title: Genetic ablation of metadherin inhibits autochthonous prostate cancer progression and metastasis.
abstract: Metadherin (MTDH) overexpression in diverse cancer types has been linked to poor clinical outcomes, but definitive genetic proof of its contributions to cancer remains incomplete. In particular, the degree to which MTDH may contribute to malignant progression in vivo is lacking. Here, we report that MTDH is amplified frequently in human prostate cancers where its expression levels are tightly correlated with prostate cancer progression and poor disease-free survival. Furthermore, we show that genetic ablation of MTDH in the transgenic adenomcarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer blocks malignant progression without causing defects in the normal development of the prostate. Germline deletion of Mtdh in TRAMP mice prolonged tumor latency, reduced tumor burden, arrested progression of prostate cancer at well-differentiated stages, and inhibited systemic metastasis to distant organs, thereby decreasing cancer-related mortality ∼10-fold. Consistent with these findings, direct silencing of Mtdh in prostate cancer cells decreased proliferation in vitro and tumor growth in vivo, supporting an epithelial cell-intrinsic role of MTDH in prostate cancer. Together, our findings establish a pivotal role for MTDH in prostate cancer progression and metastasis and define MTDH as a therapeutic target in this setting. Cancer Res; 74(18); 5336-47. ©2014 AACR.
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey.
authors: Liling
authors: L
authors: Wan
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey. Institute of Health Sciences, Shanghai, China.
authors: Guohong
authors: G
authors: Hu
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey.
authors: Yong
authors: Y
authors: Wei
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey.
authors: Min
authors: M
authors: Yuan
authors: Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors: Roderick T
authors: RT
authors: Bronson
authors: Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong Province, P.R. China.
authors: Qifeng
authors: Q
authors: Yang
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Javed
authors: J
authors: Siddiqui
authors: Department of Urology and Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Kenneth J
authors: KJ
authors: Pienta
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey. Tumor Progression and Genomic Instability Program, The Cancer Institute of New Jersey, New Brunswick, New Jersey. ykang@princeton.edu.
authors: Yibin
authors: Y
authors: Kang
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; C483038:Mtdh protein, mouse; D016601:RNA-Binding Proteins