Abstract
Background/aimsThe expression levels of long non-coding RNA XIST are significantly associated with paclitaxel (Pac) sensitivity in ovarian cancer, but the mechanism of action remains unclear. Therefore, this experimental design was based on lncRNA XIST analysis to regulate the effect of XIST on the tumor stem cell and paclitaxel sensitivity in ovarian cancer.MethodsSphere assay and fluorescence activated cell sorting (FACS) were used to determine the expression levels of XIST and sensitivity to paclitaxel treatment. The effect of the proliferation was detected by MTT assay. Target gene prediction and screening, luciferase reporter assays were used to validate downstream target genes for lncRNA XIS and KMT2C. The expression of KMT2C was detected by RT-qPCR and Western blotting. RT-qPCR was used to detect the expression of cancer stem cell-associated genes SOX2, OCT4 and Nanog. The tumor changes in mice were detected by in vivo experiments in nude mice.ResultsThere was an inverse correlation between the expression of XIST and cancer stem cell (CD44 + /CD24−) population. XIST promoted methylation of histone H3 methylation at lysine 4 by enhancing the stability of lysine (K)-specific methyltransferase 2C (KMT2C) mRNA. XIST acted on the stability of KMT2C mRNA by directly targeting miR-93-5p. Overexpression of miR-93-5p can reverse the XIST overexpression-induced KMT2C decrease and sphere number increase. Overexpression of KMT2C inhibited XIST silencing-induced proliferation of cancer stem cells, and KMT2C was able to mediate paclitaxel resistance induced by XIST in ovarian cancer. The study found that XIST can affect the expression of KMT2C in the ovarian cancer via targeting miR-93-5p.ConclusionXIST promoted the sensitivity of ovarian cancer stem cells to paclitaxel in a KMT2C-dependent manner.
Highlights
Ovarian cancer is one of the three major malignant tumors in female reproductive organs [1, 2]
The expression levels of X-chromosome inactivating specific transcript (XIST) were correlated with cancer stem cell population and sensitivity to Taxol treatment
In order to explore the relation between the sphere formation efficiency (SFE) and the expression of XIST, XIST was knocked down in the SKOV3, labelled as SKOV3-KD, and overexpressed in TOV21G, respectively, labelled as TOV21G-OE (Fig. SB)
Summary
Ovarian cancer is one of the three major malignant tumors in female reproductive organs [1, 2]. Long non-coding RNAs (lncRNAs) are a class of noncoding RNA molecules that are more than 200 nucleotides in length and do not encode proteins [7]. They are involved in many biological processes, such as participation in protein coding [8]. In vitro and in vivo functional analysis have shown that lncRNAs are involved in a variety of cancer malignant behaviors such as unrestricted proliferation, metastasis, radiation therapy, and cancer stem cell phenotype [12, 13]. The regulation mechanism of lncRNAs in paclitaxel resistance has not been reported
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