HOXA5 determines cell fate transition and impedes tumor initiation and progression in breast cancer through regulation of E-cadherin and CD24.
HOXA5 determines cell fate transition and impedes tumor initiation and progression in breast cancer through regulation of E-cadherin and CD24.
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DOI：
10.1038/onc.2016.95
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Sukumar, S.
中科院分区：
文献类型：
--
作者：
Teo, W. W.;Merino, V. F.;Cho, S.;Korangath, P.;Liang, X.;Wu, R-C;Neumann, N. M.;Ewald, A. J.;Sukumar, S.
HOXA 5表达的缺失经常发生在乳腺癌中，并与较高的病理分级和较差的疾病结局相关。然而，HOX蛋白如何驱动哺乳动物细胞的分化还知之甚少。在本文中，我们研究了乳腺癌中HOXA 5丢失的细胞和分子后果，以及视黄酸在HOXA 5功能中所起的作用。对HOXA 5缺失的MCF 10 A乳腺上皮细胞的全局基因表达数据进行分析，然后进行验证，指出HOXA 5在维持上皮谱系的几种典型分子特征中的作用，如细胞-细胞粘附，紧密连接和分化标志物。在永生化的MCF 10A或转化的MCF 10A-Kras细胞中耗尽HOXA 5减少了它们的CD 24 +/CD 44 lo群体，增强了自我更新能力，并减少了E-钙粘蛋白（CDH 1）和CD 24的表达。在MCF 10A-Kras的情况下，HOXA 5损失增加了基质胶中的分支和肿胀形态，所有特征都提示上皮向基底的转变。此外，原位移植的MCF 10A-Kras-scr异种移植物生长为分化良好的假腔癌，而MCF 10A-Kras-shHOXA 5细胞形成侵袭性低分化癌。相反，在侵袭性SUM 149或SUM 159乳腺癌细胞中HOXA 5的异位表达逆转了在HOXA 5耗尽细胞中观察到的细胞和分子改变。视黄酸是已知的HOXA 5表达的上游调节剂。在MCF 10A细胞中，HOXA 5的缺失减缓了细胞从分化程度较低的CD 24 −/CD 44+到分化程度较高的CD 24 +/CD 44+状态的转变。通过视网膜处理促进这种转变，视网膜处理上调内源性H 0XA 5表达，并引起封闭蛋白和封闭蛋白-7（CLDN 7）的再表达。如荧光素酶和ChIP分析所示，通过HOXA 5与其启动子序列的直接结合，CDH 1和CD 24的表达在转录上上调。因此，乳腺细胞中HOXA 5的缺失导致上皮性状的丧失、干细胞性和细胞可塑性的增加以及更具侵袭性表型的获得。
Loss of HOXA5 expression occurs frequently in breast cancer and correlates with higher pathological grade and poorer disease outcome. However, how HOX proteins drive differentiation in mammalian cells is poorly understood. In this paper, we investigated cellular and molecular consequences of loss of HOXA5 in breast cancer, and the role played by retinoic acid in HOXA5 function. Analysis of global gene expression data from HOXA5-depleted MCF10A breast epithelial cells, followed by validation, pointed to a role for HOXA5 in maintaining several molecular traits typical of the epithelial lineage such as cell-cell adhesion, tight junctions and markers of differentiation. Depleting HOXA5 in immortalized MCF10A or transformed MCF10A-Kras cells reduced their CD24+/CD44lo population, enhanced self-renewal capacity, and reduced expression of E-cadherin (CDH1) and CD24. In the case of MCF10A-Kras, HOXA5 loss increased branching and protrusive morphology in Matrigel, all features suggestive of epithelial to basal transition. Further, orthotopically implanted xenografts of MCF10A-Kras-scr grew as well-differentiated pseudo-luminal carcinomas, while MCF10A-Kras-shHOXA5 cells formed aggressive, poorly differentiated carcinomas. Conversely, ectopic expression of HOXA5 in aggressive SUM149 or SUM159 breast cancer cells reversed the cellular and molecular alterations observed in the HOXA5-depleted cells. Retinoic acid is a known upstream regulator of HOXA5 expression. HOXA5 depletion in MCF10A cells engineered to express doxycycline-induced shHOXA5 slowed transition of cells from a less differentiated CD24−/CD44+ to the more differentiated CD24+/CD44+ state. This transition was promoted by retinal treatment which upregulated endogenous HOXA5 expression, and caused re-expression of, Occludin, and claudin-7 (CLDN7). Expression of CDH1 and CD24 was transcriptionally upregulated by direct binding of HOXA5 to their promoter sequences as demonstrated by luciferase and ChIP analyses. Thus, loss of HOXA5 in mammary cells leads to loss of epithelial traits, an increase in stemness and cell plasticity, and the acquisition of more aggressive phenotypes.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.4161/cc.8.20.9761
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Ginestier C;Wicinski J;Cervera N;Monville F;Finetti P;Bertucci F;Wicha MS;Birnbaum D;Charafe-Jauffret E
通讯作者：
Charafe-Jauffret E
影响因子：
2.7
作者：
Aubin, J;Lemieux, M;Jeannotte, L
通讯作者：
Jeannotte, L
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA