Connective Tissue Growth Factor inhibits Cancer Metabolism and Autophagy
| Autor: | Wei-Ting Lai, 賴瑋婷 |
|---|---|
| Rok vydání: | 2017 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 In Taiwan, oral cancer (in particular oral squamous cell carcinoma, OSCC) is the fourth leading cause of death in males, and is one of the causes with high death rate worldwide. In this study, we seek to uncover the underlying mechanism of OSCC and help the development of new therapeutic strategies for OSCC. First, we analyzed 82 OSCC cases and confirmed that OSCC patients with high ataxia telangiectasia mutated interactor (ATMIN) expression showed poor differentiation, higher TNM stages, greater lymph-node metastasis, and shorter accumulated survival time. Evidence from a buccal orthotopic implantation mouse model showed that silencing of ATMIN expression reduced lymph node metastasis and prolongs the survival of mice. ATMIN is now considered as a poor prognosis biomarker, and our study results help to identify possible therapeutic targets of downstream genes for designing effective therapeutic strategies for OSCC. Second, my previous studies showed that connective tissue growth factor (CTGF/CCN2) significantly blocked glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production. Moreover, CTGF showed no effects in normal bronchial and oral epithelial cells. We demonstrated that CTGF decreased glycolysis, mitochondrial oxidative phosphorylation, ATP generation and mitochondrial DNA (mtDNA) copy number by increasing the degradation of mitochondrial transcription factor A (mtTFA) through ubiquitin proteasome pathway and in turn reduced migration and invasion of OSCC cells. Autophagy can promote cancer cell survival or resistance under conditions of poor nutrient supply, chemotherapy or target therapy. In this study, we demonstrated that CTGF inhibited late stage autophagy through blocking autophagosome-lysosome fusion under starvation condition. We further showed that cotreatment of CTGF could markedly enhance the therapeutic efficiency of Erbitux in vivo Finally, we showed that overexpression of CTGF significantly decreased Rab5A expression, which is essential for completion of autophagy. Furthermore, expression of a wild type or constitutive active form of Rab5A could restore CTGF-inhibited autophagy flux. We investigated the clinical importance of CTGF-Rab5A axis in OSCC patients, the results showed that high Rab5A mRNA expression was significantly associated with an advanced clinical pathological TNM stage. A reverse correlation between CTGF and Rab5A was also demonstrated. The findings in this study demonstrated that ATMIN and Rab5A can be poor prognostic biomarkers in OSCC. I believe that CTGF has the potential to be developed as an additive therapeutic agent for cancer treatment in the future. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|