Sheng Weiwei, Dong Ming, Chen Chuanping, Wang Zixin, Li Yunwei, Wang Kewei, Li Yuji, Zhou Jianping
Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China;
FASEB J. 2017 Jun;31(6):2429-2438. doi: 10.1096/fj.201601240R. Epub 2017 Feb 21.
Our earlier work showed that Musashi (MSI)-2 promoted the development of pancreatic cancer (PC) by down-regulating Numb, which prevented murine double-minute (MDM)-2-mediated p53 ubiquitin degradation. Thus, we investigate the relationship among MSI2, Numb, MDM2, and p53 in PC and , an association that has not been reported to our knowledge. MSI2 had no relationship with mutant p53 (mtp53) and wild-type p53 (wtp53) in normal PC cells. However, in response to gemcitabine or cisplatin treatment, MSI2 silencing simultaneously down-regulated MDM2 and up-regulated Numb and wtp53 protein levels. Moreover, these 4 endogenous proteins can be coimmunoprecipitated as a quaternary complex. Numb small interfering RNA (siRNA) reversed the MSI2 silencing-induced p53 increase. During treatment with chemical agents, MSI2 silencing decreased drug resistance and cell motility and inhibited tumor growth , all of which were significantly reversed by p53 siRNA. MSI2 was also negatively associated with Numb and positively associated with MDM2 expression in tissue. Overexpression of MSI2, MDM2, and mtp53 and weak expression of Numb were closely associated with aggressive clinicopathologic characteristics and poor prognosis for patients with PC. MSI2 negatively regulates wtp53 protein by up-regulating MDM2 and down-regulating Numb after treatment with chemical agents. MSI2 promotes drug resistance and malignant biology of PC in a p53-dependent manner.-Sheng, W., Dong, M., Chen, C., Wang, Z., Li, Y., Wang, K., Li, Y., Zhou, J. Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer.
我们早期的研究表明，Musashi（MSI）-2通过下调Numb促进胰腺癌（PC）的发展，Numb可阻止鼠双微体（MDM）-2介导的p53泛素化降解。因此，我们研究了PC中MSI2、Numb、MDM2和p53之间的关系，据我们所知，这一关联尚未见报道。在正常PC细胞中，MSI2与突变型p53（mtp53）和野生型p53（wtp53）均无关联。然而，在吉西他滨或顺铂治疗后，MSI2沉默同时下调了MDM2并上调了Numb和wtp53蛋白水平。此外，这4种内源性蛋白可作为四元复合物进行共免疫沉淀。Numb小干扰RNA（siRNA）逆转了MSI2沉默诱导的p53增加。在化学药物治疗期间，MSI2沉默降低了耐药性和细胞运动性并抑制了肿瘤生长，所有这些均被p53 siRNA显著逆转。在组织中，MSI2也与Numb呈负相关，与MDM2表达呈正相关。MSI2、MDM2和mtp53的过表达以及Numb的低表达与PC患者侵袭性的临床病理特征和不良预后密切相关。化学药物治疗后，MSI2通过上调MDM2和下调Numb对wtp53蛋白进行负调控。MSI2以p53依赖的方式促进PC的耐药性和恶性生物学行为。-盛，W.，董，M.，陈，C.，王，Z.，李，Y.，王，K.，李，Y.，周，J. Musashi-2、Numb、MDM2和P53在胰腺癌耐药性和恶性生物学中的协同作用
