title: Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma.
abstract: 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.
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada. Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Kyung Seok
authors: KS
authors: Han
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Na
authors: N
authors: Li
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Peter A
authors: PA
authors: Raven
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Susan
authors: S
authors: Ettinger
authors: Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Sung Joon
authors: SJ
authors: Hong
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Martin E
authors: ME
authors: Gleave
authors: Vancouver Prostate Centre and Department of Urologic Science, University of British Columbia, Vancouver, British Columbia, Canada. dralanso@mail.ubc.ca.
authors: Alan I
authors: AI
authors: So
mesh_terms: D000818:Animals; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009367:Neoplasm Staging; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099200:Scaffold Protein ILK
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099200:Scaffold Protein ILK; C486307:ZEB1 protein, human