Project Details
Abstract
Mitochondria provide cell energy through oxidative phosphorylation processed on respiratory chain proteins. It
has been suggested that mitochondrial dysfunction and mitochondrial DNA (mtDNA) mutations trigger aerobic
glycolysis in cancer cells. The majority of colorectal cancers arise through an adenoma-carcinoma sequence
underpinned by somatic mutations. However in normal mucosa and benign adenomatous polyps, sometimes
mitochondrial dysfunction and mtDNA mutations can be detected, but, whether these changes promote colorectal
carcinogenesis are still unknown.
This project proposal sets out a programme of work designed to study mitochondrial function and
mtDNA mutation in colorectal adenomatous polyps, adenocarcinoma and peripheral normal mucosa, which
our knowledge of their nature and effects on the adenoma-carcinoma sequence is unknown. We will firstly
study the bioenergetical changes between adenoma, adenocarcinoma and normal mucosa. Secondly, we will
detect any mtDNA mutations and the change of mtDNA copy number. Following this, defects in respiratory
chain proteins will be explored. Finally, we will evaluate the relationship between mitochondrial status and
common somatic mutations during the adenoma-carcinoma sequence, e.g. APC, KRAS and P53. We expect
this can answer fundamental questions about colorectal carcinogenesis and help us evaluate the possibility of
early cancer prediction through detecting mitochondrial dysfunction and mtDNA mutation.
Our preliminary data showed that the same mtDNA variants were detected in adenomatous polyps,
adenocarcinoma and peripheral normal mucosa. Only a minority of cancer tissues had defects in
mtDNA-encoded respiratory chain proteins as detected by immunohistochemical staining. Furthermore, the
bioenergetics profiles acquired by Seahorse XF24-3 analyser showed glycolysis was predominant in 72.2%
of polyps and 84.5% of adenocarcinomas compared with peripheral normal mucosa, suggesting the
metabolism of polyps is similar to that of adenocarcinomas. These findings suggest a potential role of
mitochondrial function and mtDNA mutation in colorectal carcinogenesis. To clarify this, we have the
following goals to achieve in three years:
1. To analyze the changes in bioenergetics during the adenoma-adenocarcinoma sequence.
2. To find the common mtDNA mutations and changes of mtDNA copy number during carcinogenesis.
3. To analyze the defects in respiratory chain proteins during cancer progression
4. To analyze the common genomic mutations and correlate with mitochondrial dysfunction and mtDNA
mutation
Our lab is a well equipped research unit located in Likuo Chang Gung Memorial Hosptal. We believe
this project can help us not only to understand the fundamental relationships between mitochondria and
colorectal carcinogenesis, but also to find a novel strategy to predict cancer through detecting mitochondrial
dysfunction and mtDNA mutation.
Project IDs
Project ID:PC10308-1330
External Project ID:MOST103-2314-B182-021
External Project ID:MOST103-2314-B182-021
Status | Finished |
---|---|
Effective start/end date | 01/08/14 → 31/07/15 |
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