The emerging role of KCl cotransport in tumor biology

• Main Authors: Yih-FungChen, 陳宜芳
• Other Authors: Meng-Ru Shen
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/34372627312940774359

博士 === 國立成功大學 === 基礎醫學研究所 === 98 === The KCl cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an important role in cancer development and progression. My thesis focuses on the emerging role for KCl cotransport in tumor biology and the novel mechanisms by which KCl cotransport regulates cancer malignant behaviors. My thesis includes four parts. (1) KCC4 expression is associated with cancer metastasis and clinical outcome. This part of study aims to investigate the contribution of individual KCC isoforms in cancer metastasis using cervical cancer and ovarian cancer as the model. The results indicate that metastatic cancer tissues express abundant KCC4 which benefits cancer cells in invasiveness. In the metastatic cancer tissues, KCC4 colocalizes with IGF-1 or EGF, indicating a likely in vivo stimulation of KCC4 function by growth factors. (2) Membrane trafficking of KCC4 is important for cancer cell invasion. Here I test the hypothesis that the regulation of specific KCC activation in cancer cells is a dynamic process which can be significantly upregulated by IGF-1 or EGF. The results indicate that IGF-1 and EGF stimulate the membrane recruitment of KCC4, in which KCC4 interacts with an actin-binding protein, ezrin, at lamellipodia. In addition to ion transport, KCC4 can function as a membrane scaffold to facilitate the modulation of cytoskeletal reorganization that is required for the invasive migration of cancer cells. (3) KCl cotransporter is an evolutionarily conserved assembly factor for actin-containing cellular protrusions. The novel functions of KCC in epithelial development were investigated using Drosophila melanogaster as a model. With the generation of KCC null mutants, it is suggested that fly KCC has essential role in the embryonic development and in the regulation of neural activity and salt homeostasis. Moreover, KCC is present in actin-bundle containing cellular protrusions of wing hairs and may play a role in the development of wing epithelium. (4) KCl cotransport is important for actin reorganization and focal adhesion dynamics during cancer cell migration. Here I test the hypothesis that KCl cotransport regulates cancer cell invasive migration is via the modulation of actin cytoskeleton and focal adhesions. The results suggest that KCl cotransport is necessary for actin reorganization and focal adhesion dynamics during cancer cell migration. Taken together, the results of my thesis provide the rationale for the clinical application of KCC as the therapeutic target and the prognostic biomarkers of metastatic cancers.