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Evaluation of lumican effects on morphology of invading breast cancer cells, expression of integrins and downstream signaling
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-03-11 , DOI: 10.1111/febs.15289 Konstantina Karamanou 1, 2, 3 , Marco Franchi 4 , Maurizio Onisto 5 , Alberto Passi 6 , Demitrios H. Vynios 1 , Stéphane Brézillon 2, 3
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-03-11 , DOI: 10.1111/febs.15289 Konstantina Karamanou 1, 2, 3 , Marco Franchi 4 , Maurizio Onisto 5 , Alberto Passi 6 , Demitrios H. Vynios 1 , Stéphane Brézillon 2, 3
Affiliation
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The small leucine‐rich proteoglycan lumican regulates estrogen receptors (ERs)‐associated functional properties of breast cancer cells, expression of matrix macromolecules, and epithelial‐to‐mesenchymal transition. However, it is not known whether the ER‐dependent lumican effects on breast cancer cells are related to the expression of integrins and their intracellular signaling pathways. Here, we analyzed the effects of lumican in three breast cancer cell lines: the highly metastatic ERβ‐positive MDA‐MB‐231, cells with the respective ERβ‐suppressed (shERβMDA‐MB‐231), and lowly invasive ERα‐positive MCF‐7/c breast cancer cells. Scanning electron microscopy, confocal microscopy, real‐time PCR, western blot, and cell adhesion assays were performed. Lumican effects on breast cancer cell morphology were also investigated in 3‐dimensional collagen cultures. Lumican treatment induced cell–cell contacts and cell grouping and inhibited microvesicles and microvilli formation. The expression of the cell surface adhesion receptor CD44, its isoform and variants, hyaluronan (HA), and HA synthases was also investigated. Lumican inhibited the expression of CD44 and HA synthases, and its effect on cell adhesion revealed a major role of α1, α2, α3, αVβ3, and αVβ5 integrins in MDA‐MB‐231 cells, but not in MCF‐7/c cells. Lumican upregulated the expression of α2 and β1 integrin subunits both in MDA‐MB‐231 and in shERβMDA‐MB‐231 as compared to MCF‐7/c cells. Downstream signaling pathways for integrins, such as FAK, ERK 1/2 MAPK 42/44, and Akt, were found to be downregulated by lumican. Our data shed light to the molecular mechanisms responsible for the anticancer activity of lumican in invasive breast cancer.
中文翻译：
卢米肯对侵袭性乳腺癌细胞形态，整合素表达和下游信号传导的影响评估
富含亮氨酸的小蛋白多糖Lumican调节乳腺癌细胞的雌激素受体（ERs）相关功能，基质大分子表达以及上皮到间质转化。但是，尚不知道ER依赖性发光素对乳腺癌细胞的作用是否与整联蛋白的表达及其细胞内信号通路有关。在这里，我们分析了lumican在三种乳腺癌细胞系中的作用：高度转移性ERβ阳性的MDA-MB‐231，具有相应ERβ抑制的细胞（shERβMDA‐MB‐231）和低浸润性ERα阳性MCF- 7 / c乳腺癌细胞。进行了扫描电子显微镜，共聚焦显微镜，实时PCR，蛋白质印迹和细胞粘附测定。在3维胶原蛋白培养物中还研究了Lumican对乳腺癌细胞形态的影响。Lumican处理可诱导细胞间接触和细胞分组，并抑制微囊泡和微绒毛的形成。还研究了细胞表面粘附受体CD44，其同工型和变体，透明质酸（HA）和HA合酶的表达。Lumican抑制了CD44和HA合成酶的表达，其对细胞粘附的影响揭示了MDA-MB-231细胞中α1，α2，α3，αVβ3和αVβ5整合素的主要作用，而在MCF-7 / c细胞中则没有。与MCF-7 / c细胞相比，Lumican在MDA-MB-231和shERβMDA-MB-231中均上调了α2和β1整合素亚基的表达。发现整联蛋白的下游信号传导途径，例如FAK，ERK 1/2 MAPK 42/44和Akt，均被lumican下调。
更新日期：2020-03-11
中文翻译：
卢米肯对侵袭性乳腺癌细胞形态，整合素表达和下游信号传导的影响评估
富含亮氨酸的小蛋白多糖Lumican调节乳腺癌细胞的雌激素受体（ERs）相关功能，基质大分子表达以及上皮到间质转化。但是，尚不知道ER依赖性发光素对乳腺癌细胞的作用是否与整联蛋白的表达及其细胞内信号通路有关。在这里，我们分析了lumican在三种乳腺癌细胞系中的作用：高度转移性ERβ阳性的MDA-MB‐231，具有相应ERβ抑制的细胞（shERβMDA‐MB‐231）和低浸润性ERα阳性MCF- 7 / c乳腺癌细胞。进行了扫描电子显微镜，共聚焦显微镜，实时PCR，蛋白质印迹和细胞粘附测定。在3维胶原蛋白培养物中还研究了Lumican对乳腺癌细胞形态的影响。Lumican处理可诱导细胞间接触和细胞分组，并抑制微囊泡和微绒毛的形成。还研究了细胞表面粘附受体CD44，其同工型和变体，透明质酸（HA）和HA合酶的表达。Lumican抑制了CD44和HA合成酶的表达，其对细胞粘附的影响揭示了MDA-MB-231细胞中α1，α2，α3，αVβ3和αVβ5整合素的主要作用，而在MCF-7 / c细胞中则没有。与MCF-7 / c细胞相比，Lumican在MDA-MB-231和shERβMDA-MB-231中均上调了α2和β1整合素亚基的表达。发现整联蛋白的下游信号传导途径，例如FAK，ERK 1/2 MAPK 42/44和Akt，均被lumican下调。
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