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Our previous studies found overexpression of Musashi2 (MSI2) conduced to the progression and chemoresistance of pancreatic cancer (PC) by negative regulation of Numb and wild type p53 (wtp53). Now, we further investigated the novel signalling involved with MSI2 in PC. We identified inositol‐3‐phosphate synthase 1 (ISYNA1) as a novel tumour suppressor regulated by MSI2. High MSI2 and low ISYNA1 expression were prevalently observed in 91 PC tissues. ISYNA1 expression was negatively correlated with MSI2 expression, T stage, vascular permeation and poor prognosis in PC patients. What's more, patients expressed high MSI2 and low ISYNA1 level had a significant worse prognosis. And in wtp53 Capan‐2 and SW1990 cells, ISYNA1 was downregulated by p53 silencing. ISYNA1 silencing promoted cell proliferation and cell cycle by inhibiting p21 and enhanced cell migration and invasion by upregulating ZEB‐1. However, MSI2 silencing upregulated ISYNA1 and p21 but downregulated ZEB‐1, which can be rescued by ISYNA1 silencing. Moreover, reduction of cell migration and invasion resulting from MSI2 silencing was significantly reversed by ISYNA1 silencing. In summary, MSI2 facilitates the development of PC through a novel ISYNA1‐p21/ZEB‐1 pathway, which provides new gene target therapy for PC. [ABSTRACT FROM AUTHOR]

Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signal pathway and molecular mechanism involving the oncogenic role of CRT in PC. Methods: We investigated the potential role and mechanism of CRT in regulating intracellular free Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo. Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling. [ABSTRACT FROM AUTHOR]

Background: Methylsterol monooxygenase 1 (MSMO1), as a completely unique tumor biomarker, plays a vital role in the malignant progression of various cancer. Until now, the potential function and pathway of MSMO1 in the development of pancreatic cancer (PC) has not been explored yet, to our knowledge. Methods: We systematically explored the detail function of MSMO1 in Epithelial-mesenchymal transition (EMT) and cell proliferation of PC in vitro and in vivo . Results: MSMO1 expression was much lower in PC tissues than that in paired normal pancreas. MSMO1 positive expression was negatively associated with T stage, lymph node metastasis and vascular permeation of PC patients. Meanwhile, positive MSMO1 expression indicated a significantly better prognosis and an independent favorable prognostic factor. MSMO1 silencing promoted cell invasion and migration via activating EMT and PI3K-AKT-mTOR pathway [p-PI3K (Tyr458), p-AKT (Ser473) and p-mTOR (Ser2448)] in Capan-2, Panc-1 and SW1990 cells. In vivo , subcutaneous tumor size was enhanced by MSMO1 silencing following with the consistent change of EMT and PI3K/AKT signaling shown in vitro . The motivation of EMT and PI3K-AKT-mTOR pathway was also demonstrated in MSMO1 silencing mouse PANC02 cells. Conclusion: Down-regulation of MSMO1 in PC was associated with advanced progression and poor prognosis of PC patients. MSMO1 acts as a tumor suppressor via inhibiting the aggressive malignant biology of PC accompanying with regulating EMT and PI3K/AKT signaling., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)