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Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

 Kyung Seok Han  ;  Na Li  ;  Peter A. Raven  ;  Ladan Fazli  ;  Susan Ettinger  ;  Sung Joon Hong  ;  Martin E. Gleave  ;  Alan I. So 
 MOLECULAR CANCER THERAPEUTICS, Vol.14(4) : 1024-1034, 2015 
Journal Title
Issue Date
Animals ; Biomarkers ; Carcinoma, Renal Cell/genetics* ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology* ; Cell Line, Tumor ; Cell Movement ; Cell Survival/genetics ; Disease Models, Animal ; Down-Regulation ; Epithelial-Mesenchymal Transition/genetics* ; Gene Expression ; Gene Knockdown Techniques ; Heterografts ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Neoplasm Staging ; Phenotype ; Protein-Serine-Threonine Kinases/genetics* ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Snail Family Transcription Factors ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Zinc Finger E-box-Binding Homeobox 1
Renal cell carcinoma (RCC) is the most common malignancy in the kidney. Antiangiogenic targeted therapies inhibit the progression of RCC, but have limited impacts on invasion or metastasis of tumor cells. Integrin-linked kinase (ILK) is a serine/threonine kinase implicated in the regulation of cell growth/survival, cell-cycle progression, epithelial-mesenchymal transition (EMT), invasion/migration, and angiogenesis. However, the role of ILK in RCC has not been evaluated. We investigated the role of ILK on cancer progression and metastasis and the therapeutic potential of ILK inhibition in RCC. Our investigation reveals that ILK is expressed at a low level in normal cells and low-stage RCC cells and is highly expressed in advanced and metastatic cells. Caki-1, a metastatic RCC cell line, showed higher expression of molecular EMT markers, including Snail and Zeb1, but decreased activity of GSK3β. Knockdown of ILK using small interference (si)-ILK minimally inhibited tumor proliferation and cell-cycle progression was not significantly affected. However, ILK knockdown suppressed the formation of stress fibers and focal adhesions and impeded phenotypic EMT markers, including cell migration and invasion, in Caki-1 and UMRC-3 cells. Finally, in vivo knockdown of ILK suppressed the progression, invasion, and metastasis of primary RCC in nude mice by downregulation of EMT markers (Snail, Zeb1, vimentin, and E-cadherin). Our results show that ILK may be essential for invasion and metastasis in RCC and regulates vimentin and E-cadherin expression by regulating the EMT-related transcription factors Snail and Zeb1. These results suggest that ILK may be a potential target in RCC.
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1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Han, Kyung Seok(한경석)
Hong, Sung Joon(홍성준) ORCID logo https://orcid.org/0000-0001-9869-065X
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