MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1
MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1
复制标题
MiR-200c 通过靶向 UBQLN1 抑制自噬并增强乳腺癌细胞的放射敏感性。
DOI：
10.1002/ijc.29065
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发表时间：
2015-03-01
影响因子：
6.4
通讯作者：
Chen, Longhua
中科院分区：
文献类型：
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作者：
Sun, Quanquan;Liu, Tongxin;Chen, Longhua
放射抗性是乳腺癌治疗过程中的一个主要挑战。进一步了解辐射抗性的机制可以提供应对这一挑战的策略。在我们的研究中，我们比较了miR-200 c在四种不同乳腺癌细胞系中的表达：两种代表性基底癌细胞（MDA-MB-231和BT549）与两种代表性管腔癌细胞（MCF-7和BT474）。结果显示，与正常乳腺上皮细胞系MCF-10A相比，miR-200 c在两种基底癌细胞系中的表达实际上较低，而miR-200 c在管腔癌细胞中的表达较高。miR-200 c在MDA-MB-231细胞中的异位表达抑制了辐射诱导的自噬，并使乳腺癌细胞对辐射敏感。我们还鉴定了UBQLN 1作为miR-200 c的直接功能靶标，其参与辐射诱导的自噬和辐射抗性。在35例人乳腺癌组织样本中，我们检测到miR-200 c与UBQLN 1和LC 3的表达之间存在负相关性。这些结果表明，所确定的miR-200 c/UBQLN 1介导的自噬途径可能有助于阐明人类乳腺癌的放射抗性，并可能代表一种治疗策略。对于正常细胞，自噬对于肿瘤细胞在应激条件下存活至关重要，因此与肿瘤对化疗和放疗的抗性有关。目前的研究表明，miR-200 c可以通过抑制辐射诱导的自噬相关机制使乳腺癌细胞对辐射敏感。作者还确定了ubiquilin 1（UBQLN 1）作为miR-200 c，自噬和乳腺癌细胞辐射抗性之间的联系。这些结果为miR-200 c在乳腺癌细胞放射敏感性中的分子功能提供了新的见解，并为通过miR-200 c增强乳腺癌治疗的放射敏感性提供了理论基础。
Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR-200c vs. UBQLN1 and LC3. These results indicate that the identified miR-200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.What's new? As for normal cells, autophagy is critical for tumor cells to survive stressful conditions, and thus has been implicated in tumor resistance to chemotherapy and radiotherapy. The present study showed that miR-200c could sensitize breast cancer cells to radiation via a mechanism associated with inhibition of irradiation-induced autophagy. The authors also identified ubiquilin 1 (UBQLN1) as a link between miR-200c, autophagy, and radioresistance of breast cancer cells. These results provide new insights into the molecular functions of miR-200c in the radiosensitivity of breast cancer cells and offer a rationale for enhancing radiosensitivity via miR-200c for the treatment of breast cancer.