Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells
Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells
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Artemin 通过促进乳腺癌细胞中 TWIST1-BCL-2 依赖性癌症干细胞样行为来刺激放射和化疗耐药性
DOI：
10.1074/jbc.m112.365163
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发表时间：
2012-12-14
影响因子：
4.8
通讯作者：
Lobie, Peter E.
中科院分区：
文献类型：
--
作者：
Banerjee, Arindam;Qian, PengXu;Lobie, Peter E.
据报道，Artemin（ARTN）可促进雌激素受体阴性乳腺癌（ER-MC）细胞的TWIST 1依赖性上皮向间质转化，与转移和不良生存结局相关。因此，我们研究了ARTN在乳腺癌细胞中促进癌症干细胞（CSC）样表型的潜在作用。ER-MC细胞对电离辐射（IR）或紫杉醇的获得性抗性伴随着ARTN表达的增加。在IR或紫杉醇耐药的ER-MC细胞中，小干扰RNA（siRNA）介导的ARTN耗竭恢复了细胞对IR或紫杉醇的敏感性。与单层培养相比，在乳腺球中生长的ER-MC细胞中ARTN的表达富集，并且在乳腺球和ALDH 1+群体中也沿着BMI 1、TWIST 1和DVL 1。ARTN促进乳腺球生长和ER-MC细胞的自我更新，并增加ALDH 1+群体，而siRNA介导的ARTN耗竭减少了这些CSC样细胞的行为。此外，在ER-MC患者队列中，ARTN表达增加与ALDH 1表达显著相关。ARTN的强制表达也显著增强了异种移植模型中ER-MC细胞在低接种量下的肿瘤起始能力。ARTN促进CSC样细胞表型是通过TWIST 1调节BCL-2表达介导的。ARTN还增强了雌激素受体阳性乳腺癌（ER + MC）细胞中的乳腺球形成和ALDH 1+群体。ARTN的表达增加及其功能后果可能是乳腺癌细胞在不利的肿瘤微环境中促进细胞存活和更新的一种常见适应机制。
Artemin (ARTN) has been reported to promote a TWIST1-dependent epithelial to mesenchymal transition of estrogen receptor negative mammary carcinoma (ER-MC) cells associated with metastasis and poor survival outcome. We therefore examined a potential role of ARTN in the promotion of the cancer stem cell (CSC)-like phenotype in mammary carcinoma cells. Acquired resistance of ER-MC cells to either ionizing radiation (IR) or paclitaxel was accompanied by increased ARTN expression. Small interfering RNA (siRNA)-mediated depletion of ARTN in either IR- or paclitaxel-resistant ER-MC cells restored cell sensitivity to IR or paclitaxel. Expression of ARTN was enriched in ER-MC cells grown in mammospheric compared with monolayer culture and was also enriched along with BMI1, TWIST1, and DVL1 in mammospheric and ALDH1+ populations. ARTN promoted mammospheric growth and self-renewal of ER-MC cells and increased the ALDH1+ population, whereas siRNA-mediated depletion of ARTN diminished these CSC-like cell behaviors. Furthermore, increased ARTN expression was significantly correlated with ALDH1 expression in a cohort of ER-MC patients. Forced expression of ARTN also dramatically enhanced tumor initiating capacity of ER-MC cells in xenograft models at low inoculum. ARTN promotion of the CSC-like cell phenotype was mediated by TWIST1 regulation of BCL-2 expression. ARTN also enhanced mammosphere formation and the ALDH1 + population in estrogen receptor-positive mammary carcinoma (ER + MC) cells. Increased expression of ARTN and the functional consequences thereof may be one common adaptive mechanism used by mammary carcinoma cells to promote cell survival and renewal in hostile tumor microenvironments.