Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo.
Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo.
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DOI：
10.1186/bcr3201
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发表时间：
2012-05-25
期刊：
影响因子：
--
通讯作者：
Ottewell PD
中科院分区：
文献类型：
--
作者：
Holen I;Whitworth J;Nutter F;Evans A;Brown HK;Lefley DV;Barbaric I;Jones M;Ottewell PD
大多数乳腺癌死亡是转移的结果;然而，人们对乳腺癌发病背后的遗传改变知之甚少。基因分析已经确定，与非转移性肿瘤相比，转移性原发性乳腺肿瘤中粘附分子斑珠蛋白的表达减少了三倍。在这项研究中，我们证明了斑珠蛋白在肿瘤细胞从原发部位脱落到循环中的功能作用。我们研究了斑珠蛋白敲低对乳腺癌细胞增殖、迁移、粘附和体外侵袭以及对肿瘤生长和体内浸润的影响。MCF 7和T47 D细胞用靶向斑珠蛋白基因的miRNA序列或乱序载体稳定转染。通过定量聚合酶链反应（qPCR）和蛋白质印迹法监测基因和蛋白质表达。通过细胞计数、流式细胞术以及划痕和Boyden小室测定来测量细胞增殖、粘附、迁移和侵袭。对于体内实验，将斑珠蛋白敲除细胞和对照细胞接种到小鼠的乳房脂肪垫中，并分别用卡尺测量、流式细胞术和微计算机断层扫描（μCT）监测肿瘤生长、肿瘤细胞脱落到血流中以及转移性骨病变的证据。斑珠蛋白和γ-连环蛋白的表达在所有使用的敲减细胞系中减少了80%以上，但在用乱序序列转染后没有改变。与对照组相比，减少的斑珠蛋白导致体外和体内MCF 7和T47 D细胞增殖显著增加，显著更多的肿瘤细胞脱落到携带斑珠蛋白敲减肿瘤的小鼠的血流中。此外，与对照细胞相比，斑珠蛋白敲低细胞显示出通过基底膜的侵袭增加>250%，并表现出细胞间粘附减少。斑珠蛋白表达减少增加乳腺癌细胞的侵袭行为。这是斑珠蛋白/γ-连环蛋白在转移过程中的功能作用的首次证明，表明该分子可能代表抗转移治疗的靶点。
The majority of deaths from breast cancer are a result of metastases; however, little is understood about the genetic alterations underlying their onset. Genetic profiling has identified the adhesion molecule plakoglobin as being three-fold reduced in expression in primary breast tumors that have metastasized compared with nonmetastatic tumors. In this study, we demonstrate a functional role for plakoglobin in the shedding of tumor cells from the primary site into the circulation. We investigated the effects of plakoglobin knockdown on breast cancer cell proliferation, migration, adhesion, and invasion in vitro and on tumor growth and intravasation in vivo. MCF7 and T47D cells were stably transfected with miRNA sequences targeting the plakoglobin gene, or scramble vector. Gene and protein expression was monitored by quantitative polymerase chain reaction (qPCR) and Western blot. Cell proliferation, adhesion, migration, and invasion were measured by cell counting, flow cytometry, and scratch and Boyden Chamber assays. For in vivo experiments, plakoglobin knockdown and control cells were inoculated into mammary fat pads of mice, and tumor growth, shedding of tumor cells into the bloodstream, and evidence of metastatic bone lesions were monitored with caliper measurement, flow cytometry, and microcomputed tomography (μCT), respectively. Plakoglobin and γ-catenin expression were reduced by more than 80% in all knockdown cell lines used but were unaltered after transfection with the scrambled sequence. Reduced plakoglobin resulted in significantly increased in MCF7 and T47D cell proliferation in vitro and in vivo, compared with control, with significantly more tumor cells being shed into the bloodstream of mice bearing plakoglobin knockdown tumors. In addition, plakoglobin knockdown cells showed a >250% increase in invasion through basement membrane and exhibited reduced cell-to-cell adhesion compared with control cells. Decreased plakoglobin expression increases the invasive behavior of breast cancer cells. This is the first demonstration of a functional role for plakoglobin/γ-catenin in the metastatic process, indicating that this molecule may represent a target for antimetastatic therapies.
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影响因子：
3.9
作者：
Coleman, RE
通讯作者：
Coleman, RE
DOI：
10.1083/jcb.118.3.671
发表时间：
1992-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Knudsen KA;Wheelock MJ
通讯作者：
Wheelock MJ
缺氧会增强乳腺癌中的 Notch 信号传导，导致 E-钙粘蛋白表达减少，细胞迁移和侵袭增加。
影响因子：
8.8
作者：
Chen, J.;Imanaka, N.;Chen, J.;Griffin, J. D.
通讯作者：
Griffin, J. D.
影响因子：
2.8
作者：
Park, Daehoon;Karesen, Rolf;Sauer, Torill
通讯作者：
Sauer, Torill
影响因子：
7.5
作者：
Esposito, Nicole N.;Chivukula, Mamatha;Dabbs, David J.
通讯作者：
Dabbs, David J.