Speckle-type POZ domain protein (SPOP), an adaptor in the E3 ubiquitin ligase complex, recognizes substrates and promotes protein degradation via the ubiquitin-proteasome system. It appears to help regulate progression of several cancers, and we show here that it acts as a tumor suppressor in pancreatic cancer. Our analysis of patient tissues showed decreased SPOP expression, which was associated with poor prognosis. SPOP knockdown in SW1990 (in vitro/vivo) and PANC-1 (in vitro) cells led to significantly greater proliferation, migration, and invasion. Co-immunoprecipitation experiments in SW1990 cells showed that SPOP interacted with the stem-cell marker NANOG, and this interaction has recently been shown to play a critical role in regulating progression of prostate cancer. We showed that, in one patient with pancreatic cancer, the expression of a truncated form of SPOP (p.Q360*) lacking the nuclear localization signal led to nuclear accumulation of NANOG, which promoted growth and metastasis of pancreatic cancer cells. Our results suggest that SPOP suppresses progression of pancreatic cancer by promoting the ubiquitination and subsequent degradation of NANOG. These results identify the SPOP-NANOG interaction as a potential therapeutic target against pancreatic cancer.

Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-κB (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α-SMA and Col1a1. Therefore, we determined whether suppressing NF-κB/p65 alleviated CP by treating mice with the NF-κB/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-κB/p65 inhibition.These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis. K E Y W O R D S chronic pancreatitis, Hic-5, NF-κB, pancreatic stellate cells, triptolide | 1489 CHEN Et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Chen H, Tan P, Qian B, et al. Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-κB (p65)/IL-6 signalling pathway.

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