Conditional Onconomics: Genome-Wide Screen of Genes Essential for the Malignant Phenotype of Human Hepatocellular Carcinoma

  • Hsieh, Sen-Yung (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

The long-term goals of this study are to identify the genes/pathways essential for the development of human hepatocellular carcinoma (HCC) via genomewide approaches, thereby discovering core signaling pathways for HCC, and identifying potential targets for future development of anti-HCC therapy. Over the past three years we have been engaged in the following studies with achievements: 1. We developed a novel high efficiency method identifying 601 de-regulated genes in HCC. We then used lentivirus-based shRNA assays conducting a loss-of-function screening (Pan et al. 2006). Twenty-eight presented as tumor suppressors, because silencing the expression of each transformed non-tumorigenic HepG2 into tumorigenic cells, while 10 were oncogenes because silencing expression suppressed tumorigenesis of Huh7 cells. Investigations on these tumor suppressors and oncogenes are ongoing (Lee et al. 2009; Lu et al. 2009). 2. We also identified that RBB3 and GFBP2 are shed into peripheral circulation and can be good serum markers for HCC detection. In combination with serum alpha-fetoprotein, the detection sensitivity and specificity are higher than 95% (patents in application). 3. We have identified genes/proteins related to unleashing cell proliferation in HCC cells via profiling the proteome dynamics during the cell cycle progression in human HCC cells (Hsieh et al.2008). We also identified molecules/pathways involved in apoptosis evasion in HCC cells (Hsieh et al. 2009). These genes are candidates for anti-HCC therapeutic targets. We will continue the aforementioned studies with special emphasis on the following aims: Aim 1: to identify the core oncogenic signaling pathways in human HCC. We hypothesize that transformation from non-tumorigenic HepG2 to tumorigenic cells by silencing single gene expression will elicit novel pathways essential for tumor initiation. The core oncogenic signaling pathways for HCC tumor initiation can thus be identified by fishing out the common pathways ensuing upon tumorigenic transformation from multiple subclones of the tumor transformed HepG2 cells. This will be collaborated with our colleagues at both Chang Gung University and Hospital with the aids of computer analyses. Aim 2: to identify novel therapeutic targets for anti-HCC therapy. Through above studies we have identified several potential targets for anti-HCC therapy. Of them, ERBB3 (rather than EGFR and HER2) plays a crucial role in EGFR/ERBB oncogenic signaling. We plan to further investigate the mechanisms leading to resistance to EGFR- and ERBB2-target in HCC cells. Meanwhile we found silencing of NPM1 expression greatly sensitizes cells to radiation, cytotoxic agents and sorafenib via a novel non-canonical P53-independent pathway in HCC cells. The molecular basis will be further analyzed and the role of NPM1 as a co-target for ant-HCC target therapy will be investigated. Aim3: to continue characterization of novel tumor suppressor genes and oncogenes. For example, we found that overexpression of RFP (RET finger protein) leads to mitosis disruption with consequence of aneuploidy formation. Ongoing studies include identify its target proteins and implicated pathways. Transgenic mice with liver-specific overexpression of RFP have been generated. They will be used to further dissect the role of aneuploidy in tumorigenesis.

Project IDs

Project ID:PA9905-0082
External Project ID:NSC99-3112-B182-008
StatusFinished
Effective start/end date01/05/1030/04/11

Keywords

  • hepatocellular carcinoma
  • oncogene addiction
  • oncogene
  • tumor suppressor gene
  • cancer targeted therapy

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