Abstract
Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression.
Highlights
Renal cell carcinoma (RCC) is the most common type of kidney tumor and the most lethal urological cancer [19, 29], with high metastatic rate and poor prognosis in diagnosed renal cell carcinoma (RCC) patients [21, 38]
Addition of miR-145 could reverse the androgen receptor (AR)-enhanced VHL expression (Figure 5D) with a consequent increase of downstream signals. These results suggest that AR-suppressed miR-145 signals can override the opposing AR-enhanced VHL to result in the increase of the HIF2α/VEGF signals in VHL wild-type RCC ACHN cells (Figure 5D)
Few studies linked the miRNAs to AR function in RCC progression even though recent reports demonstrated that some miRNAs might play a role in AR-mediated signals in prostate cancer progression [18, 20, 30, 34]
Summary
Renal cell carcinoma (RCC) is the most common type of kidney tumor and the most lethal urological cancer [19, 29], with high metastatic rate and poor prognosis in diagnosed RCC patients [21, 38]. The epidemiological studies indicated that the gender difference with male: female ratio in RCC incidence is 1.6: 1.0 [8, 11], suggesting that sex hormones and their receptors may play important roles in the development of RCC. Studies with clinical surveys found the AR could be detected at various stage of RCC, yet the linkage of AR expression to the RCC proliferation and metastasis remains unresolved www.impactjournals.com/oncotarget [5, 15, 33]. MicroRNAs (miRNAs) can function as tumor suppressors or oncogenes in various cancers [36] and early studies suggested that miRNAs might play important roles in RCC progression [32]. We identified a new signal showing AR-suppressed miRNA-145 played a key role to influence the RCC proliferation and invasion via upregulation of HIF2α/VEGF/MMP9/CCND1 signals
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