Androgen receptor‐regulated circ FNTA activates KRAS signaling to promote bladder cancer invasion

Abstract

The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA‐FNTA (circFNTA) to increase BCa cell invasion and chemo‐resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5′ promoter region to increase circFNTA levels, which then sponges the microRNA miR‐370‐3p to increase the expression of its host gene FNTA. This AR‐mediated ADAR2/circFNTA/miR‐370‐3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo‐sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo‐sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR‐370‐3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo‐sensitivity.

CircRNAs in anticancer drug resistance: recent advances and future potential

“…In summary, circRNAs have been thoroughly proven to participate in anticancer drug resistance. We reviewed Ovarian Cancer Cdr1as MiR-1270/SCAI axis Down [156] Bladder Cancer circ_000285 NA Down [157] circFNTA MiR-370-3p/FNTA axis Up [158] Ref Reference…”

“…Chi et al [ 157 ] reported that the serum circ_0000285 level was decreased in cisplatin-resistant bladder cancer patients compared to cisplatin-sensitive bladder cancer patients and that a low circ_0000285 level indicated poor prognosis, suggesting circRNA_000285 as a biomarker for the cisplatin treatment response in bladder cancer. In addition, Chen et al [ 158 ] found that deletion of circFNTA reduces cisplatin resistance in bladder cancer. High expression of circFNTA can activate KRAS signaling via the miR-370-3p/FNTA axis, thereby contributing to cisplatin resistance.…”

<p>Aloperine Exerts Antitumor Effects on Bladder Cancer in vitro</p>

“…BC is the second most common cancer of the genitourinary system, ranking 13th in mortality, although mortality rates are rising in most countries. 6,22 Most are transitional epithelial cell carcinomas. The lateral and posterior walls of the bladder are the most common, followed by the trigonometric region and the apical region.…”

Analysis of mRNAs and ncRNAs and Prediction Competing Endogenous RNA Networks in Colorectal Cancer Chemo-Resistance by Whole-Transcriptome Sequencing

“…At present, a large number of studies have shown that, in addition to mRNAs, non-coding RNAs also related to drug resistance of cancers, including gastric cancer [33], bladder cancer [34], lung adenocarcinoma [35]. Moreover, in CRC drug resistance studies, it was reported that LINC00957 could increase 5uorouracil resistance and result in poor survival of patients [36], hsa_circ_0079662 was related to oxaliplatin resistance via TNF-α pathway [25], microRNA-375-3p was involved in 5-uorouracil resistance by targeting thymidylate synthase [37].…”