LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis

Abstract

This paper tried to explore ANRIL expression in ovarian cancer and how it affects cisplatin-sensitivity of ovarian cancer cells via regulation of let-7a/high-mobility group protein A2 (HMGA2) axis. qRT-PCR was used to detect ANRIL and let-7a levels in ovarian cancer tissues and cell lines (SKOV3 and SKOV3/DDP). Then cells were randomly assigned into Blank, negative control siRNA, ANRIL siRNA, let-7a inhibitor, and ANRIL siRNA+let-7a-inhibitor groups. CCK-8 assay was applied for assessing cell viability of cells treated with different concentrations of cisplatin. Flow cytometry was employed to test cell apoptosis rate. qRT-PCR and Western blot were performed for related molecules detection. Nude mice transplanted with SKOV3/DDP cells were used to confirm the effects of ANRIL siRNA on the cisplatin-sensitivity. Ovarian cancer tissues and cisplatin-resistant cells had increased ANRIL expression and decreased let-7a expression, and those patients with higher clinical stage and pathological grade showed higher ANRIL and lower let-7a. Dual-luciferase reporter-gene assay confirmed the targeting relationship between ANRIL and let-7a, and between let-7a and HMGA2. The cell viability and cisplatin IC50 were decreased in ANRIL siRNA group exposed to different concentrations of cisplatin, with enhanced apoptosis, as well as elevated let-7a and declined HMGA2, which would be reversed by let-7a inhibitor. Meanwhile, ANRIL down-regulation enhanced the inhibitory effect of cisplatin on tumor growth of nude mice and reduced tumor weight. Silencing ANRIL expression reduced HMGA2 expression to promote the apoptosis and improve cisplatin-sensitivity of ovarian cancer cells via up-regulating let-7a expression.

Low GAS5 expression may predict poor survival and cisplatin resistance in cervical cancer

“…When ceRNA acquires transcriptional activity, it competes for miRNA targets, binds to RISC complexes, which results in the separation of miRNA-RISC complexes from parent genes and increased parental gene expression 48 . Miao et al 49 . reported that in ovarian cancer, ANRIL could interact with let-7a to further reduce HMGA2 levels, which promoted the apoptosis and improved the cisplatin sensitivity of ovarian cancer cells.…”

<p>LncRNA MALAT1 Regulates the Progression and Cisplatin Resistance of Ovarian Cancer Cells via Modulating miR-1271-5p/E2F5 Axis</p>

“…In recent years, DDP is an important drug for the therapy of OC, while OC cells prone to generate drug resistance in OC treatment. 24 Moreover, lncRNAs were proved to be associated with DDP resistance in OC. For example, Long et al confirmed that lncRNA GAS5 increased DDP-resistance and promoted OC cell growth through modulating MAPK pathway.…”

The Challenges and Opportunities of LncRNAs in Ovarian Cancer Research and Clinical Use

“…Interestingly, although this effect has been less studied, some lncRNAs control cell metabolism by regulating key enzymes in metabolic pathways, contributing mainly to stimulating glycolysis instead of aerobic metabolism (the Warburg effect). In the glycolysis pathway from glucose to pyruvate, the expression of hexokinase 2, catalyzing the first step, is activated by LINC00504 [70]; NRCP activates the second enzyme in the pathway, glucose-6-phosphate isomerase [26]; after that, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 is induced by LINC00092 [31]; in the fourth step catalyzed by aldolase, two forms of the enzyme, A and C, are activated by NRCP [26]. The final step is catalyzed by pyruvate kinase isozyme M2, which is activated by both LINC00504 and H19 [70,132].…”

“…For instance, Linc00176 acts as a scaffold to keep BCL3 and p50 together (NF-κB family) and at the same time recruits this complex to the ceruloplasmin promoter to activate its expression [139]. Some reports of transcriptional regulation by lncRNAs do not fit this classification at all, as in the case of FAL1, which increases the stability of BMI (another subunit of PRC), thereby allowing epigenetic marking of the p21 gene to be silenced [31,42].…”

“…Thus, CREB1 activates HAS-AS2 transcription [79]; FOXO4 activates PVT1 transcription [74]; Nkx3-1, HNF-1, aMEF-2 and MEF-2A are TFs take part in the transcriptional regulation of LOC100190986 [21]. Some signaling pathways that trigger lncRNA transcription have also been identified; for instance, CXCL14 produced by surrounding fibroblasts triggers LINC00092 transcription [31]; TGF-β1 activates MALAT1 [21], PTAR [154] and PTAL [153] transcription; or pEGFR activates ABHD11-AS1 through STAT3 [136]. The lncRNA UCA1 has been described as being activated by a super-enhancer [157].…”