Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway

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.

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

“…In particular, alpha 2 integrin (ITGA2) forms a heterodimer with beta 1 subunit (α2β1) and functions as a collagen and laminin receptor [25] and is involved in the disease progression. Overexpression of ITGA2 increases cell proliferation and invasiveness of cancer cells by activation of the PD-L1/STAT3 axis [26]. In addition, ITGA2-induced chemoresistance is reversed by upregulation of miR-135b-5p, which inhibits MAPK/ERK and EMT pathways in gastric cancer cells [27].…”

Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway

“…Flag-ITGA2 plasmids were constructed by Shanghai Genechem Co., LTD. Human expression vectors for flag-ITGA2 recombinant proteins were generated using the pcDNA3.1 backbone vector, as described previously [42]. Selected antibodies included ITGA2 (Abcam, ab133557, dilution ratio 1:1000), GAPDH (Proteintech, 10494-1-AP, dilution ratio 1:2000), AKT (Cell Signaling Technology, 2920, dilution ratio 1:1000), pAKT-S473 (Cell Signaling Technology, 4060, dilution ratio 1:1000), TLR4 (Proteintech, 19811-1-AP, dilution ratio 1:1000), and Caspase-3 (Proteintech, 19677-1-AP, dilution ratio 1:1000).…”

Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis

“…Furthermore, ITGA2 controls the MAPK pathways and EMT in gastric cancer cells, and these events closely contribute to the chemo-resistance of gastric cancer [55]. A recent study has shown that ITGA2 increases the expression of PD-L1 by activating the STAT3 pathway in pancreatic cancer [56]. These studies indicate that overexpression of ITGA2 activates various molecular pathways and important effects on malignant transformation of cancer cells.…”