Regulatory role of interleukin 6 (IL-6) on Notch signalling and impact on liver cancer

Summary

This project focuses on the possible regulatory role of IL-6 on Notch signalling and whether an interaction between IL-6 and Notch signalling will impact the development of liver cancer.

Supervisor(s)

Dr Liang Qiao, Professor Jacob George

Research Location

Westmead - Westmead Millennium Institute

Program Type

PHD

Synopsis

Inflammation is closely linked to carcinogenesis. About 15-20% of all cancer cases are causally linked to inflammation-related tissue injury. HCC is a prime example of inflammation-associated cancer since chronic HBV and HCV infections are major etiological factors. The most important inflammatory cytokines is interleukin 6 (IL-6). IL-6 is a protein secreted by adipocytes, inflammatory cells (such as monocytes, macrophages, and T cells), and tumor cells. IL-6 plays a pleiotropic role in the regulation of hematopoiesis, liver regeneration, immune responses, inflammation, bone metabolism, neural development, and the development of liver cancer. Activation of IL-6 leads to the activation of several cell proliferation signaling pathways including mitogen-activated protein kinase (MAPK), phosphoinositol 3'-kinase (PI3K)/Akt, Janus-activated kinase (JAK)/signal transducers and activation of transcription (STAT). We have recently discovered that activation of IL-6 signaling could directly activate the Notch signaling, a molecular pathway that is critically involved in the determination of cell fate and stem cell maintenance. Recent publications including one in Science suggest that IL-6 is critically involved in HCC formation in mice and increased serum IL-6 is observed in HCC patients, it was proposed that IL-6 is an oncogenic agent during the process of liver carcinogenesis. However, at the molecular level, precisely how IL-6 promotes hepatic carcinogenesis has not been fully elucidated. We speculate that IL-6 may participate in the development of HCC by activating Notch signaling pathway.
Hence, the overall objective of this project is to investigate whether Notch signaling is a critical component in the IL-6 mediated mitogenic effect that results in liver cancer formation. Specifically, we aim to:
(1) Test if IL-6 possesses a regulatory role for Notch signaling in normal hepatocytes and HCC cell lines;
(2) Determine the biological consequences of the IL-6-Notch interaction in HCC and,
(3) Determine whether IL-6-Notch interaction plays a role during liver carcinogenesis in animals

Additional Information

In vitro culture of human liver cancer cell lines;
     Establishment of mouse model of liver cancer using hepatic carcinogen DEN;
     ELISA assay to measure the IL-6 levels in cell culture medium and animal serum;
     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: histology, immunostaining; 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.

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Keywords

Liver cancer, interleukin 6, Notch signalling, Signal transduction, mouse model of liver cancer

Opportunity ID

The opportunity ID for this research opportunity is: 1318

The University of Sydney - Research Supervisor Connect

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