Sun Bing, Kawahara Masahiro, Ehata Shogo, Nagamune Teruyuki
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Cell Signal. 2014 Sep;26(9):1863-9. doi: 10.1016/j.cellsig.2014.04.001. Epub 2014 Apr 12.
Dysregulation of signalling pathways by changes of gene expression contributes to hallmarks of cancer. The ubiquitously expressed chaperone protein AAG8 (aging-associated gene 8 protein, encoded by the SIGMAR1 gene) is often found to be overexpressed in various cancers. AAG8 is involved in ER (endoplasmic reticulum)-associated degradation and has been intensively elaborated in neuroscience. However, its rationale in carcinogenesis has rarely been noticed. In this study, we explored the intrinsic oncogenetic roles of AAG8 in cancer cells and found that AAG8 promoted carcinogenesis both in vitro and in vivo. We further characterized AAG8, for the first time to our knowledge, as a STAT3 activator and elucidated that it alternatively activated STAT3 in addition to IL6/JAK pathway. Based on these findings and a drug screening study, we demonstrated that combined inhibition of AAG8 and IL6/JAK signalling synergistically limits cancer cell growth. Taken together, our findings shed light on the fundamental evidences for identification of AAG8 as an oncoprotein and potential target for cancer prevention, as well as highlight the importance of ER proteins in contributing to JAK/STAT signaling and carcinogenesis.
基因表达变化导致的信号通路失调是癌症的标志之一。普遍表达的伴侣蛋白AAG8（衰老相关基因8蛋白，由SIGMAR1基因编码）在多种癌症中常被发现过表达。AAG8参与内质网相关降解，在神经科学领域已有深入研究。然而，其在致癌过程中的原理却很少被关注。在本研究中，我们探究了AAG8在癌细胞中的内在致癌作用，发现AAG8在体外和体内均促进致癌作用。据我们所知，我们首次将AAG8鉴定为STAT3激活剂，并阐明它除了通过IL6/JAK途径外，还能以其他方式激活STAT3。基于这些发现和一项药物筛选研究，我们证明联合抑制AAG8和IL6/JAK信号能协同限制癌细胞生长。综上所述，我们的研究结果为将AAG8鉴定为癌蛋白和癌症预防的潜在靶点提供了基本证据，同时也突出了内质网蛋白在JAK/STAT信号传导和致癌过程中的重要性。
