Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells
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Qinlong Li1,8,*, Lijuan Yin1,*, Lawrence W. Jones2, Gina C-Y Chu1, Jason B-Y. Wu1, Jen-Ming Huang1, Quanlin Li3, Sungyong You4, Jayoung Kim4, Yi-Tsung Lu5, Stefan Mrdenovic1, Ruoxiang Wang1, Michael R. Freeman4, Isla Garraway6, Michael S. Lewis7, Leland W. K. Chung1, Haiyen E. Zhau1
1Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Urological Research, Huntington Medical Research Institutes, Huntington Memorial Hospital, Pasadena, CA, USA
3Biostatistics and Bioinformatics, Department of Medicine, Los Angeles, CA, USA
4Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
5John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA
6Department of Urology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and Division of Urology, Greater Los Angeles Veteran's Affairs Healthcare System, Los Angeles, CA, USA
7Sepulveda Research Corporation VA Medical Center, Los Angeles, CA, USA
8Current address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
*These authors contributed equally to this work
Haiyen E. Zhau, email: Haiyen.Zhau@cshs.org
Leland W. K. Chung, email: Leland.Chung@cshs.org
Michael S. Lewis, email: firstname.lastname@example.org
Isla Garraway, email: email@example.com
Keywords: bone and brain metastases, RANKL-independent, targeting, biomarker, cell signal network
Received: July 07, 2016 Accepted: October 28, 2016 Published: November 07, 2016
Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.
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