title: KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis.
abstract: Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Gastroenterology, Hepatology & Nutrition, Unit 1644, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: kepxie@mdanderson.org.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors