KLF4alpha Upregulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients with Pancreatic Cancer.
Summary of "KLF4alpha Upregulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients with Pancreatic Cancer."
BACKGROUND &
AIMS:
: Krüppel-like factor (KLF)4 is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation.
METHODS:
: We identified different isoforms of KLF4 in pancreatic cancer cells by reverse transcriptase-PCR, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4alpha and characterize its function. Using real-time PCR, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4alpha in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4alpha on pancreatic tumorigenesis.
RESULTS:
: We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4alpha, KLF4beta, KLF4gamma, and KLF4delta. KLF4alpha localized primarily to the cytoplasm; its protein and mRNA were upregulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors, compared with normal pancreatic tissue. Transgenic expression of KLF4alpha reduced expression of p27Kip1 and p21CIP1, promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4alpha in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma.
CONCLUSIONS:
: We identified a splice variant of KLF4 (KLF4alpha) that is upregulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice is associated with reduced survival times of patients.
Affiliation
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Journal Details
This article was published in the following journal.
Name: Gastroenterology
ISSN: 1528-0012
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20727893
- DOI: http://dx.doi.org/10.1053/j.gastro.2010.08.022
Medical and Biotech [MESH] Definitions
Stathmin
A ubiquitous phosphoprotein that serves as an intracellular substrate for a variety of SIGNAL TRANSDUCTION PATHWAYS. PHOSPHORYLATION of stathmin occurs during CELL CYCLE progression, and stathmin functions as a microtubule-destabilizing protein that promotes MICROTUBULE depolymerization during INTERPHASE and late MITOSIS. Stathmin is expressed at very high levels in a variety of human CANCERS.
Cyclin-dependent Kinase Inhibitor Proteins
A group of cell cycle proteins that negatively regulate the activity of CYCLIN/CYCLIN-DEPENDENT KINASE complexes. They inhibit CELL CYCLE progression and help control CELL PROLIFERATION following GENOTOXIC STRESS as well as during CELL DIFFERENTIATION.
Leukemia, Prolymphocytic, T-cell
A lymphoid leukemia characterized by a profound LYMPHOCYTOSIS with or without LYMPHADENOPATHY, hepatosplenomegaly, frequently rapid progression, and short survival. It was formerly called T-cell chronic lymphocytic leukemia.
G1 Phase
The period of the CELL CYCLE preceding DNA REPLICATION in S PHASE. Subphases of G1 include "competence" (to respond to growth factors), G1a (entry into G1), G1b (progression), and G1c (assembly). Progression through the G1 subphases is effected by limiting growth factors, nutrients, or inhibitors.
Ciliary Neurotrophic Factor
A neurotrophic factor that promotes the survival of various neuronal cell types and may play an important role in the injury response in the nervous system.
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