assay, and immunohistochemistry. The protein-protein interaction between ITGA2 and STAT3 was detected via co-immunoprecipitation.ResultsOur study showed that ITGA2 was markedly overexpressed in several malignant tumor cells and clinical tissues. Blocking ITGA2 inhibited the proliferation and invasion ability of cancer cells significantly, whereas overexpressed ITGA2 increased the degree of those processes considerably. Additionally, the RNA-seq assay indicated that ITGA2 transcriptionally regulated the expression of PD-L1 in pancreatic cancer. We also demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Our results suggest that ITGA2 plays a critical role in cancer cell progression and the regulation of PD-L1 by activating the STAT3 pathway.ConclusionsWe identified a novel mechanism by which ITGA2 plays a critical role in modulating cancer immune response by transcriptionally increasing the expression of PD-L1 in cancer cells. Thus, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy against cancer.
Highlights
According to findings in the Global Health Observatory data repository from 2011, malignant tumors caused more deaths than coronary heart diseases or stroke
We further revealed that Integrin alpha 2 (ITGA2) interacted with Signal transducer and activator of transcription 3 (STAT3) and up-regulated programmed deathligand 1 (PD-L1) expression by increasing the phosphorylation of STAT3 in cancer cells
The overexpression of ITGA2 correlates with unfavorable prognoses in malignant tumors After analyzing the mRNA expression level of ITGA2 in several cancers and non-tumor tissues using the Gene Expression Profiling Interaction Analysis (GEPIA) web tool, we found that the mRNA expression level of ITGA2 was significantly up-regulated in pancreatic adenocarcinoma (PAAD) and stomach adenocarcinoma (STAD) (Fig. 1)a
Summary
According to findings in the Global Health Observatory data repository from 2011, malignant tumors caused more deaths than coronary heart diseases or stroke (http://apps.who.int/gho/data/node.main.CODWORLD?lang=en). Studying the pathogenesis of malignant tumors is essential for identifying more therapeutic targets for cancer treatment. Increasing evidence has suggested that ITGA2 might play an essential role in modulating tumor cell migration, invasion, and metastasis [10, 11]. The specific mechanism of how ITGA2 is involved in all this is still confusing. The loss of ADAR1 could lead to the up-regulation of ITGA2 in hepatocellular carcinoma [12]. We hypothesized that ITGA2 might regulate immune checkpoint blockade responses in tumors. Recent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. The specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear
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