Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer

Abstract

Galectin-1, a b-galactoside-binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1-silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-kB (NF-kB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-kB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease. 25: 148625: -149525: , 201425: . doi: 10.1681 Renal cell carcinoma (RCC) accounts for approximately 4% of all adult malignancies. 1 More than one third of patients will present with locally advanced or metastatic disease at the time of diagnosis. 2 The 5-year survival rate of metastatic RCC is only 10% because of resistance to chemotherapy and radiation therapy. 3 Although cytokine therapy with IFN-a and IL-2 is the gold standard treatment, its overall efficacy rate is limited by its significant toxicity. 4 Recently, several molecular targeting drugs, including sunitinib and temsirolimus, have been approved for advanced RCC. 4 However, treatment response is not long-standing and overall survival remains poor. Thus, the identification of novel molecular targets in RCC is urgently needed for the development of effective therapies. J Am Soc Nephrol

Galectin-3 in Renal Pathology: More Than Just an Innocent Bystander?

“…RCC has a higher incidence in males and tops out at the 6th and 7th decade of life. In one-third of all patients, RCC is already metastatic or locally advanced at time of diagnosis [59] . Significantly higher galectin-1 and -3 levels in tumor tissue have been detected in comparison with the nontumorous surrounding tissue by mRNA expression analysis [60][61][62] .…”

Studies on the role of goat heart galectin-1 as a tool for detecting post-malignant changes in glycosylation pattern

“…The close involvement of galectins in various cancer types continues to be established (Huang et al, 2014;Song et al, 2014). GHG-1 mediated agglutination of erythrocytes collected from breast and prostate cancer patients showed a differential pattern of hemolytic activity when compared to healthy controls.…”

Galectin‐3 promotes CXCR2 to augment the stem‐like property of renal cell carcinoma

“…We purchased the human RCC cell line A‐498 (VHL mutation) from Bioresource Collection and Research Center (BCRC; Hsinchu, Taiwan). These cell lines were cultured as described in a previous study …”

“…Lentivirus‐mediated silencing and overexpression of Gal‐3 and CXCR2 of the RCC cells were performed as described in a previous study . We obtained pLKO.1 plasmid containing shRNA targeting human Gal‐3 (shGal‐3#1, Clone ID TRCN0000029305; shGal‐3#2, Clone ID TRCN0000029307) and CXCR2 (shCXCR2, Clone ID TRCN0000009138) from the National RNAi Core Facility (Academia Sinica, Taipei, Taiwan).…”