<p>Circular RNA circNRIP1 Sponges microRNA-138-5p to Maintain Hypoxia-Induced Resistance to 5-Fluorouracil Through HIF-1α-Dependent Glucose Metabolism in Gastric Carcinoma</p>

Abstract

Background: Hypoxia-induced chemoresistance is recognized as a major obstacle to the successful treatment of gastric cancer (GC). Circular RNAs (circRNAs) have been proposed to implicate in resistance to chemotherapeutic drugs. However, whether circNRIP1 is involved in the development of hypoxia-induced 5-fluorouracil (5-FU) resistance remains largely unknown. Methods: Gene expression was evaluated using quantitative real-time polymerase chain reaction and Western blot. The impact of circNRIP1 on hypoxia-induced resistance to 5-FU was investigated by determining glucose consumption, lactate production and glucose-6-phosphate (G6P) levels. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide assay was performed to assess cell survival. Results: circNRIP1 was upregulated in GC cells. Hypoxia induced the upregulation of circNRIP1 and reduced the sensitivity of GC cells to 5-FU, as evidenced by the increase in multidrug resistance 1 gene, P-glycoprotein, hypoxia-inducible factor-1α (HIF-1α) and G6P levels, glucose consumption, lactate production, as well as cell survival. Silencing of circNRIP1 enhanced the sensitivity of GC cells to 5-FU under a hypoxic condition. microRNA (miR)-138-5p was confirmed as a downstream target gene of circNRIP1, and upregulation of miR-138-5p could reverse the effect of circNRIP1 on hypoxia-induced 5-FU resistance. Additionally, HIF-1α was a target gene of miR-138-5p. More significantly, the effect of circNRIP1 on hypoxia-induced 5-FU resistance was markedly blocked by 2-DG treatment. Conclusion: circNRIP1 functioned as a miR-138-5p sponge to enhance hypoxia-induced resistance to 5-FU through modulation of HIF-1α-dependent glycolysis, which provides a novel potential approach to overcome hypoxia-induced 5-FU resistance in GC.

CircASXL1 Knockdown Restrains Hypoxia-Induced DDP Resistance and NSCLC Progression by Sponging miR-206

“… 14 In addition, Xu et al demonstrated that circ_0004771 could regulate hypoxia-mediated 5-Fluorouracil resistance to gastric cancer. 15 Huang et al also illustrated that circ_0001946 repressed lung cancer development and regulated DDP resistance. 16 However, the effects of circASXL1 on DDP resistance and NSCLC progression under hypoxia were unknown.…”

Depletion of Circular RNA circ_CORO1C Suppresses Gastric Cancer Development by Modulating miR-138-5p/KLF12 Axis

“… 29 Additionally, miR-138-5p was sponged by circular RNA circNRIP1, involved in hypoxia-induced 5-FU resistance of GC cells. 30 Similarly, downregulation of miR-138-5p was detected in GC tissues and cells. Apart from this, interference of miR-138-5p largely weakened the inhibition effect of circ_CORO1C knockdown on GC development, indicating that circ_CORO1C exerted its oncogenic role by absorbing miR-138-5p.…”

Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR‐149‐5p/TGF‐β2 axis

“…According to research, the biological function of circRNAs is separated into the following categories: act as a miRNA sponge, 17 a RNA‐binding proteins and protein decoys, 18 a regulators of transcription 19,20 . Interestingly, miRNA sponging, which is circRNA act as competitive endogenous RNA (ceRNA) to keep miRNA away from their target gene, is the most commonly reported role of circRNAs 21 . For example, circular RNA circCCDC9 can act as a miR‐6792‐3p sponge to suppress the progression of gastric cancer through regulating CAV1 expression 22 .…”