The role of galectin and CXC chemokine receptor in tumor progression of renal cell carcinoma

• Main Authors: Chang-Shuo Huang, 黃昶碩
• Other Authors: Kuang-Hui Sun
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/87459142018794245376

博士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 102 === Renal cell carcinoma (RCC) is the most common kidney cancer noted in adult population. More than one-third of patients will present with locally advanced or metastatic disease at the time of diagnosis. Although targeted therapy has been the standard of care for metastatic RCC, the overall survival remains poor and drug resistance still occurs. Thus, the identification of novel molecular targets in RCC is urgently needed for the development of the effective therapies. Small population of cancer cells called cancer stem cells (CSCs) play important roles in drug resistance and relapse of cancers. Galectin, a beta-galactoside-binding lectin, is involved in many physiological and pathologic processes, including cell adhesion, cell motility, inflammation, tumorigenicity, and tumor metastasis. Chemokines and chemokine receptors are involved in immune response, inflammation, and tumor progression. In this thesis, we investigated the role of galectins and chemokine system in the progression of RCC. We found galectin-1 was significantly overexpressed in both human renal cancer cell lines and tissues. Higher levels of galectin-1 were also related to advanced tumor stage and grade. Functionally, knockdown of galectin-1 in RCC cells reduced cell invasion, migration, 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 silencing also decreased the CXCR4 expression levels in RCC cells, whereas the restoration of CXCR4 reversed the decreased tumor cell motility and clonogenic ability of galectin-1-knockdown cells, suggesting that galectin-1-enhanced tumorigenicity is mediated by CXCR4 activation. Furthermore, galectin-1 modulated CXCR4 expression was via ERK signaling and NF-kB activation. Clinically, a positive correlation is found between galectin-1 and CXCR4 expression. Moreover, the concomitant overexpression of both galectin-1 and CXCR4 adversely affected overall and disease-free survivals of RCC patients. We further used the sphere culture system to enrich tumor spheres from the RCC cell lines and then characterize the expression of galectins, chemokines, and chemokine receptors in RCC tumor spheres. A subpopulation of RCC cells were capable of growing as tumor spheres and had higher mRNA expression levels of several stemness-related genes, such as Oct4, SOX2, and Nanog. The highest expression of galectin-3 was significantly observed in tumor spheres of RCC. Besides, enriched RCC tumor spheres expressed high levels of chemokines, such as CXCL1, CXCL3, CXCL5, CXCL7, CXCL8, CXCL13, and CXCL16, as well as chemokine receptors, CXCR2, CXCR3, and CXCR4. Upon suppression of galectin-3, CXCR2, or CXCR4 in parental A-498 cells, invasion, migration, sphere-forming ability, and stemness-associated gene expression were significantly decreased. However, the detailed molecular mechanism is need further studied. Our study provides insights into the influence of galectin-1, galectin-3, CXCR2, and CXCR4 in RCC development. Galectin-1 activates CXCR4 to promote tumor progression and poor survival outcome in RCC. Galectin-3, CXCR2, and CXCR4 might be involved in maintaining stem-like properties of RCC tumor spheres. Taken together, galectin-1, galectin-3, CXCR2, and CXCR4 could be biomarkers for prognosis and innovative targets for combined modality therapy for RCC.