LEF1, β-Catenin and MTDH contribute to tumorigenesis of hepatocellular carcinoma via enhancement on the tumor-initiating cell-like properties

• Main Authors: Hsin-Yu Tseng, 曾心渝
• Other Authors: Jaw-Ching Wu
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/23333029945275650018

碩士 === 國立陽明大學 === 臨床醫學研究所 === 100 === Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death in the world and the second one in Taiwan. Only about 20-30% of HCC patients are diagnosed at early stage to receive curative treatment (tumor resection, liver transplantation or logo-regional ablation therapy). High incidence of HCC recurrence is frequently encountered even in patients who receive therapy supposed to be “curative”. Chemotherapy and target therapy provide limited effects to advanced HCC. To improve long-term survival in these patients, it is still imperative to investigate molecular mechanisms contributing to the progression of this cancer. Cancer stem cell or tumor-initiating cell hypothesis is widely studied in past decades. The tumor-initiating cells can result in a bulky tumor even though they are of small population. The tumor-initiating cells can also enhance tumor development and metastasis of HCC and other cancers. In the past, tumor-initiating cell populations are recognized by methods of cell surface markers or side populations. However, the above-mentioned two methods frequently fail to identify cell population with tumor initiating cell properties. Many signaling pathways, like wnt signaling pathway, are activated during HCC formation. LEF1, β-Catenin and MTDH are involved in wnt signaling pathway. In our preliminary data, LEF1 was upregulated in recurrent HCC. It is hypothesized that LEF1 may play a role in tumor initiating and progression. In this study, we isolated HCC tumor-initiating cell-like cells based on their characteristic function using ultra-low attachment petri dishes and identified the changes of expression of LEF1, β-Catenin and MTDH. The tumor-initiating cell-like tumor spheres from human HCC cell line Mahlavu showed increased expression of wnt signaling pathway members (LEF1 and β-Catenin), enhanced colony-forming ability and invasion ability when compared with adherent cells. In addition, knocking down LEF1, β-Catenin, and MTDH led to decreased sphere-forming ability, colony-forming ability and invasion ability. At molecular levels, knocking down LEF1, β-Catenin and MTDH resulted in not only the down-regulation of stemness gene Oct4 but also the EMT regulator Twist, Snail and Slug, indicating above three genes is involved in EMT-mediated tumor progression of HCC. In summary, the results of this study indicated that LEF1, β-Catenin and MTDH are important molecules in HCC and they may contribute to HCC progression and invasion via enhancement on EMT.