Hypoxia Enhances Metastatic Efficiency in Lung Cancer Cells

• Main Authors: Yi-Ta Tsai, 蔡易達
• Other Authors: Shing-Chuan Shen
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/66646266167015770892

碩士 === 臺北醫學大學 === 醫學科學研究所 === 98 === Malignant solid tumors are difficult to be eradicated owing to its metastatic ability. Clinical studies show that loss of E-cadherin is common to many tumors. Recent studies have implicated a significant role of hypoxia inducible factor 1?? (HIF-1??) in cell transformation in which a tumor comprising mostly sedentary epithelial type of cells changed into a tumor with invasive and metastatic fibroblastic type of cells. Previous studies have implicated that intratumoural hypoxia and epithelial - mesenchymal transition (EMT) play crucial role in the progression and aggressiveness of many cancer types. Several transcription repressors (TWIST, Slug and Snail) play a crucial role in the regulation of EMT by suppressing several epithelial markers and adhesion molecules including E-cadherin in breast and colorectal carcinoma. Thus, we will investigate the effect of hypoxia inducible factor 1?nα(HIF-1α) and EMT associated tumorigenesis in A549 human lung carcinoma cells. We found that hypoxia treatment significantly down-regulated the expression of E-cadherin and up-regulated the TWIST and Slug. In addition, down-regulated E-cadherin was followed by the redistribution of its binding protein, β-catenin, which moved from cytoplasm to nucleus, implicating that some genes related to cell adhesion and proliferation might have been activated. We found that hypoxia induced A549 cells to express α-smooth muscle actin (α-SMA) which is usually expressed in active myofibroblast. Consistently, we also observed in A549 cells the synthesis of type I collagen , fibronectin mRNA and expression of connective tissue growth factor (CTGF). At the same, using A549 cells, we also found that hypoxia up-regulated the expression of matrix metalloprotease (MMPs). The observation suggests that cells had adopted a more invasive potential with morphogenic alteration. In vitro metastasis assay, hypoxia was also found to enhances cell migration. Our investigation taken together supports the hypoxia induces epithelial transition that leads to fibrogenesis and eventually contributes to metastatic process.