AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1α and inducing cell migration and invasion

Abstract

The angiotensin II type I receptor (AGTR1) has a strong influence on tumor growth, angiogenesis, inflammation and immunity. However, the role of AGTR1 on lymph node metastasis (LNM) in breast cancer, which correlates with tumor progression and patient survival, has not been examined. AGTR1 was highly expressed in lymph node-positive tumor tissues, which was confirmed by the Oncomine database. Next, inhibition of AGTR1 reduced tumor growth and LNM in orthotopic xenografts by bioluminescence imaging (BLI). Losartan, an AGTR1-specific inhibitor, decreased the chemokine pair CXCR4/SDF-1α levels in vivo and inhibited AGTR1-induced cell migration and invasion in vitro . Finally, the molecular mechanism of AGTR1-induced cell migration and LNM was assessed by knocking down AGTR1 in normal cells or CXCR4 in AGTR1 high cells. AGTR1-silenced cells treated with losartan showed lower CXCR4 expression. AGTR1 overexpression caused the upregulation of FAK/RhoA signaling molecules, while knocking down CXCR4 in AGTR1 high cells downregulated these molecules. Collectively, AGTR1 promotes LNM by increasing the chemokine pair CXCR4/SDF-1α and tumor cell migration and invasion. The potential mechanism of AGTR1-mediated cell movement relies on activating the FAK/RhoA pathway. Our study indicated that inhibiting AGTR1 may be a potential therapeutic target for LNM in early-stage breast cancer.

A signature of seven immune-related genes predicts overall survival in male gastric cancer patients

“…In GC, the utility of AGTR1 inhibitor signi cantly suppress GC cell proliferation and stromal brosis [28]. It has been proved that AGTR1 could enhance malignant phenotype of several cancer cells to promote tumor progression [29][30][31].…”

Differences in expression of genes related to drug resistance and miRNAs regulating their expression in skin fibroblasts exposed to adalimumab and cyclosporine A

“…Yamani et al described that overexpression of AGTR1 was associated with response to rejection after transplantation [43]. Observations by Ma et al showed that AGTR1 can be a useful supplementary marker and explained that overexpression of this gene was strongly associated with promoting epithelial-mesenchymal transition [44], what also showed that during cyclosporine therapy a higher risk of carcinogenesis might be observed [45]. These and our results suggest that during the cyclosporine A treatment, a drug resistance phenomenon may be observed, however its frequency is lower compared with the adalimumab therapy.…”

Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions

“…Moreover, it was shown that Ang II induced CSC marker expression and facilitated tumor cell survival in NSCLC cells line [77]. Recent data from a breast cancer model revealed an additional mechanism whereby ATR1 promotes tumor cell contraction, migration and invasion by upregulating the C-X-C chemokine receptor type 4 (CXCR4)/Stromal cell derived factor-1α (SDF-1α) signaling through the Focal adhesion kinase (FAK)/Ras homolog family member A (RhoA)/Rho associated kinase 1/2 (ROCK1/2)/Myosin light-chain kinase (MLC) pathway, ultimately inducing metastatic disease [78]. Taken together, these findings support a role for mediators of the Ang II/ATR1 axis as lung cancer modulators, particularly influencing malignant cell growth, dedifferentiation, and migration ( Figure 2).…”