DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer
DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer
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DLGAP1-AS2 促进雌激素受体信号传导并赋予乳腺癌他莫昔芬耐药性
DOI：
10.1007/s11033-022-07244-0
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发表时间：
2022-04-21
影响因子：
2.8
通讯作者：
Shi, Yawei
中科院分区：
文献类型：
--
作者：
Liang, Xiaoli;Zhao, Yang;Shi, Yawei
背景三苯氧胺是治疗雌激素受体阳性（ER+）乳腺癌的一线内分泌药物。不幸的是，大约30-40%接受他莫昔芬治疗的患者由于他莫昔芬耐药而经历复发或进展至致命的晚期。方法采用qPCR方法检测LncRNA DLGAP 1反义RNA 2（DLGAP 1-AS 2）在胃癌细胞中的表达。通过MTT、克隆形成、TUNEL和流式细胞术检测DLGAP 1-AS 2对三苯氧胺耐药性的影响。DLGAP 1-AS 2调节他莫昔芬耐药的机制进行了研究，通过qPCR，RNA下拉试验和RNA免疫沉淀（RIP）assays.ResultsOur结果表明，DLGAP 1-AS 2是显着上调乳腺癌和他莫昔芬可以诱导DLGAP 1-AS 2的表达。进一步的研究表明，上调DLGAP 1-AS 2可以增加细胞活力并抑制凋亡，而下调DLGAP 1-AS 2则导致相反的效果。机制上，DLGAP 1-AS 2可以结合到AFF 3蛋白，以抑制其降解，这进一步促进ER signaling.ConclusionsOur研究阐明，DLGAP 1-AS 2促进ER信号转导诱导他莫昔芬耐药，并针对DLGAP 1-AS 2可能是一个有前途的策略，以克服他莫昔芬耐药的乳腺癌。
BackgroundTamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear.MethodsThe expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays.ResultsOur results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling.ConclusionsOur research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer.