title: Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer.
abstract: 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 PCin vitroandinvivo, 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 motilityin vitroand inhibited tumor growthin vivo, 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.
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sheng
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China; dongming@cmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Dong
authors.affiliation: Clinical Laboratory, The Sixth Peoples' Hospital of Shenyang City, Shenyang, China.
authors.forename: Chuanping
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Zixin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, First Hospital of China Medical University, Shenyang, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C438151:MSI2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: cell invasion; chemosensitivity; clinical significance; tumor growth