The Role of Mitochondrial Function and DNA Mutation in Colorectal Carcinogenesis

  • Lin, Wey-Ran (PI)

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

Project Details


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
Effective start/end date01/08/1431/07/15


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