Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis.
BACKGROUND
Metastatic clear cell renal cell carcinoma (ccRCC) patients have <9% 5-year survival rate, do not respond well to targeted therapy and eventually develop resistance. A better understanding of molecular pathways of RCC metastasis is the basis for the discovery of novel prognostic markers and targeted therapies.


METHODS
We investigated the biological impact of galectin-1 (Gal-1) in RCC cell lines by migration and invasion assays. Effect of Gal-1 expression on the mitogen-activated protein kinase pathway was assessed by proteome array.


RESULTS
Increased expression of Gal-1 increased cell migration while knocking down Gal-1 expression by siRNA resulted in reduced cellular migration (P<0.001) and invasion (P<0.05). Gal-1 overexpression increased phosphorylation of Akt, mTOR and p70 kinase. Upon hypoxia and increased HIF-1α, Gal-1 increased in a dose-dependent manner. We also found miR-22 overexpression resulted in decreased Gal-1 and HIF-1α. Immunohistochemistry analysis showed that high Gal-1 protein expression was associated with larger size tumor (P=0.034), grades III/IV tumors (P<0.001) and shorter disease-free survival (P=0.0013). Using the Cancer Genome Atlas data set, we found that high Gal-1 mRNA expression was associated with shorter overall survival (41 vs 78 months; P<0.01).


CONCLUSIONS
Our data suggest Gal-1 mediates migration and invasion through the HIF-1α-mTOR signaling axis and is a potential prognostic marker and therapeutic target.
1] The Keenan Research Center in the Li Ka Shing Knowledge Institute and the Department of Laboratory Medicine, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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White
Department of Chemistry and Centre for Research in Mass Spectrometry, 4700 Keele Street York University, Toronto, Ontario M3J 1P3, Canada.
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Masui
The Keenan Research Center in the Li Ka Shing Knowledge Institute and the Department of Laboratory Medicine, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
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Newsted
Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, Athens 157 01, Greece.
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Scorilas
1] The Keenan Research Center in the Li Ka Shing Knowledge Institute and the Department of Laboratory Medicine, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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Romaschin
Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada.
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Bjarnason
Department of Chemistry and Centre for Research in Mass Spectrometry, 4700 Keele Street York University, Toronto, Ontario M3J 1P3, Canada.
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Siu
1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Chemistry and Centre for Research in Mass Spectrometry, 4700 Keele Street York University, Toronto, Ontario M3J 1P3, Canada.
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Yousef
D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D037483:Galectin 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; C489397:UBASH3B protein, human