Duan Xiaofeng, Iwanowycz Stephen, Ngoi Soo, Hill Megan, Zhao Qiang, Liu Bei
Department of Microbiology & Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.
Front Oncol. 2021 Apr 9;11:629846. doi: 10.3389/fonc.2021.629846. eCollection 2021.
During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.
在肿瘤发生和发展过程中，内在和外在因素会引发内质网（ER）应激和未折叠蛋白反应，导致分子伴侣的表达增加，以应对应激并维持肿瘤细胞存活。热休克蛋白（HSP）GRP94，也称为GP96，是HSP90的内质网旁系同源物，已被证明在肿瘤诱导的应激过程中促进存活信号传导，并通过其多个客户分子（包括Toll样受体、整合素、低密度脂蛋白受体相关蛋白6、糖蛋白A重复优势蛋白、胰岛素样生长因子和人表皮生长因子受体2）调节免疫反应。临床上，GRP94的表达升高与多种癌症的侵袭性表型和不良临床结局相关。因此，GRP94是恶性肿瘤中一个潜在的分子标志物和治疗靶点。在本综述中，我们将对GRP94在肿瘤发生过程中的分子特征进行深入分析，并总结GRP94在常见癌症（包括乳腺癌、结肠癌、肺癌、肝癌、多发性骨髓瘤等）中的各自作用。最后，我们将简要回顾选择性靶向GRP94治疗癌症的潜在治疗价值。
