Ssadh Hussain Al, Spencer Patrick S, Alabdulmenaim Waleed, Alghamdi Rana, Madar Inamul Hasan, Miranda-Sayago Jose M, Fernández Nelson
School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, United Kingdom.
Pathology Department, College of Medicine, Qassim University, Qassim, Saudi Arabia.
Oncotarget. 2017 Sep 14;8(54):92143-92156. doi: 10.18632/oncotarget.20922. eCollection 2017 Nov 3.
Interactions between pairs of membrane-bound receptors can enhance tumour development with implications for targeted therapies for cancer. Here we demonstrate clear heterotypic interaction between CD74 and CD44, which might act in synergy and hence contribute to breast cancer progression. CD74, a type II transmembrane glycoprotein, is a chaperone for MHC class II biosynthesis and a receptor for the MIF. CD44 is the receptor for hyaluronic acid and is a Type I transmembrane protein. Interactions between CD74, MIF and the intra-cytoplasmic domain of CD44 result in activation of ERK1/2 pathway, leading to increased cell proliferation and decreased apoptosis. The level of CD44 in the breast tumor cell lines CAMA-1, MDA-MB-231, MDA-MB-435 and the immortalized normal luminal cell line 226LDM was higher than that of CD74. It was also observed that CD74 and CD44 exhibit significant variation in expression levels across the cells. CD74 and CD44 were observed to accumulate in cytoplasmic compartments, suggesting they associate with each other to facilitate tumour growth and metastasis. Use of a novel and validated colocalisation and image processing approach, coupled with co-immunoprecipitation, confirmed that CD74 and CD44 physically interact, suggesting a possible role in breast tumour growth. This is the first time that CD74 and CD44 colocalization has been quantified in breast cancer cells using a non-invasive and validated bioimaging procedure. Measuring the co-expression levels of CD74 and CD44 could potentially be used as a 'biomarker signature' to monitor different stages of breast cancer.
膜结合受体对之间的相互作用可促进肿瘤发展，这对癌症的靶向治疗具有重要意义。在此，我们证明了CD74与CD44之间存在明显的异型相互作用，它们可能协同作用，从而促进乳腺癌进展。CD74是一种II型跨膜糖蛋白，是MHC II类生物合成的伴侣蛋白以及MIF的受体。CD44是透明质酸的受体，是一种I型跨膜蛋白。CD74、MIF与CD44的胞质内结构域之间的相互作用导致ERK1/2通路激活，进而导致细胞增殖增加和细胞凋亡减少。乳腺癌细胞系CAMA-1、MDA-MB-231、MDA-MB-435以及永生化正常管腔细胞系226LDM中CD44的水平高于CD74。还观察到CD74和CD44在不同细胞中的表达水平存在显著差异。观察到CD74和CD44在细胞质区室中积累，表明它们相互结合以促进肿瘤生长和转移。使用一种新颖且经过验证的共定位和图像处理方法，并结合免疫共沉淀，证实了CD74和CD44存在物理相互作用，提示其在乳腺肿瘤生长中可能发挥作用。这是首次使用非侵入性且经过验证的生物成像程序对乳腺癌细胞中CD74和CD44的共定位进行定量。测量CD74和CD44的共表达水平有可能用作“生物标志物特征”来监测乳腺癌的不同阶段。
