Development of a fluorescently labeled thermostable DHFR for studying conformational changes associated with inhibitor binding |
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| Authors: | Goodey N M Alapa M T Hagmann D F Korunow S G Mauro A K Kwon K S Hall S M |
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| Affiliation: | aNational Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan;bCenter for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan;cDepartment of Biotechnology, Asia University, Taichung 41354, Taiwan;dCollege of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan;eInstitute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei 11221, Taiwan |
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| Abstract: | The tissue kallikrein (KLK) family contains 15 genes (KLK1–KLK15) tandemly arranged on chromosome 19q13.4 that forms the largest cluster of contiguous protease genes in the human genome. Here, we provide mechanistic evidence showing that the expression of KLK13, one of the most recently identified family members, is significantly up-regulated in metastatic lung adenocarcinoma. Whilst overexpression of KLK13 resulted in an increase in malignant cell behavior, knockdown of its endogenous gene expression caused a significant decrease in cell migratory and invasive properties. Functional studies further demonstrated that KLK13 is activated via demethylation of its upstream region. The elevated KLK13 protein then enhances the ability of tumor cells to degrade extracellular laminin that, subsequently, facilitates cell metastatic potential in the in vivo SCID mouse xenograft model. KLK13 was also found to induce the expression of N-cadherin to help promote tumor cell motility. Together, these results reveal the enhancing effects of KLK13 on tumor cell invasion and migration, and that it may serve as a diagnostic/prognostic marker and a potential therapeutic target for lung cancer. |
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| Keywords: | Abbreviations: KLK, kallikrein ECM, extracellular matrix shRNA, small hairpin RNA |
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