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.

中文翻译：

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Musashi2通过新型ISYNA1-p21 / ZEB-1途径促进胰腺癌的进展。

我们以前的研究发现，通过Numb和野生型p53（wtp53）的负调控，Musashi2（MSI2）的过表达有助于胰腺癌（PC）的发展和化学耐药性。现在，我们进一步研究了PC中MSI2涉及的新型信号传导。我们将肌醇-3-磷酸合酶1（ISYNA1）确定为受MSI2调控的新型肿瘤抑制因子。在91个PC组织中普遍观察到MSI2高表达和ISYNA1低表达。ISYNA1表达与PC患者的MSI2表达，T分期，血管渗透和不良预后呈负相关。此外，表达高MSI2和低ISYNA1水平的患者预后明显差。在wtp53 Capan-2和SW1990细胞中，ISYNA1被p53沉默下调。ISYNA1沉默通过抑制p21促进细胞增殖和细胞周期，并通过上调ZEB-1增强细胞迁移和侵袭。但是，MSI2沉默可上调ISYNA1和p21，但下调ZEB-1，可通过ISYNA1沉默来挽救。此外，ISYNA1沉默显着逆转了由MSI2沉默导致的细胞迁移和侵袭的减少。总之，MSI2通过新颖的ISYNA1-p21 / ZEB-1途径促进了PC的发展，该途径为PC提供了新的基因靶标疗法。