Identification and characterization of liver cancer stem cells from chemically induced liver cancer

Summary

This project aims to study the possible role of cancer stem cells in liver cancer.

Supervisor(s)

Dr Liang Qiao, Professor Jacob George

Research Location

Westmead - Westmead Millennium Institute

Program Type

PHD

Synopsis

Primary liver cancer or hepatocellular carcinoma (HCC) is the 5th most common malignancy world wide. Over the past 20 years or so, an increase in HCC incidence has been witnessed in several Western countries including Australia. In addition, HCC incidence in Australia is expected to triple by 2020. As liver cancer usually occurs on top of other liver diseases (so called pre-cancerous conditions, such as liver cirrhosis, liver fibrosis, chronic hepatitis, and so on), liver is usually compromised and liver function reserve in HCC patients is markedly reduced. Consequently, conventional therapies such as chemotherapy and radiotherapy are either ineffective or inappropriate for the advanced HCC. Thus, the prognosis of late stage liver cancer is usually very poor, with an average natural survival of 3-6 months. Clearly, more efficient therapeutic approaches are needed for liver cancer.
In order to develop the novel and efficient treatment modalities for liver cancer, it is essential to better understand the molecular mechanisms involved in the development, progression, metastasis and treatment-resistance of HCC. It is now believed that normal hepatic stem cells play a pivotal role during liver development and regeneration. In addition, liver cancer is now regarded a stem cell disease, i.e., HCC may derive from a group of cells called “liver cancer stem cells”. Indeed, the existence of cancer stem cells (CSCs) have been proven in many cancer types, such as leukemia, breast cancer, glioblastoma, prostate cancer, gastric carcinoma, colon and lung cancer, and liver cancer. Current cancer treatment options are largely directed at the differentiated cancer cells, whereas CSCs in the whole cancer tissues are barely targeted. Several studies have suggested that treatment failure of many cancers is likely due to the escape of CSCs from being targeted. However, the definite CSC population responsible for the maintenance and growth of HCC remain poorly characterized.
Notch signaling is critically involved in fate determination of many types of cells including stem cells. Notch ligands, receptors and their downstream target genes are widely expressed in mammalian tissues including embryonic and adult liver cells and human HCC tissues. Based on the published data and our own data, we speculate that Notch signaling is an important molecular regulator for the self-renewal, growth, differentiation and death of liver cancer stem cells. However, robust data supporting this speculation are lacking at the present time.
Thus, in the current project, we aim to (1) isolate and characterize the potential CSCs from human liver cancer cell lines and chemically-induced mouse liver cancer tissues; (2) investigate whether Notch signaling regulates the biological functions of these potential liver CSCs such as proliferation, differentiation, and apoptosis.

Additional Information

In vitro culture of human liver cancer cell lines;
     Establishment of mouse model of liver cancer using hepatic carcinogen DEN;
     Isolation of liver cancer stem cells from liver cancer cell lines and mouse liver cancer tissues;
     Basic molecular biological techniques such as extraction of total RNA and protein from cultured cells and tissues; reverse transcription of RNA to cDNA; quantitation of total RNA and protein; real time PCR (qPCR); plasmid purification; bacterial transformation; cloning and sub-cloning; transfection of cells with siRNA and plasmids; Western Blotting.
     Other cell biology techniques: flow cytometry; histology, immunohistochemistry; confocal microscopy; light and fluorescence microscopy; cell proliferation assay; apoptosis assay; migration assay; colony-formation assay.

About the Storr Liver Unit
The Western Clinical School's Storr Liver Unit investigates the pathogenesis of liver disease, and the diverse causes of liver injury, such as drugs and toxins, metabolic factors and viruses. Internationally acclaimed, the Unit has made substantial contributions to defining how the liver responds to injury, and how genes involved in the metabolisms of drugs and toxic products of liver metabolism are regulated.
Liver cancer is Australia's fastest growing cancer, and this is an opportunity to take a role in the research of this emerging health focus. The Unit is well funded and thus there is the opportunity to employed cutting edge techniques and tools to bring each project to fruition. Joining a successful research team with expertise in liver disease and cancer, there will also be opportunity to collaborate with internationally-renowned cancer researchers at the Westmead Millennium Institute. As part of the community of over 400 researchers based on the Westmead campus, there will be the possibility to utilise the Institute's state-of-the-art molecular, translational and cell biological facilities.

Keywords

Liver cancer, liver cancer stem cells, Notch signalling, Signal transduction

Opportunity ID

The opportunity ID for this research opportunity is: 1315

Other opportunities with Dr Liang Qiao

• Characterization of ARL6IP5, PTPLB, and NIN in liver cancer
• Regulatory role of Notch signalling on hepatic stellate cells in the development of NASH and liver fibrosis
• Regulatory role of interleukin 6 (IL-6) on Notch signalling and impact on liver cancer

Other opportunities with Professor Jacob George

• The Role of Leptin in Modulating Alcohol-Associated Hepatic fibrosis: An in vitro study
• Characterization of ARL6IP5, PTPLB, and NIN in liver cancer
• Regulatory role of interleukin 6 (IL-6) on Notch signalling and impact on liver cancer