| 赵 戈,樊 菁,孟慧敏,崔风强,巫 姜,李松朋,王 敏,王 廷.KLF4在来曲唑耐药性乳腺癌病理组织中的表达与作用[J].,2019,19(4):614-619 |
| KLF4在来曲唑耐药性乳腺癌病理组织中的表达与作用 |
| Expression and Functional Analysis of KLF4 in Letrozole-Resistant Breast Cancer |
| 投稿时间：2018-08-04 修订日期：2018-08-28 |
| DOI：10.13241/j.cnki.pmb.2019.04.003 |
| 中文关键词: 乳腺癌 来曲唑 KLF4 雌激素受体 转录调控 |
| 英文关键词: Breast cancer (BCa) letrozole KLF4 Estrogen receptor alpha (ER-α) Transcriptional regulation |
| 基金项目:国家自然科学基金项目(30570982) |
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| 中文摘要: |
| 摘要 目的：探讨转录因子KLF4在来曲唑(Letrozole)耐药性乳腺癌(breast cancer, BCa)病理组织和细胞中的表达特点及其在来曲唑耐药性病理发生过程中的作用特点及机制。方法：采用实时定量PCR、Western blotting和免疫组织化学法检测KLF4在来曲唑耐药性BCa病理组织和细胞中的表达特点；MTT和细胞凋亡ELISA法检测过表达外源性KLF4对BCa细胞来曲唑药物的影响；荧光素酶报告基因活性检测分析KLF4对编码雌激素受体α(ER-α)的ESR1的转录激活作用。结果：KLF4在来曲唑耐药性乳腺癌病理组织及细胞中呈异常高表达(P<0.05)；采用10-5 M的来曲唑处理MCF7细胞可显著抑制细胞活力，并促进细胞发生凋亡，而在细胞中过表达外源性KLF4后，这一来曲唑毒性作用可被有效逆转(P<0.05)，细胞活力甚至恢复到来曲唑未处理前状态；荧光素酶报告基因活性检测显示在外源性雌激素E2刺激下，GLucONTM-ESR1报告载体的荧光素酶活性显著升高，这一升高趋势可被10-5 M的来曲唑处理有效抑制；当转染外源性KLF4后，来曲唑对GLucONTM-ESR1报告载体的荧光素酶活性的抑制效应被进一步加强(P<0.01)。结论：KLF4可能通过转录调控作用直接抑制ER-?琢表达及活性，进而参与对来曲唑耐药性病理发生过程的关键调节作用。 |
| 英文摘要: |
| ABSTRACT Objective: To study the expression profiles of transcription factor KLF4 in letrozole-resistant breast cancer (BCa) tis- sues and in experimentally-induced letrozole-resistant BCa cells and to characterize the potential functions and underlying mechanisms of this key transcription factor during the pathogenesis of letrozole resistance. Methods: The expression profiles of KLF4 in letrozole-resis- tant BCa tissues and in experimentally-induced letrozole-resistant BCa cells were evaluated using RT-qPCR, Western blotting and im- munohistochemistry. The effects of the overexpression of exogenous KLF4 on cell viability and apoptosis were determined using MTT assay and apoptotic ELISA. Finally, the potential transcriptional regulation of ESR1 gene (encoding estrogen receptor alpha, ER-α) by KLF4 was assessed using luciferase reporter assay. Results: Expression of KLF4 transcriptional factor was significantly induced in letro- zole-resistant BCa tissues and in experimentally-induced letrozole-resistant BCa cells (P<0.05). Treatment with 10-5 M of letrozole sig- nificantly inhibited cell proliferation, and resulted in an increased apoptosis in BCa cells. This cytotoxicity of letrozole was noticeably re- versed by overexpression of the exogenous KLF4(P<0.05), with cell viability even restoring to the normal level. The luciferase reporter assay demonstrated that stimulation with the exogenous estrogen E2 notably stimulated the relative luciferase activity of GLucONTM-ESR1 reporter, and this stimulatory effects were substantially compromised by challenges with 10-5 M of letrozole. By contrast, ectopic expres- sion of the exogenous KLF4 further enhanced the inhibitory effects of letrozole on GLucONTM-ESR1 activity (P<0.01). Conclusion: KLF4 may suppress the expression and activity of ER-?琢 at the transcriptional level. KLF4 inhibition of ESR1 transcription may therefore par- ticipate in the the pathogenesis of letrozole resistance in BCa. |
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