Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis

Abstract

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.

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

“…Subsequent testing of other cancer cell lines associated with human and mouse melanoma (A375 and B16-F0), mouse breast carcinoma (4T1), and human prostate carcinoma (LNCaP) confirmed the hypoxia-induced expression of galectin-1 at both mRNA and protein levels [42]. In renal cell carcinoma cell line CAK-1, the mimicking of hypoxia stress with CoCl 2 , which inhibits prolyl hydroxylase and HIF-1a ubiquitination, also resulted in an almost 14-fold, dose-dependent increase in galectin-1 protein expression [43]. Interestingly, the transcriptional control of galectin-1 upregulation under hypoxic conditions seems to be specific to the type of responsive cells and not always dependent on classical hypoxia-induced transcription factors.…”

“…The current experimental findings related to the miRNA-mediated regulation of galectin expression have been limited to few studies. In particular, the transfection of a renal carcinoma cell line CAK-1 miR-22 was found to be very efficient in inhibiting both galectin-1 and HIF-1a [43]. A sequence called miR-322 was claimed to recognize human galectin-3 3 0 UTR, and the silencing of miR-322 with antisense oligo was found to upregulate galectin-3 mRNA transcripts in several cancer cell lines [149].…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…Increased Gal-1 levels favor cell migration and promote phosphorylation of Akt, mTOR (mechanistic target of rapamycin), and p70 kinase, which are involved in proliferation, cell growth, and survival processes [206]. …”

High expression of galectin-7 associates with poor overall survival in patients with non-metastatic clear-cell renal cell carcinoma

“…Similar to galectin-1, 3, 8 and 9, high galectin-7 expression acts as an adverse predictor for survival in patients with RCC [27–30]. In RCC, galetin-1 can activate HIF-1α-mTOR signaling axis, enhance the migration ability of tumor cells, and promote tumor progression [27].…”