title: The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer.
abstract: OBJECTIVE
  Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the current study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway.
  
  
  METHODS
  MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biological functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods.
  
  
  RESULTS
  MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC.
  
  
  CONCLUSIONS
  Lost expression of KLF4, a transcriptional repressor of MSI2 results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis. Clin Cancer Res; 23(3); 687-96. ©2016 AACR.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.|Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jiujie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Oncology, Shanghai East Hospital, Shanghai Tongji University, Shanghai, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Quan
authors.affiliation: Department of Oncology, Shanghai East Hospital, Shanghai Tongji University, Shanghai, P.R. China.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, Shanghai East Hospital, Shanghai Tongji University, Shanghai, P.R. China. kepxie@mdanderson.org qyma56@xjtu.edu.cn gaoyon@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China. kepxie@mdanderson.org qyma56@xjtu.edu.cn gaoyon@hotmail.com.
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. kepxie@mdanderson.org qyma56@xjtu.edu.cn gaoyon@hotmail.com.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D064593:Heterografts; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic; D014410:Tumor Stem Cell Assay
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C438151:MSI2 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins