Abstract
Background: Circular RNAs have been widely explored as potential biomarkers and therapeutic targets in bladder cancer; however, few have been functionally characterized.Results: ciRs-6 is expressed at low levels in cancer tissues and advanced tumor grades and stages, and its expression correlates with better outcomes for bladder cancer patients. In vitro and in vivo, ciRs-6 was shown to suppress bladder cancer growth by sponging miR-653 to elevate March1 levels. March1 is an E3 ubiquitin ligase that has been proven to suppress bladder cancer growth; knocking down March1 in ciRs-6 overexpressed bladder cancer cells reversed the tumor suppressive effect of ciRs-6.Conclusions: Our study identifies an oncogenic role of ciRs-6 and suggests its usefulness as a novel biomarker for bladder cancer diagnosis and prognosis and as a therapeutic target for bladder cancer.Methods: ciRs-6 was identified by RNA-seq and qPCR; CCK8 assays, clone forming assays and cell cycle analyses were performed to evaluate the in vitro effect of ciRs-6 in bladder cancer; further, a mouse subcutaneous tumor model was designed for in vivo analysis. RNA pulldown assays, miRNA capture experiments and dual luciferase assessments were applied for mechanistic studies.
Highlights
Despite multiple therapeutic options for bladder cancer, including surgery, BCG perfusion or chemotherapy, rapid growth and frequent metastatic potential in highly advanced cancers greatly limit clinical treatments [1]
Noncoding RNAs constitutes a major part of epigenetic regulation, and circular RNAs have recently been further explored as a popular RNA that promotes cancer [3]. ciRS-7 negatively regulates bladder cancer proliferation by activating p21 [4]; hypoxia elevates circELP3 to promote bladder cancer progression and drug resistance [5]; the circular RNA CEP128 promotes bladder cancer cell propagation and migration by regulating MAPK signaling [5]; and circHIPK3 decreases lung metastasis through suppressing heparanase expression in bladder cancer [6]
CircPRMT5 is significantly upregulated in serum and urine exosomes in bladder cancer patients, and its levels statistically correlates with tumor metastasis [8]. circ-ITCH [9], circHIPK3 [6] and circMTO1 [10] were all found to be decreased in bladder cancer tissues, and their levels negatively correlate with grade, stage, invasion and lymph node metastasis in bladder cancer patients
Summary
Despite multiple therapeutic options for bladder cancer, including surgery, BCG (bacille calmette-guerin) perfusion or chemotherapy, rapid growth and frequent metastatic potential in highly advanced cancers greatly limit clinical treatments [1]. CiRS-7 negatively regulates bladder cancer proliferation by activating p21 [4]; hypoxia elevates circELP3 to promote bladder cancer progression and drug resistance [5]; the circular RNA CEP128 promotes bladder cancer cell propagation and migration by regulating MAPK signaling [5]; and circHIPK3 decreases lung metastasis through suppressing heparanase expression in bladder cancer [6]. Because of the advantages of a ring structure, circular RNAs are able to resist various kinds of exonuclease, making them more stable than any other noncoding RNAs [7] This stability is especially reflected in its role as a biomarker for predicting pathological and prognostic features in cancer. Results: ciRs-6 is expressed at low levels in cancer tissues and advanced tumor grades and stages, and its expression correlates with better outcomes for bladder cancer patients. RNA pulldown assays, miRNA capture experiments and dual luciferase assessments were applied for mechanistic studies
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