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
External Project ID:NSC99-3112-B182-008
Status | Finished |
---|---|
Effective start/end date | 01/05/10 → 30/04/11 |
Keywords
- hepatocellular carcinoma
- oncogene addiction
- oncogene
- tumor suppressor gene
- cancer targeted therapy
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