KLF6 Loss of Function in Human Prostate Cancer Progression Is Implicated in Resistance to Androgen Deprivation
| Autor: | Anna C. Ferrari, Xiaomei Liu, John Mandeli, Pamela D. Unger, Charisse Loder, Jonathan Melamed, Alejandro Gomez-Pinillos, Ralf Kurek, Enrique Carrillo-de Santa Pau, Ruifang Qiao, Robert E. Gallagher, Carole Oddoux |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Transcriptional Activation Transcription Genetic Cell Survival medicine.drug_class DNA Mutational Analysis Kruppel-Like Transcription Factors Biology Pathology and Forensic Medicine Prostate cancer Exon Germline mutation Cell Line Tumor Proto-Oncogene Proteins LNCaP Kruppel-Like Factor 6 medicine Humans Microdissection Cell Proliferation Prostatic Neoplasms Cancer Regular Article Exons medicine.disease Androgen Molecular biology Alternative Splicing KLF6 Androgens Disease Progression |
| Zdroj: | The American Journal of Pathology. 181(3):1007-1016 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2012.06.008 |
| Popis: | Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy. |
| Databáze: | OpenAIRE |
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