Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
FEBS J. 2022 Dec;289(24):7970-7986. doi: 10.1111/febs.16179. Epub 2021 Sep 19.
CD44, a non-kinase transmembrane glycoprotein, is ubiquitously expressed on various types of cells, especially cancer stem cells (CSCs), and has been implicated in cancer onset and aggressiveness. The major ligand for the CD44, hyaluronan (HA), binds to and interacts with CD44, which in turn triggers downstream signaling cascades, thereby promoting cellular behaviors such as proliferation, motility, invasiveness and chemoresistance. The CD44-HA interaction is cell-specific and strongly affected by the state of CD44 activation. Therefore, the binding of HA to CD44 is essential for the activation of CD44 during which the detailed regulatory mechanism needs to be clarified. Different CD44 activation states distribute in human carcinoma and normal tissue; however, whether CD44 activation is a critical requirement for tumor initiation, progression and notorious CSC properties remains to be clarified. A deeper understanding of the regulation of CD44 activation may facilitate the development of novel targeted drugs in the future. Here, we review the current findings concerning the states of CD44 activation on the cell surface, the underlying regulatory mechanisms of CD44 activation, the known role for CD44 activation in tumor progression and CSC hallmarks, as well as the potential of HA-coated nanoparticle for targeting activated CD44 for cancer therapy.
CD44 是一种非激酶跨膜糖蛋白，广泛表达于各种类型的细胞上，尤其是癌症干细胞（CSC），并与癌症的发生和侵袭性有关。CD44 的主要配体透明质酸（HA）与 CD44 结合并相互作用，进而触发下游信号级联反应，从而促进细胞增殖、迁移、侵袭和耐药等行为。CD44-HA 相互作用具有细胞特异性，并受 CD44 激活状态的强烈影响。因此，HA 与 CD44 的结合对于 CD44 的激活至关重要，在此过程中需要阐明详细的调节机制。不同的 CD44 激活状态分布于人类癌组织和正常组织中；然而，CD44 的激活是否是肿瘤起始、进展和恶性 CSC 特性的关键要求仍有待阐明。深入了解 CD44 激活的调节机制可能有助于未来开发新型靶向药物。本文综述了细胞表面 CD44 激活状态、CD44 激活的潜在调节机制、CD44 激活在肿瘤进展和 CSC 特征中的已知作用，以及针对激活的 CD44 的 HA 包覆纳米颗粒在癌症治疗中的潜在应用。
