Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth

Abstract

Recent studies have demonstrated that the androgen receptor (AR) could play important roles to promote renal cell carcinoma (RCC) cell proliferation, and other studies have also indicated that suppressing the argininosuccinate synthase 1 (ASS1) could promote proliferation of various tumors. The potential of AR promoting cell proliferation in RCC via altering ASS1, however, remains unclear. Here we found that the expression of ASS1 was lower in RCC tissues than in adjacent normal renal tissues, and a lower ASS1 expression was linked to a worse prognosis in RCC patients. Mechanism dissection showed that AR could decrease ASS1 expression to promote RCC cell proliferation via ASS1P3, a pseudogene of ASS1. The results of RIP assay and AGO2 assay revealed that AR could bind ASS1P3 to increase RCC cell proliferation via altering miR-34a-5p function, which could bind to the 3′UTR of ASS1 to suppress its protein expression. ASS1P3 could function as a miRNA decoy for miR-34a-5p to regulate ASS1 in RCC. Preclinical study also supports the in vitro data. Together, these results demonstrated that ASS1P3 could function as a competing endogenous RNA to suppress RCC cell progression, and targeting this newly identified AR-mediated ASS1P3/miR-34a-5p/ASS1 signaling might help in blocking proliferation.

Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM)viaaltering TWIST1 nonsense-mediated decay through lncRNA-TANAR

“…The androgen receptor (AR) can promote progression and hematogenous metastasis in ccRCC through ASS1P3/miR-34a-5p/ASS1 and miR-185-5p/HIF-2a/VEGF signaling, respectively. This is consistent with the higher incidence and more malignant phenotypes in males according to data from the Surveillance Epidemiology and End Results (SEER) database (5)(6)(7). Furthermore, targeting AR with the antiandrogen enzalutamide could restore sunitinib sensitivity in the sunitinib-resistant PDX mouse model, suggesting enhancing TKI efficacy through inhibition of AR to better suppress ccRCC progression (8).…”

“…Mounting evidence has demonstrated that AR functions as an oncogene in ccRCC, promoting progression and hematogenous metastasis (5,6,23), despite the presence of few retrospective literatures based on TCGA database implied AR may contribute to better prognosis in RCC (9). architecture where cancer cells are embedded in the extracellular matrix (ECM) contacting with cover glass, this novel Collagen I-based 3D culture system prevents cancer cells from the influence of the coverslip, thus a more physiologically relevant in vitro VM model (19).…”

lncRNA 00312 Attenuates Cell Proliferation and Invasion and Promotes Apoptosis in Renal Cell Carcinoma via miR-34a-5p/ASS1 Axis

“…The interbinding function of lncRNA 00312 and miR-34a-5p was also confirmed by luciferase report assay. The miR-34a-5p has been proved to have important biological functions in many tumors, including RCC [23,26,27]. In addition, we further demonstrated that miR-34a-5p is involved in the inhibitory role of lncRNA 00312 on invasion and proliferation of RCC.…”

“…Previous studies also showed that argininosuccinate synthase 1 (ASS1) is a target of miR-34a-5p and can be negatively regulated by miR-34a-5p [23]. ASS1, an enzyme that catalyzes the synthesis of arginine succinic acid by citrulline and aspartic acid, catalyzes the reaction of citrulline with aspartic acid to produce arginine succinic acid [30].…”

“…Cell Carcinoma. Previous studies have shown that miR-34a-5p can bind and negatively regulate ASS1 expression to exert biological functions [23]. In this study, in order to verify whether ASS1 is involved in the function of lncRNA 00312 in RCC, we transfected si-ASS1 and lncRNA 00312 overexpression vector in RCC cells.…”