Long Non-coding RNA CDKN2B Antisense RNA 1 Gene Contributes to Paclitaxel Resistance in Endometrial Carcinoma.

Chao Shang,Chi C Cheong,Cheng N Ao,Lirong Meng

doi:10.3389/fonc.2019.00027

Abstract

Endometrial cancer (EC) is the most common malignancy of the female reproductive tract. In this study, we clarified the clinical significance of CDKN2B antisense RNA 1 (CDKN2B-AS) gene, and its effects on paclitaxel sensitivity in EC. Firstly, CDKN2B-AS gene was highly expressed in EC tissues and cell lines. The high-expression of CDKN2B-AS gene was associated with high pathological grade and low paclitaxel sensitivity of EC tissues. Knockdown of CDKN2B-AS gene sensitized Ishikawa/PA and HEC1A/PA cells to paclitaxel, and promoted paclitaxel-induced cytotoxicity. Secondly, the low-expression of miR-125a-5p was closely associated with low paclitaxel sensitivity of EC cells, and up-regulation of miR-125a-5p could increase paclitaxel sensitivity of Ishikawa/PA and HEC1A/PA cells. MiR-125a-5p also mediated the suppressive effects of knockdown of CDKN2B-AS on paclitaxel resistance in EC cells. Thirdly, B-cell lymphoma-2 (Bcl2) and Multidrug Resistance-Associated Protein 4 (MRP4) genes were target genes of miR-125a-5p, which modulated paclitaxel resistance of Ishikawa/PA and HEC1A/PA cells through targeted silencing Bcl2 and MRP4. In conclusion, high-expression of CDKN2B-AS is associated with a poor response to paclitaxel of EC patients, and knockdown of CDKN2B-AS inhibits paclitaxel resistance through miR-125a-5p-Bcl2/MRP4 pathway in EC patients. Our findings help elucidate the molecular mechanisms of chemoresistance in EC patients.

Highlights

Endometrial cancer (EC) is one of the most common malignancy of the female reproductive tract and is increasing in incidence
Our preliminary experiments showed that CDKN2B antisense RNA 1 (CDKN2B-AS) gene was associated with paclitaxel resistance of EC, we attempted to study the molecular mechanism of CDKN2B-AS triggered regulation for chemotherapy resistance of EC
The over-expression of CDKN2B-AS was associated with the low paclitaxel sensitivity of EC patients (Table 1 and Figure 1C), and the expression level of CDKN2B-AS in Ishikawa/PA and HEC1A/PA cells was significantly higher than that in Ishikawa and HEC1A cells (Figure 1D), which preliminarily confirmed that CDKN2B-AS participated in the genesis of chemotherapy resistance in EC cells

Summary

Introduction

Endometrial cancer (EC) is one of the most common malignancy of the female reproductive tract and is increasing in incidence. The mortality of EC is next to ovarian and cervical cancer, and that is currently increasing year-by-year [1, 2]. Chemotherapy is extensively used for treatment of EC, and it can significantly improve the prognosis and inhibit the recurrence and metastasis [3]. Drug resistance reduces the sensitivity to chemotherapeutic drugs, and contributes a barrier, leading to treatment failure of EC. Several scholars have proposed diverse hypotheses, accounting for chemotherapy failure of EC patients, including DNA repair deregulation, aberrant function of efflux pumps, imbalance of signaling pathway, and so on Brasseur et al [4], Shang et al [5], and Liu et al [6]

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