Suppression of Tak1 Promotes Prostate Tumorigenesis

More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In thi...

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Published inCancer research (Chicago, Ill.) Vol. 72; no. 11; pp. 2833 - 2843
Main Authors Wu, Min, Shi, Lihong, Cimic, Adela, Romero, Lina, Sui, Guangchao, Lees, Cynthia J., Cline, J. Mark, Seals, Darren F., Sirintrapun, Joseph S., McCoy, Thomas P., Liu, Wennuan, Kim, Jin Woo, Hawkins, Gregory A., Peehl, Donna M., Xu, Jianfeng, Cramer, Scott D.
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.06.2012
Subjects
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line
Cell Movement
Cell Proliferation
Humans
Male
MAP Kinase Kinase Kinases - analysis
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - physiology
Medical sciences
Mice
Neoplasm Invasiveness
Pharmacology. Drug treatments
Prostatic Neoplasms - etiology
Prostatic Neoplasms - pathology
Prostatic Neoplasms - prevention & control
Tumor Suppressor Proteins - physiology
Tumors
Tumorigenicity
Urogenital system
Carcinogenesis
Prostate
Online AccessGet full text
ISSN0008-5472
1538-7445
1538-7445
DOI10.1158/0008-5472.CAN-11-2724

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Abstract More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH2-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer. Cancer Res; 72(11); 2833–43. ©2012 AACR.
AbstractList More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH(2)-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.
More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH(2)-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH(2)-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.
More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH2-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer. Cancer Res; 72(11); 2833–43. ©2012 AACR.
Over 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β Activated Kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and JNK activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.
Author Wu, Min
Sirintrapun, Joseph S.
Cimic, Adela
Hawkins, Gregory A.
Lees, Cynthia J.
Shi, Lihong
Liu, Wennuan
Sui, Guangchao
Cline, J. Mark
McCoy, Thomas P.
Xu, Jianfeng
Peehl, Donna M.
Cramer, Scott D.
Romero, Lina
Kim, Jin Woo
Seals, Darren F.
AuthorAffiliation 6 Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
7 Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
3 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
1 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
4 Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
5 Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
2 Molecular Genetics & Genomics Graduate Program, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
8 Department of Urology, Stanford University School of Medicine, Stanford CA, 94305, USA
AuthorAffiliation_xml – name: 3 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
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– name: 1 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
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Issue 11
Keywords Tumorigenicity
Urogenital system
Carcinogenesis
Prostate
Language English
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2012 AACR
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Snippet More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes...
Over 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β...
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StartPage 2833
SubjectTerms Animals
Antineoplastic agents
Biological and medical sciences
Cell Line
Cell Movement
Cell Proliferation
Humans
Male
MAP Kinase Kinase Kinases - analysis
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - physiology
Medical sciences
Mice
Neoplasm Invasiveness
Pharmacology. Drug treatments
Prostatic Neoplasms - etiology
Prostatic Neoplasms - pathology
Prostatic Neoplasms - prevention & control
Tumor Suppressor Proteins - physiology
Tumors
Title Suppression of Tak1 Promotes Prostate Tumorigenesis
URI https://www.ncbi.nlm.nih.gov/pubmed/22467172
https://www.proquest.com/docview/1018634031
https://pubmed.ncbi.nlm.nih.gov/PMC3654674
Volume 72
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