Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.

Ping He
Ping He
Institute of Population Research
State College | United States
Jong Won Yang
Jong Won Yang
Yonsei University Wonju College of Medicine
Vincent W Yang, MD, PhD
Vincent W Yang, MD, PhD
Stony Brook University School of Medicine
Professor and Chair
Stony Brook, NY | United States
Agnieszka B Bialkowska
Agnieszka B Bialkowska
Stony Brook University School of Medicine
Stony Brook | United States

Gastroenterology 2018 04 15;154(5):1494-1508.e13. Epub 2017 Dec 15.

Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York. Electronic address:

Background & Aims: Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs.

Methods: We performed studies in adult mice with conditional disruption of Klf5 (Klf5) and/or expression of Kras (LSL-Kras) via Cre recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of Kras and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-Kras mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed.

Results: Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre;LSL-Kras mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-Cre;LSL-Kras;Klf5 mice formed fewer PanINs. After cerulein administration, Ptf1a-Cre;LSL-Kras mice formed more extensive ADM than Ptf1a-Cre;LSL-Kras;Klf5 mice. Pancreata from Ptf1a-Cre;LSL-Kras;Klf5 mice had increased expression of the tumor suppressor NDRG2 and reduced phosphorylation (activation) of STAT3, compared with Ptf1a-Cre;LSL-Kras mice. In UN-KC-6141 cells, PI3K and MEK signaling increased expression of KLF5; a high level of KLF5 increased proliferation. Cells with knockdown of Klf5 had reduced proliferation, compared with control cells, had reduced expression of ductal markers, and formed smaller tumors (71.61 ± 30.79 mm vs 121.44 ± 34.90 mm from control cells) in flanks of mice.

Conclusion: Levels of KLF5 are increased in human PDAC samples and in PanINs of Ptf1a-Cre;LSL-Kras mice, compared with controls. KLF5 disruption increases expression of NDRG2 and reduces activation of STAT3 and reduces ADM and PanINs formation in mice. Strategies to reduce KLF5 activity might reduce progression of acinar cells from ADM to PanIN and pancreatic tumorigenesis.
PDF Download - Full Text Link
( Please be advised that this article is hosted on an external website not affiliated with
Source Status ListingPossible
April 2018
8 Reads

Similar Publications

Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues.

J Pathol 2012 Apr 17;226(5):723-34. Epub 2012 Jan 17.

Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions, pancreatic intraepithelial neoplasia (PanIN), display a ductal phenotype. However, there is evidence in genetically defined mouse models for PDAC harbouring a mutated kras under the control of a pancreas-specific promoter that ductal cancer might arise in the centroacinar-acinar region, possibly through a process of acinar-ductal metaplasia (ADM). In order to further elucidate this model of PDAC development, an extensive expression analysis and molecular characterization of the putative and already established (PanIN) precursor lesions were performed in the Kras(G12D/+) ; Ptf1a-Cre(ex1/+) mouse model and in human tissues, focusing on lineage markers, developmental pathways, cell cycle regulators, apomucins, and stromal activation markers. Read More

View Article
April 2012

Identification and manipulation of biliary metaplasia in pancreatic tumors.

Gastroenterology 2014 Jan 30;146(1):233-44.e5. Epub 2013 Aug 30.

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. Electronic address:

Background & Aims: Metaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Read More

View Article
January 2014

NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas.

Gastroenterology 2015 May 23;148(5):1024-1034.e9. Epub 2015 Jan 23.

Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. Electronic address:

Background & Aims: Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis. Read More

View Article
May 2015

Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS.

Gastroenterology 2016 Jan 25;150(1):218-228.e12. Epub 2015 Sep 25.

The Department of Pathology, Columbia University Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Department of Otolaryngology and Head and Neck Surgery, Columbia University Medical Center, New York, New York. Electronic address:

Background & Aims: Activin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis.

Methods: We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. Read More

View Article
January 2016