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

Although targeted therapy is usually the first-line treatment for advanced renal cell carcinoma (RCC), some patients can experience drug resistance. Cancer stem cells are tumour-initiating cells that play a vital role in drug resistance, metastasis and cancer relapse, while galectins (Gal) participate in tumour progression and drug resistance. However, the exact role of galectins in RCC stemness is yet unknown. In this study, we grew a subpopulation of RCC cells as tumour spheres with higher levels of stemness-related genes, such as Oct4, Sox2 and Nanog. Among the Gal family, Gal-3 in particular was highly expressed in RCC tumour spheres. To further investigate Gal-3's role in the stemness of RCC, lentivirus-mediated knockdown and overexpression of Gal-3 in RCC cells were used to examine both in vitro and in vivo tumorigenicity. We further assessed Gal-3 expression in RCC tissue microarray using immunohistochemistry. Upon suppressing Gal-3 in parental RCC cells, invasion, colony formation, sphere-forming ability, drug resistance and stemness-related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down-regulated in Gal-3-knockdown tumour spheres, while CXCR2 overexpression in Gal-3-knockdown RCC restored the ability of sphere formation. Gal-3 overexpression in RCC promoted both in vitro and in vivo tumorigenicity, and its expression was correlated with CXCR2 expression and tumour progression in clinical tissues. RCC patients with higher co-expressions of Gal-3 and CXCR2 demonstrated a worse survival rate. These results indicate that highly expressed Gal-3 may up-regulate CXCR2 to augment RCC stemness. Gal-3 may be a prognostic and innovative target of combined therapy for treating RCC.

Galectin-1 upregulates CXCR4 to promote tumor progression and poor outcome in kidney cancer.

Galectin-1, a ß-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-κB (NF-κB). 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-κB. 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.

Tumor necrosis factor-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a nuclear factor kappa B-independent mechanism.

Chronic low dose of tumor necrosis factor-α (TNF-α) stimulation promotes tumorigenesis by facilitating tumor proliferation and metastasis. The plasma levels of TNF-α are increased in patients with renal cell carcinoma (RCC). Furthermore, high-grade clear cell RCC cell lines secrete more TNF-α than low-grade ones, and allow low-grade cell lines' gain of invasive ability. However, the molecular mechanism of TNF-α in mediating progression of RCC cells remains unclear. In the present study, TNF-α induced epithelial-mesenchymal transition (EMT) of RCC cells by repressing E-cadherin, promoting invasiveness and activating matrix metalloproteinase (MMP) 9 activity. RCC cells underwent promoted growth in vivo following stimulation with TNF-α. In addition, TNF-α induced phosphorylation of extracellular signal-regulated kinase, nuclear factor kappa B (NF-κB) and Akt in a time-dependent manner, and increased nuclear translocation and promoter activity of NF-κB. To investigate the role of NF-κB activation in TNF-α-induced EMT of RCC, we employed chemical inhibitors (NF-κB activation inhibitor and Bay 11-7082) and transfected dominant-negative (pCMV-IκBαM) and overexpressive (pFLAG-p65) vectors of NF-κB. While overexpression of NF-κB p65 alone could induce E-cadherin loss in RCC, EMT phenotypes and MMP9 expressions induced by TNF-α were not reversed by the inhibitors of NF-κB activation. These results suggest that the TNF-α signaling pathway is involved in the tumorigenesis of RCC. However, NF-κB activation is not crucial for invasion and EMT enhanced by TNF-α in RCC cells.