CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling.
CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling.
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DOI：
10.1111/cas.14673
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发表时间：
2020-12
期刊：
影响因子：
5.7
通讯作者：
Mii S
中科院分区：
文献类型：
--
作者：
Taki T;Shiraki Y;Enomoto A;Weng L;Chen C;Asai N;Murakumo Y;Yokoi K;Takahashi M;Mii S
间质侵袭被认为是肺腺癌患者的一个重要预后因素。肺内肿瘤间质形成和间质侵袭的机制已被研究，但仍不清楚。CD109是一种糖基磷脂酰肌醇锚定糖蛋白，在包括肺癌在内的多种人类恶性肿瘤中高度表达。在本研究中，我们研究了CD109蛋白在肺部恶性肿瘤中的体内功能。最初，根据免疫组织化学分析，我们确定了CD109蛋白在人类肺腺癌中的高表达与显著较差的预后之间的关联。我们还发现，在CD109缺失的基因工程小鼠肺腺癌模型中，CD109缺失显著减少了间质侵袭性病变的面积，这与在人类肺腺癌中观察到的结果相关联。进一步，我们用质谱仪鉴定了潜伏的转化生长因子-β结合蛋白-1(LTBP1)是一种与CD109相互作用的蛋白，并用免疫共沉淀法证实了它们之间的相互作用。重要的是，在LTBP1存在的情况下，CD109表达的增加促进了间质转化生长因子-β的激活。因此，提示CD109与β在肿瘤间质中的相互作用对转化生长因子-LTBP1信号的调控意义，也揭示了CD109的表达水平在促进肺癌细胞增殖、迁移和侵袭，从而预测肺腺癌患者预后方面的重要作用。因此，CD109蛋白有可能成为治疗该病的潜在靶点。间质侵袭被认为是肺腺癌患者的一个重要预后因素。我们确定，CD109缺陷显著减少了肺腺癌模型小鼠的间质侵袭，延长了生存时间。此外，我们发现潜在的转化生长因子-β结合蛋白-1是一种与CD109相互作用的间质蛋白，强调了肿瘤细胞和间质之间的相互作用在肺腺癌进展中的重要性。
Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109‐deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF‐β binding protein‐1 (LTBP1) as a CD109‐interacting protein using mass spectrometry and confirmed their interaction by co‐immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF‐β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF‐β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease. Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. We determined that CD109 deficiency significantly reduced stromal invasion and prolonged survival of the lung adenocarcinoma mouse model. Furthermore, we identified latent TGF‐β binding protein‐1 as a CD109‐interacting stromal protein, highlighting the significance of interaction between tumor cells and stroma in lung adenocarcinoma progression.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
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Lu X
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作者：
Litvinov, Ivan V.;Bizet, Albane A.;Philip, Anie
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Philip, Anie
影响因子：
82.9
作者：
Chuang CH;Greenside PG;Rogers ZN;Brady JJ;Yang D;Ma RK;Caswell DR;Chiou SH;Winters AF;Grüner BM;Ramaswami G;Spencley AL;Kopecky KE;Sayles LC;Sweet-Cordero EA;Li JB;Kundaje A;Winslow MM
通讯作者：
Winslow MM