Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model

Qiang Zhang; Dongping Wei; Mingjia Tan; Haomin Li; Meredith A Morgan; Yi Sun

doi:10.1016/j.neo.2020.03.002

Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model

Neoplasia. 2020 Apr 24;22(6):242-252. doi: 10.1016/j.neo.2020.03.002. Online ahead of print.

Authors

Qiang Zhang¹, Dongping Wei¹, Mingjia Tan¹, Haomin Li², Meredith A Morgan¹, Yi Sun³

Affiliations

¹ Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.
² Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA; Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, China. Electronic address: sunyi@umich.edu.

Abstract

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^G12D, driven by p48-Cre (KCS mice) for pancreatic specific Sag expression. Sag transgenic expression alone has no phenotypical abnormality, but in combination with Kras^G12D 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.

Keywords: ADM and mPanINs; Kras; Pancreatic tumorigenesis; SAG; Ubiquitin ligase.

Abstract

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