Abstract
Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR-mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer. Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay. Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model. KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization.
Highlights
Keratins (KRT) are a subgroup of intermediate filament proteins that are present in epithelial tissues [1]
Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7
KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization
Summary
Keratins (KRT) are a subgroup of intermediate filament proteins that are present in epithelial tissues [1]. There are 2 types of KRTs: low-molecular weight acidic type I KRTs and high-molecular weight basic or neutral type II KRTs [2]. One of the most biologically interesting KRTs is KRT19, at 40 kDa the smallest known intermediate filament. KRT19 is used as a marker for reverse transcriptase PCR (RT-PCR)– mediated detection of tumor cells disseminated in lymph nodes, peripheral blood, and bone marrow of patients with breast cancer, and its positivity is considered a prognostic indicator [3,4,5]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The early growth response-1 (Egr1) transcription factor regulates the expression of several genes including PTEN, Authors' Affiliations: 1Department of Life Science; 2Natural Science Institute, Hanyang University; 3Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University, Seoul; and 4Korean BioInformation Center, KRIBB, Daejon, Republic of Korea
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