Zhang Qiang, Wei Dongping, Tan Mingjia, Li Haomin, Morgan Meredith A, Sun Yi
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.
Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Neoplasia. 2020 Apr 24;22(6):242-252. doi: 10.1016/j.neo.2020.03.002.
SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our previous studies showed that Sag/Rbx2 co-operated with Kras or Pten loss to promote tumorigenesis in the lung and prostate, respectively, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. The role of SAG in KRAS-induced pancreatic tumorigenesis is unknown. In this study, we mined a cancer database and found that SAG is overexpressed in pancreatic cancer tissues and correlates with decreased patient survival. Whether Sag overexpression plays a causal role in pancreatic tumorigenesis is unknown. Here, we reported the generation of Sag transgenic mouse model alone (CS), or in combination with Kras, driven by p48-Cre (KCS mice) for pancreatic specific Sag expression. Sag transgenic expression alone has no phenotypical abnormality, but in combination with Kras promotes ADM (acinar-to-ductal metaplasia) conversion in vitro and mPanIN1 formation in vivo at the early stage, and impairs pancreatic functions at the late stage, as evidenced by poor glucose tolerance and significantly reduced α-Amylase activity, and induction of cytogenesis and acinar cell loss, eventually leading to atrophic pancreata and shortened mouse life-span. Mechanistically, Sag transgenic expression altered several key signaling pathways, particularly inactivation of mTORC1 signaling due to Deptor accumulation, and activation of the antioxidant Nrf2-Nqo1 axis. Thus, Sag plays a stage dependent promotion (early) and fate-changing (late) role during Kras-pancreatic tumorigenesis, likely via regulating its key substrates, which control growth-related signal transduction pathways.
SAG（凋亡敏感基因），也被称为RBX2或ROC2，是Cullin-RING连接酶（CRL）的一个RING组件，对其活性至关重要。我们之前的研究表明，Sag/Rbx2分别与Kras缺失或Pten缺失协同作用，促进肺和前列腺的肿瘤发生，但拮抗Kras以抑制皮肤肿瘤发生，这表明Sag具有组织/环境依赖性功能。SAG在KRAS诱导的胰腺肿瘤发生中的作用尚不清楚。在本研究中，我们挖掘了一个癌症数据库，发现SAG在胰腺癌组织中过表达，且与患者生存率降低相关。Sag过表达是否在胰腺肿瘤发生中起因果作用尚不清楚。在此，我们报告了由p48-Cre驱动的单独的Sag转基因小鼠模型（CS）或与Kras联合的模型（KCS小鼠），用于胰腺特异性Sag表达。单独的Sag转基因表达没有表型异常，但与Kras联合时，在体外促进腺泡-导管化生（ADM）转化，在体内早期促进mPanIN1形成，并在后期损害胰腺功能，表现为葡萄糖耐量差和α-淀粉酶活性显著降低，以及诱导细胞生成和腺泡细胞丢失，最终导致胰腺萎缩和小鼠寿命缩短。机制上，Sag转基因表达改变了几个关键信号通路，特别是由于Deptor积累导致mTORC1信号失活，以及抗氧化剂Nrf2-Nqo1轴的激活。因此，Sag在Kras诱导的胰腺肿瘤发生过程中发挥阶段依赖性促进（早期）和命运改变（后期）的作用，可能是通过调节其关键底物来控制与生长相关的信号转导通路。
