Download Colorectal cancer (CRC) remains one of the most frequently

Cancer prevention by targeting microsatellite instability
藉由偵測微衛星 DNA 不穩定來預防癌症
Advisor: Christina Chang 張玲 老師
Student: I-Chen Li 李宜蓁
Abstract:
Colorectal cancer (CRC) ranks as the third most common cancer in Taiwan according to
a report of the Department of Health in 2010. Microsatellite instability (MSI) is a hallmark of a
defective mismatch repair (MMR) system, which is caused by mutations in one of MMR genes
such as hMLH1 and hMSH2, epigenetic silencing of the hMLH1 gene, and oxidative
inactivation of the MMR function. MSI has been detected in ~90% hereditary and ~15% of
sporadic CRC, and CRC accounts for ~15% of all deaths in patients with inflammatory bowel
disease. Cells with the MSI phenotype allow frameshift mutations to accumulate in genes with
exonic microsatellites, which include genes involved in epigenetic regulation. Therefore, we
hypothesize that the MSI phenotype could serve as a nexus permitting simultaneous detection of
epigenetic and genetic events that are modulated by oxidative stress and dietary factors. The
following specific aims are proposed in my study to test a part of this hypothesis: (1) to identify
compounds that reduce H2O2-induced frameshift mutations using a dual fluorescent reporter in
CRC cells, (2) to examine gene-specific epigenetic alterations modulated by oxidative stress
and/or dietary compounds in CRC cells, and (3) to establish a transgenic zebrafish model
harboring the dual fluorescent reporter. Findings of the proposed studies will validate the utility
of our dual fluorescent reporter. Identification of frameshift-reducing and epigenetic-altering
compounds may provide opportunities for reducing the incidence and mortality of CRC patients.
Reference:
1. Oxidative stress inactivates the human DNA mismatch repair system. Am L Physiol Cell
Physiol. 283: C148-C154 (2002).
2. Microsatellite instability in colorectal cancer—the stable evidence. Nat. Rev. Clin. Oncol. 7,
153–162 (2010)