Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion.
Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion.
复制标题
LKB1缺失破坏乳腺上皮细胞极性并促进乳腺癌转移和侵袭
DOI：
10.1186/s13046-014-0070-0
复制
发表时间：
2014-09-02
期刊：
影响因子：
--
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Li J;Liu J;Li P;Mao X;Li W;Yang J;Liu P
背景LKB1，也被称为STK11，是一种作为能量代谢感受器的主激酶，参与细胞的极性调节。最近的研究表明LKB1与乳腺肿瘤的发生和乳腺癌的进展有关。然而，关于LKB1在乳腺癌细胞极性和上皮-间充质转化中的作用的研究很少。方法采用免疫组织化学方法检测80例临床乳腺癌组织及其配对的正常乳腺组织中LKB1的表达与临床病理参数及上皮性标志物E-钙粘素和高分子细胞角蛋白(HMW-CK)的关系。比较LKB1在转移性和非转移性乳腺癌细胞系中的表达。采用免疫荧光、免疫印迹、细胞迁移和侵袭实验等方法研究LKB1在乳腺癌细胞极化和上皮-间充质转化中的作用。结果LKB1的表达水平与乳腺癌的TNM分期呈显著负相关，与ER/PR状态、E-钙粘蛋白和HMW-CK的表达水平呈正相关。免疫荧光染色显示LKB1与E-钙粘附素共定位于粘连连接处。体外分析表明，LKB1的表达缺失促进了细胞的迁移、侵袭和间充质表型的获得，而在基础水平较低的MDAMB-435 S细胞中，LKB1的过表达促进了上皮表型的获得。最后，首次发现内源性LKB1基因敲除导致在3D培养中未转化的乳腺上皮细胞形成的腺泡细胞极性异常。结论LKB1的低表达与乳腺癌预后不良的标志物显著相关，如ER/PR、E-钙粘素和HMW-CK的丢失。内源性LKB1基因敲除导致细胞极性失调，导致乳腺癌细胞侵袭表型异常。
BackgroundLKB1, also known asSTK11, is a master kinase that serves as an energy metabolic sensor and is involved in cell polarity regulation. Recent studies have indicated that LKB1 is related to breast tumorigenesis and breast cancer progression. However, little work has been done on the roles of LKB1 in cell polarity and epithelial-mesenchymal transition in breast cancer. In this study, we tried to prove that loss of LKB1 disrupts breast epithelial cell polarity and causes tumor metastasis and invasion.MethodsThe relationships of LKB1 expression to clinic-pathological parameters and epithelial markers E-cadherin and high-molecular-weight -cytokeratin (HMW-CK) were investigated in 80 clinical breast cancer tissue samples and their paired normal control breast tissue samples by using immunohistochemistry. Then, the LKB1 expressions in metastatic and non-metastatic breast cancer cell lines were compared. The roles of LKB1 in cell polarity and epithelial-mesenchymal transition in breast cancer were determined by using immunofluorescence, western blot assay, and cell migration and invasive assays. Finally, the non-transformed human breast cell line MCF-10A was cultured in three dimensions to further reveal the role of LKB1 in breast epithelial cell polarity maintenance.ResultsHistopathological analysis showed that LKB1 expression level was significantly negatively correlated with breast cancer TNM stage, and positively correlated with ER/PR status and expression levels of E-cadherin and HMW-CK. Immunofluorescence staining showed that LKB1 was co-localized with E-cadherin at adheren junctions. In vitro analysis revealed that loss of LKB1 expression enhanced migration, invasion and the acquisition of mesenchymal phenotype, while LKB1 overexpression in MDA-MB-435 s cells, which have a low basal level of LKB1 expression, promoted the acquisition of epithelial phenotype. Finally, it was found for the first time that endogenous LKB1 knockdown resulted in abnormal cell polarity in acini formed by non-transformed breast epithelial cells grown in 3D culture.ConclusionOur data indicated that low expression of LKB1 was significantly associated with established markers of unfavorable breast cancer prognosis, such as loss of ER/PR, E-cadherin and HMW-CK. Knockdown of endogenous LKB1 gave rise to dysregulation of cell polarity and invasive phenotype of breast cancer cells.
登录
查看更多内容
EZH2敲低抑制了人类炎症性乳腺癌细胞的生长和侵袭。
DOI：
10.1186/1756-9966-32-70
发表时间：
2013-09-27
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Mu Z;Li H;Fernandez SV;Alpaugh KR;Zhang R;Cristofanilli M
通讯作者：
Cristofanilli M
影响因子：
3.3
作者：
Nath-Sain, Suchita;Marignani, Paola A.
通讯作者：
Marignani, Paola A.
DOI：
10.1097/jto.0b013e3181fbc28a
发表时间：
2010-12
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Marcus AI;Zhou W
通讯作者：
Zhou W
影响因子：
4
作者：
Goransson, Olga;Deak, Maria;Alessi, Dario R.
通讯作者：
Alessi, Dario R.
影响因子：
4.6
作者：
Narbonne, P;Roy, R
通讯作者：
Roy, R