In vivo functional genomics to decipher the genes/mechanisms orchestrating hepatoma invasion

Unusually high invasion rate is not only a hallmark of human hepatocellular carcinoma (HCC) but also a greatest obstacle in the improvement of therapeutic efficacy and patients’ survival. In particular, most HCC develop in cirrhosis liver. The unique liver and cirrhosis microenvironment might greatly impact on HCC invasion. However, neither the mechanisms driving HCC invasion, nor the role of liver and cirrhosis microenvironment in HCC invasion is known. This study aims to address these critical questions, so as to open a new avenue for development of novel anti-HCC treatments. We will focus only on the role of the unique extracellular matrix (ECM) of the liver and cirrhosis microenvironment in HCC invasion in this project. We thus define the following specific aims to achieve: 1. In vivo functional genomics screening for genes regulating HCC cell invasion and metastasis under the liver and cirrhosis microenvironment 2. Identification of clinically related HCC invasion genes from the candidates identified in Aim 1 by clinical correlation analysis in two cohorts of HCC patients 3. The interaction of the liver and cirrhosis microenvironment with integrin-mediated cell signaling in HCC invasion 4. The molecular mechanisms whereby the identified invasion genes are involved, including the role of LICC1 in regulating the integrin-mediated signaling and the assembly vs. disassembly of focal adhesions (FAs) in cell movement. In our pilot studies, we identified LICC1 as a novel HCC invasion gene. We found that LICC1 was localized in FAs and might facilitate FA assembly. We hypothesize that LICC1 regulates the inside-out integrin-mediated signaling, and the FA assembly/disassembly in migrating cells. Deregulation of this regulation contributes to HCC invasion. 5. Evaluation of the identified novel invasion genes (such as LICC1)/pathways as therapeutic targets for HCC treatment in mouse models We expect that this study will shed light on our understanding of the mechanisms of and the role of the liver and cirrhosis microenvironment in high HCC invasion rate , so as to contribute to development of novel therapies for improvement of HCC patients’ survival in the near future.

Project ID:PG10501-0386
External Project ID:NHRI-EX105-10408BI