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postgraduate thesis: Investigation on the involvement of mycotoxin zearalenone on colon cancer development and progression : in vitro and in vivo studies
Title | Investigation on the involvement of mycotoxin zearalenone on colon cancer development and progression : in vitro and in vivo studies |
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Authors | |
Advisors | |
Issue Date | 2020 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Lo, K. K. E. [盧冠群]. (2020). Investigation on the involvement of mycotoxin zearalenone on colon cancer development and progression : in vitro and in vivo studies. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Colon cancer (CRC) is one of the leading causes of cancer related deaths worldwide and the second leading cause of death in Hong Kong. Over the past 5 year, the survival rate of CRC patient has doubled, however, more than half of the survival only survived less than 5 years after the diagnosis. The statistics highlight the need for understanding agent that might be involved in the advancement in carcinogenesis. It is widely believed that environmental factor contributes an important role in colon cancer development. There has been a growing interest on the involvement of xenoestrogen. Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium fungi. ZEA and its metabolites can be widely found in human diets and animal feeds, such as wheat, corn, oats and rye product. Its mutagenic and carcinogenic properties have so far remained controversial. To our best knowledge, most studies have only focused on its effect on hormone-related cancer and very few publications examined the effect of ZEA on colon cancer, despite the gastrointestinal tract being the first barrier being exposed to food contaminants.
Here it was hypothesized that ZEA, via GPER is contributing to the growth of CRC. Consequently, we investigated the effects of ZEA on colon cancer cells and its underlying molecular mechanism. We found that ZEA promoted anchorage independent cell growth and cell cycle progression mediated through G protein-coupled estrogenic receptor 1 and consequently activates MAPK signalling pathway and hippo pathway effector YAP1. We further hypothesized that the potential ZEA effects on CRC development and progression is mediated through modulation of gut microbiome and mycobiome. To address this hypothesis, mouse xenograft model was performed, tumor sample was subjected to RNA-seq while caecal sample was subjected to 16s and ITS rRNA sequencing for microbiome and mycobiome analysis. We further demonstrated that ZEA promote colon cancer tumour growth in vivo. An enrichment on ribosome biogenesis, oxidative phosphorylation and glycolysis was observed in tumor, which was at least in part mediated through its activation on PI3K-AkT-mTOR. We have identified Faecalibacterium and Ruminococcaceae was enriched in ZEA 0.5 mg/kg group, which was at least in part involved in the colon cancer growth. The colon cancer tumor growth was halted at the highest dose of ZEA (1 mg.kg BW ZEA) which highlight the monotonic dose response nature of estrogenic ZEA.
This study shed the light on the potential contribution of ZEA to the progression on CRC. This indeed indicates a need for a better understanding of the underpinning molecular mechanisms associated with the carcinogenicity of ZEA. This will improve the quality of the current risk assessment related to the exposure to ZEA in human. |
Degree | Doctor of Philosophy |
Subject | Colon (Anatomy) - Cancer Mycotoxins |
Dept/Program | Biological Sciences |
Persistent Identifier | http://hdl.handle.net/10722/303888 |
DC Field | Value | Language |
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dc.contributor.advisor | El-Nezamy, HS | - |
dc.contributor.advisor | Lee, CYJ | - |
dc.contributor.author | Lo, Kwun Kwan Emily | - |
dc.contributor.author | 盧冠群 | - |
dc.date.accessioned | 2021-09-17T03:31:33Z | - |
dc.date.available | 2021-09-17T03:31:33Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Lo, K. K. E. [盧冠群]. (2020). Investigation on the involvement of mycotoxin zearalenone on colon cancer development and progression : in vitro and in vivo studies. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/303888 | - |
dc.description.abstract | Colon cancer (CRC) is one of the leading causes of cancer related deaths worldwide and the second leading cause of death in Hong Kong. Over the past 5 year, the survival rate of CRC patient has doubled, however, more than half of the survival only survived less than 5 years after the diagnosis. The statistics highlight the need for understanding agent that might be involved in the advancement in carcinogenesis. It is widely believed that environmental factor contributes an important role in colon cancer development. There has been a growing interest on the involvement of xenoestrogen. Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium fungi. ZEA and its metabolites can be widely found in human diets and animal feeds, such as wheat, corn, oats and rye product. Its mutagenic and carcinogenic properties have so far remained controversial. To our best knowledge, most studies have only focused on its effect on hormone-related cancer and very few publications examined the effect of ZEA on colon cancer, despite the gastrointestinal tract being the first barrier being exposed to food contaminants. Here it was hypothesized that ZEA, via GPER is contributing to the growth of CRC. Consequently, we investigated the effects of ZEA on colon cancer cells and its underlying molecular mechanism. We found that ZEA promoted anchorage independent cell growth and cell cycle progression mediated through G protein-coupled estrogenic receptor 1 and consequently activates MAPK signalling pathway and hippo pathway effector YAP1. We further hypothesized that the potential ZEA effects on CRC development and progression is mediated through modulation of gut microbiome and mycobiome. To address this hypothesis, mouse xenograft model was performed, tumor sample was subjected to RNA-seq while caecal sample was subjected to 16s and ITS rRNA sequencing for microbiome and mycobiome analysis. We further demonstrated that ZEA promote colon cancer tumour growth in vivo. An enrichment on ribosome biogenesis, oxidative phosphorylation and glycolysis was observed in tumor, which was at least in part mediated through its activation on PI3K-AkT-mTOR. We have identified Faecalibacterium and Ruminococcaceae was enriched in ZEA 0.5 mg/kg group, which was at least in part involved in the colon cancer growth. The colon cancer tumor growth was halted at the highest dose of ZEA (1 mg.kg BW ZEA) which highlight the monotonic dose response nature of estrogenic ZEA. This study shed the light on the potential contribution of ZEA to the progression on CRC. This indeed indicates a need for a better understanding of the underpinning molecular mechanisms associated with the carcinogenicity of ZEA. This will improve the quality of the current risk assessment related to the exposure to ZEA in human. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Colon (Anatomy) - Cancer | - |
dc.subject.lcsh | Mycotoxins | - |
dc.title | Investigation on the involvement of mycotoxin zearalenone on colon cancer development and progression : in vitro and in vivo studies | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biological Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2020 | - |
dc.identifier.mmsid | 991044351382503414 | - |