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.
Highlights
Ovarian cancer, a very prevalent gynecologic malignancy, is characterized by early-onset metastasis, poor prognosis and multidrug resistance (MDR), with epithelial ovarian cancer being the most common type globally [1,2]
Several lines of previous studies have the similar results as ours, for instance, the up-regulated ANRIL was observed in ovarian cancer patients, which was associated with major clinicopathological features of ovarian tumor, and predicted the poor prognosis [12]
The down-regulation of let-7a in ovarian cancer tissues had a significant correlation to prognosis [17], suggesting that ANRIL may have an important effect as an oncogene, while let-7a might play an anti-oncogenic role in ovarian cancer
Summary
A very prevalent gynecologic malignancy, is characterized by early-onset metastasis, poor prognosis and multidrug resistance (MDR), with epithelial ovarian cancer being the most common type globally [1,2]. The primary therapy for ovarian cancer is still surgery combined with chemotherapy, with cisplatin being one of the most common chemotherapeutic drugs [5]. MDR during chemotherapy is the main tackle of treatment failure, severely affecting the life quality of patients [6]. It is imperative to understand the mechanism of drug resistance in ovarian cancer and thereby improve the prognosis of ovarian cancer patients. Long non-coding RNA (lncRNA) consists of over 200 nucleotides and is mainly distributed in nucleus or cytoplasm, and it can affect a variety of biological processes by regulating the expression of genes [7]
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