Shang Chao, Ao Cheng N, Cheong Chi C, Meng Lirong
Department of Neurobiology, School of Life Science, China Medical University, Shenyang, China.
School of Health Sciences, Macao Polytechnic Institute, Macau, China.
Front Oncol. 2019 Jan 29;9:27. doi: 10.3389/fonc.2019.00027. eCollection 2019.
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.
子宫内膜癌（EC）是女性生殖道最常见的恶性肿瘤。在本研究中，我们阐明了细胞周期蛋白依赖性激酶抑制剂2B反义RNA 1（CDKN2B-AS）基因的临床意义及其对EC中紫杉醇敏感性的影响。首先，CDKN2B-AS基因在EC组织和细胞系中高表达。CDKN2B-AS基因的高表达与EC组织的高病理分级和低紫杉醇敏感性相关。敲低CDKN2B-AS基因可使Ishikawa/PA和HEC1A/PA细胞对紫杉醇敏感，并促进紫杉醇诱导的细胞毒性。其次，miR-125a-5p的低表达与EC细胞的低紫杉醇敏感性密切相关，上调miR-125a-5p可增加Ishikawa/PA和HEC1A/PA细胞对紫杉醇的敏感性。miR-125a-5p还介导了敲低CDKN2B-AS对EC细胞紫杉醇耐药性的抑制作用。第三，B细胞淋巴瘤-2（Bcl2）和多药耐药相关蛋白4（MRP4）基因是miR-125a-5p的靶基因，其通过靶向沉默Bcl2和MRP4调节Ishikawa/PA和HEC1A/PA细胞的紫杉醇耐药性。总之，CDKN2B-AS的高表达与EC患者对紫杉醇的反应不佳相关，敲低CDKN2B-AS通过miR-125a-5p-Bcl2/MRP4途径抑制EC患者的紫杉醇耐药性。我们的研究结果有助于阐明EC患者化疗耐药的分子机制。
