Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
Division of Cardiology, The People's Hospital of Liaoning Province, Shenyang, China.
J Cell Mol Med. 2020 Sep;24(18):10560-10572. doi: 10.1111/jcmm.15676. Epub 2020 Aug 11.
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.
我们之前的研究发现，Musashi2（MSI2）的过表达通过负向调控 Numb 和野生型 p53（wtp53）促进了胰腺癌（PC）的进展和化疗耐药性。现在，我们进一步研究了 MSI2 在 PC 中涉及的新信号通路。我们鉴定出肌醇-3-磷酸合酶 1（ISYNA1）是一种受 MSI2 调控的新型肿瘤抑制因子。在 91 份 PC 组织中，普遍观察到高 MSI2 和低 ISYNA1 表达。ISYNA1 表达与 MSI2 表达、T 分期、血管渗透和 PC 患者的预后不良呈负相关。更重要的是，表达高 MSI2 和低 ISYNA1 水平的患者预后显著更差。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。然而，MSI2 沉默上调 ISYNA1 和 p21，但下调 ZEB-1，这可以通过 ISYNA1 沉默来挽救。此外，MSI2 沉默导致的细胞迁移和侵袭减少通过 ISYNA1 沉默得到显著逆转。总之，MSI2 通过一种新型的 ISYNA1-p21/ZEB-1 通路促进了 PC 的发展，为 PC 提供了新的基因靶向治疗。
