Androgen receptor promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of MMP-9 and COX-2

Abstract

Dysregulated androgen receptor (AR) signaling is implicated in several types of tumor, including carcinomas of the prostate, breast, liver and bladder. However, the contribution of AR to the progression of upper urinary tract urothelial carcinomas (UUTUC) has not been fully investigated. In the present study, we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells. We investigated the role of the AR in UUTUC by using UUTUC-derived BFTC 909 cells. The overexpression of AR promotes the migration and invasion of BFTC 909 cells. Expression of migration/invasion-related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses. The results showed that AR-enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix-degrading enzyme MMP-9 and cyclooxygenase (COX)-2. Subsequently, the blocking of MMP-9 and COX-2 signaling by inhibitors suppressed AR-enhanced cell migration and invasion. The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT. Thus, the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer.

Gender differences in incidence and outcomes of urothelial and kidney cancer

“…64 Overexpression of AR has been associated with tumour cell migration and invasion in UTUC cell lines, suggesting AR could be a therapeutic target in patients who are positive for AR expression (Figure 2). 65 Currently, available data are still not sufficient to make any conclusions concerning the effect of gender in patients with UTUC. However, male patients seem to have a higher incidence of the disease, whereas survival might be independent of gender.…”

High Consumption of Green Tea Suppresses Urinary Tract Recurrence of Urothelial Cancer via Down-regulation of Human Antigen-R Expression in Never Smokers

“…molecules including vascular endothelial growth factors, cyclooxygenase, and matrix metalloproteins via stability of their mRNA (26)(27)(28)(29). These HuR-related molecules play important roles in carcinogenesis, cancer cell proliferation, angiogenesis, and tumor invasion in UC (30)(31)(32)(33). In fact, HuR was reportedly associated with metastasis and survival via the regulation of cancer cell proliferation, angiogenesis, and expression of vascular endothelial growth factor-A and -C in BC patients (17).…”

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver

“…AR roles in migration/invasion of UUTUC cells and its linkage to chemotherapy UUTUC patients with locally advanced and poorly differentiated tumors may have a poorer outcome since they may experience disease recurrence and subsequently die from metastatic UUTUC. 57,62 Chen et al 63 found that addition of functional AR into UUTUC transformed cell lines, SV-HUC and BFTC 909, led to increased cell migration and invasion that might be mediated by the upregulation of the metastasis-related genes, matrix metalloproteinase-9, Rock-1 and Cox 2 by the AR. Targeting the AR with ASC-J9, in the UUTUC BFTC 909 cells resulted in increased cell sensitivity to both chemotherapeuic agents, doxorubicin and mitomycin C. 63 Hsieh et al 64 also found that addition of the AR in BFTC 909 cells increased cell viability on treatment with chemotherapeutic agents, cisplatin and doxorubicin, an effect that might be mediated through modulation of the membrane transporter protein ABCG2, a multi-drug chemoresistance factor in cancer cells.…”