LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals

Abstract

While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment.

A magic drug target: Androgen receptor

“…Currently, enzalutamide is in combination with gemcitabine and cisplatin at phase I clinical trial for the therapy of bladder cancer (NCT02300610). For kidney cancer, AR and AR signaling also play an important role, and the molecular mechanisms have recently been gradually revealed especially by Chang's group . It is proved that an increased AR expression results in higher hematogenous metastasis and lower lymphatic metastasis of clear cell renal cell carcinoma .…”

“…For kidney cancer, AR and AR signaling also play an important role, 141,142 and the molecular mechanisms have recently been gradually revealed especially by Chang's group. [143][144][145][146][147] It is proved that an increased AR expression results in higher hematogenous metastasis and lower lymphatic metastasis of clear cell renal cell carcinoma. 145 At present, an early phase I clinical trial is in process for enzalutamide to treat kidney cancer before surgery (NCT02885649).…”

Long noncoding RNA TUG1 promotes cell proliferation and migration of renal cell carcinoma via regulation of YAP

“…6 Aberrant expression of lncRNAs leads to the occurrence of many diseases, including cancer, through transcriptional and posttranscriptional regulation of oncogenes and tumor suppressors. 8,9 By screening genes controlled by taurine in retinal cells, taurine-upregulated gene 1 (TUG1) was identified as a novel lncRNA, which is upregulated by taurine and is essential for cell differentiation. 8,9 By screening genes controlled by taurine in retinal cells, taurine-upregulated gene 1 (TUG1) was identified as a novel lncRNA, which is upregulated by taurine and is essential for cell differentiation.…”

Emerging roles of long non‐coding RNAs in the toxicology of environmental chemicals

“…Steroid receptor RNA activator served as coactivator or scaffold and played a key role in hormone‐related biological processes (Liu, Wu et al, ). Another lncRNA, named as SARCC, can bind to AR protein and induce the degradation and functional loss of AR (Zhai et al, ).…”