| Summary: | 碩士 === 慈濟大學 === 醫學生物技術研究所 === 99 === Hepatocellular carcinoma(HCC) is the third most common cause of death from cancer. The poor prognosis of HCC are due to recurrence resulted from intrahepatic metastasis(IM). Thus far, the most suitable targets for blocking the molecular pathway of metastasis of HCC are still lacking. To address the issue, a thorough understanding of molecular and cellular processes for tumor metastasis of HCC are essential.
A lot of recent studies highlighted that tumor metastasis may be triggered by microenvironmental cytokines and chemokines secreted from stromal, inflammatory cells and tumor cells itself, collectively called as metastatic factors. Among the metastatic factors, HGF, was found to be closely associated with HCC metastasis. Specifically, some clinical studies point out that HGF were elevated in metastatic HCC tissues.
HGF may trigger intracellular signaling via c-Met receptor for a lot of cellular effects including Epithelial-Mesenchymal Transition (EMT), migration of a lot of HCC cell lines. In my project, I investigated several critical signal components down stream of c-met for HGF-induced migration and intrahepatic metastasis of HepG2. In the beginning I found that HGF may induce activation of ERK(extracellular signal-regulated kinases) and PKC(protein kinase C) and generation of ROS(reactive oxygen species), which were required for mediating HGF-induced migration of HepG2. Furthermore, I found that ROS was required for HGF-induced ERK phosphorylation suggesting it located upstream of ERK. On the other hand PKC activation was not required for HGF-induced ERK phosphorylation and may trigger another downstream signal.
To investigate which is (are) the molecular target(s) of ROS for activation of ERK (MAPK) cascade, BIAM assay and MALDI-TOF analysis were performed. The results demonstrated several candidate proteins including 60 kDa heat shock protein (Hsp60), Protein disulfide-isomerase (PDI), Protein disulfide-isomerase A3 (ERp57), calreticulin and tubulin may be oxidized in HepG2 treated with HGF within 30 min- 6h. Actually, some prior researchs have pointed out that these proteins are involved in some important signal pathways. It is tempting to identify and characterize the role of these proteins in HGF-induced tumor progression of HCC.
On the other hand, animal model experiment has also suggested that HGF could trigger intrahepatic metastasis in SCID mice. In the future, critical signal components in the HGF-induced tumor progression of HCC may be employed as targets for prevention of HCC.
|
|---|
