Hypoxia-elevated circELP3 contributes to bladder cancer progression and cisplatin resistance

Abstract

Hypoxia plays a critical role in cancer biology. It induces genomic instability, which in turn helps cancer cells respond adaptively to meet the needs of carcinogenesis, cancer progression and relapse. Circular RNA has not been reported among the variety of downstream factors in this adaptive response. Although a few studies have demonstrated the important role of circular RNAs in driving human bladder cancer progression, their carcinogenic roles are still under investigated. Here, we identified a hypoxia-elevated circular RNA, circELP3, that contributes to bladder cancer progression and cisplatin resistance. Decreasing the level of circELP3 via siRNA clearly reduced the in vitro proliferation and cisplatin resistance of bladder cancer cells and promoted apoptosis. Interfering with circELP3 suppressed tumor xenograft growth in nude mice in vivo. In addition, lower circELP3-expressing bladder cancer cells displayed poorer self-renewal capacity, as demonstrated by lower levels of sphere formation and stem cell marker expression. Furthermore, in human bladder cancer patients, strong correlations between a high circELP3 level and advanced tumor grade and lymph node metastasis were observed. In summary, we provide the first direct evidence that circular RNA participates in the adaptive response to hypoxia and may play a role in the progression and drug resistance of bladder cancer.

circRIP2 accelerates bladder cancer progression via miR-1305/Tgf-β2/smad3 pathway

“…Additionally, except for the role as promising biomarker, circular RNAs were also proved to work as oncogenes or tumor suppressor genes in bladder cancer. Such as, ciRS-7 enables to suppress cancer growth by elevating p21 [6]; circELP3 promotes progression and drug resistance of bladder cancer [7]; circHIPK3 decreases lung metastasis through suppressing heparanase expression [9]; circular RNA CEP128 promotes bladder cancer cell (See figure on previous page.) Fig.…”

“…Hence, researches of circular RNAs are divided into 2 parts, one is to identify its carcinogenic role, the other is to prove its application as a biomarker [5]. Serving as an oncogene or tumor suppressor gene, in bladder cancer, ciRS-7 is found to suppress bladder cancer growth by elevating p21 [6]; hypoxia elevates circELP3 to promote bladder cancer progression and drug resistance [7]; circular RNA CEP128 promotes bladder cancer cell propagation and migration via regulating MAPK signaling [8]; and circHIPK3 decreases lung metastasis through suppressing heparanase expression [9]. Besides, as a biomarker [10], up-regulated circPRMT5 in the exosomes from serum and urine positively correlates with metastasis of bladder cancer patients [11].…”

“…To identify more circular RNAs in bladder cancer, we re-analyzed our previous RNA-sequence in 2 paired bladder cancer tissues [7]. Among various circular RNAs that specifically reduced in bladder cancer, circRIP2 ranks the top 3.…”

<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

“…11 CircRNAs may also play a key role in the development of drug resistance. Recently, multiple studies have highlighted the key roles of ncRNAs in chemoresistance of cancer, such as HCC, 142,249 lung cancer, 250,251 gastric cancer, 252,253 breast cancer, 254,255 multiple myeloma, 256 acute myeloid leukemia, 234 prostate cancer, 257 bladder cancer, 258 among others. The up-to-date information regarding the role of circRNAs in the resistance of tumors to chemotherapy has been recently summarized with multiple mechanisms, such as modulating various regulatory pathways and processes including the ceRNA regulatory network axis, EMT process, regulation of ABC transporters, apoptosis, autophagy, and CSCs, among others although many physiological processes and biological signaling pathways through which circRNAs are involved in drug resistance still remained unknown.…”

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…There are many other factors in the TME that can affect drug sensitivity, such as an aberrant vasculature failing to transport drugs. With diverse functions, circRNAs such as ciRS-7 have already been shown to regulate various characteristics of the TME, which has been proven to regulate the sensitivity of several types of cancer to chemotherapy [26,[94][95][96][97][98].…”