MicroRNA and energy metabolism in gastrointestinal tumors
Author: Huang, Wen-Kuan
Date: 2020-09-30
Location: Marc Bygdeman Auditorium, BioClinicum J3:13, Solnavägen 30, Karolinska University Hospital, Solna
Time: 13.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Thesis (1.839Mb)
Abstract
MicroRNAs (miRNAs) contribute to cancer development and drug resistance via cellular biological processes, including metabolic pathways. Energy metabolism plays a significant role to maintain tumor proliferation in gastrointestinal (GI) cancers. However, the roles of miRNAs and energy metabolism in GI cancers are not fully understood. The studies presented in this thesis aim to provide further insights into the biological role of miRNAs, energy metabolism, and the interplay between miRNAs and energy metabolism in GI cancers, using gastrointestinal stromal tumor (GIST) and colon cancer as the models.
In Paper I, we explored the downstream target of miR-125a-5p-PTPN18 axis that contributes to imatinib resistance in GIST. We found that over-expression of miR-125a-5p and silencing of PTPN18 increased phosphorylated focal adhesion kinase (pFAK). FAK inhibitor 14, which blocks phosphorylation of Y397-FAK, enhances imatinib response in imatinib-resistant GIST cells. Furthermore, FAK inhibitor 14 could rescue the imatinib resistance mediated by overexpression of miR-125a-5p, suggesting that pFAK is the downstream target of the miR-125a-5p-PTPN18 axis.
In Paper II, we profiled the bioenergetic phenotype of imatinib-resistant GIST cells. We identified two major types of bioenergetics in imatinib-resistant GIST cell lines and clinical samples, i.e. highly metabolically active phenotype with higher glycolysis and oxidative phosphorylation (OXPHOS) and low OXPHOS types. Metabolic inhibitor assays revealed that imatinib-resistant GIST 882R cells (with highly metabolically active phenotype) were more sensitive to glycolysis inhibition than the parental GIST 882 cells, while imatinib-resistant GIST T1R cells (with low OXPHOS) were more resistant to OXPHOS inhibition than GIST T1. Our study demonstrates metabolic heterogeneity and diverse vulnerability of GIST cells to metabolic inhibitors, suggesting the potential of targeting energy metabolism for overcoming imatinib resistance in GIST.
In Paper III, we further explored the relationship between miRNA and imatinib treatment in GIST and the effect on OXPHOS. Using microarray and RT-qPCR, we identified miR-483-3p as one of the most downregulated miRNAs in imatinib-treated GISTs. Imatinib treatment resulted in downregulation of miR-483-3p and upregulation of OXPHOS in imatinib sensitive GIST cells. Modulation of miR-483-3p altered protein expression of mitochondrial respiratory Complex II, suggesting its involvement in OXPHOS regulation. This study reveals a potential role of miR-483-3p in imatinib-induced OXPHOS expression.
In Paper IV, we investigated the association of metformin treatment, an inhibitor of OXPHOS, with patient survival in colorectal cancer. We showed that metformin users were associated with 44% lower risk of mortality compared with nonusers. These findings suggest that metformin could be an adjunct to standard treatment of colorectal cancer. Overall, this thesis work provides new insights into the role of miRNAs and energy metabolism in drug response and potential clinical use in GI cancers.
In Paper I, we explored the downstream target of miR-125a-5p-PTPN18 axis that contributes to imatinib resistance in GIST. We found that over-expression of miR-125a-5p and silencing of PTPN18 increased phosphorylated focal adhesion kinase (pFAK). FAK inhibitor 14, which blocks phosphorylation of Y397-FAK, enhances imatinib response in imatinib-resistant GIST cells. Furthermore, FAK inhibitor 14 could rescue the imatinib resistance mediated by overexpression of miR-125a-5p, suggesting that pFAK is the downstream target of the miR-125a-5p-PTPN18 axis.
In Paper II, we profiled the bioenergetic phenotype of imatinib-resistant GIST cells. We identified two major types of bioenergetics in imatinib-resistant GIST cell lines and clinical samples, i.e. highly metabolically active phenotype with higher glycolysis and oxidative phosphorylation (OXPHOS) and low OXPHOS types. Metabolic inhibitor assays revealed that imatinib-resistant GIST 882R cells (with highly metabolically active phenotype) were more sensitive to glycolysis inhibition than the parental GIST 882 cells, while imatinib-resistant GIST T1R cells (with low OXPHOS) were more resistant to OXPHOS inhibition than GIST T1. Our study demonstrates metabolic heterogeneity and diverse vulnerability of GIST cells to metabolic inhibitors, suggesting the potential of targeting energy metabolism for overcoming imatinib resistance in GIST.
In Paper III, we further explored the relationship between miRNA and imatinib treatment in GIST and the effect on OXPHOS. Using microarray and RT-qPCR, we identified miR-483-3p as one of the most downregulated miRNAs in imatinib-treated GISTs. Imatinib treatment resulted in downregulation of miR-483-3p and upregulation of OXPHOS in imatinib sensitive GIST cells. Modulation of miR-483-3p altered protein expression of mitochondrial respiratory Complex II, suggesting its involvement in OXPHOS regulation. This study reveals a potential role of miR-483-3p in imatinib-induced OXPHOS expression.
In Paper IV, we investigated the association of metformin treatment, an inhibitor of OXPHOS, with patient survival in colorectal cancer. We showed that metformin users were associated with 44% lower risk of mortality compared with nonusers. These findings suggest that metformin could be an adjunct to standard treatment of colorectal cancer. Overall, this thesis work provides new insights into the role of miRNAs and energy metabolism in drug response and potential clinical use in GI cancers.
List of papers:
I. Wen-Kuan Huang, Pinar Akçakaya, Anastasia Gangaev, Linkiat Lee, Katarina Zeljic. Praveensingh Hajeri, Erik Berglund, Mehran Ghaderi, Jan Åhlén, Robert Bränström, Catharina Larsson and Weng-Onn Lui. miR-125a- 5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors. Exp Cell Res. 2018 Oct 1;371(1):287-296.
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II. Wen-Kuan Huang, Jiwei Gao, Ziqing Chen, Hao Shi, Juan Yuan, Huanhuan L. Cui, Chun-Nan Yeh, Robert Bränström, Catharina Larsson, Shuijie Li and Weng-Onn Lui. Heterogeneity of metabolic vulnerability in imatinib-resistant gastrointestinal stromal tumor. Cells. 2020 May 26;9(6):1333.
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III. Wen-Kuan Huang, Pinar Akçakaya, Katarina Zeljic, Anastasia Gangaev, Stefano Caramuta, Robert Bränström, Catharina Larsson and Weng-Onn Lui. Imatinib regulates miR-483-3p and oxidative phosphorylation in gastrointestinal stromal tumors. [Manuscript]
IV. Wen-Kuan Huang, Shu-Hao Chang, Hung-Chih Hsu, Wen-Chi Chou, Tsai-Sheng Yang, Jen-Shi Chen, John Wen-Cheng Chang, Yung-Chang Lin, Chang-Fu Kuo and Lai-Chu See. Postdiagnostic metformin use and survival of patients with colorectal cancer: A nationwide cohort study. Int J Cancer. 2020 Oct 1;147(7):1904-1916.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Wen-Kuan Huang, Pinar Akçakaya, Anastasia Gangaev, Linkiat Lee, Katarina Zeljic. Praveensingh Hajeri, Erik Berglund, Mehran Ghaderi, Jan Åhlén, Robert Bränström, Catharina Larsson and Weng-Onn Lui. miR-125a- 5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors. Exp Cell Res. 2018 Oct 1;371(1):287-296.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Wen-Kuan Huang, Jiwei Gao, Ziqing Chen, Hao Shi, Juan Yuan, Huanhuan L. Cui, Chun-Nan Yeh, Robert Bränström, Catharina Larsson, Shuijie Li and Weng-Onn Lui. Heterogeneity of metabolic vulnerability in imatinib-resistant gastrointestinal stromal tumor. Cells. 2020 May 26;9(6):1333.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Wen-Kuan Huang, Pinar Akçakaya, Katarina Zeljic, Anastasia Gangaev, Stefano Caramuta, Robert Bränström, Catharina Larsson and Weng-Onn Lui. Imatinib regulates miR-483-3p and oxidative phosphorylation in gastrointestinal stromal tumors. [Manuscript]
IV. Wen-Kuan Huang, Shu-Hao Chang, Hung-Chih Hsu, Wen-Chi Chou, Tsai-Sheng Yang, Jen-Shi Chen, John Wen-Cheng Chang, Yung-Chang Lin, Chang-Fu Kuo and Lai-Chu See. Postdiagnostic metformin use and survival of patients with colorectal cancer: A nationwide cohort study. Int J Cancer. 2020 Oct 1;147(7):1904-1916.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Lui, Weng-Onn
Co-supervisor: Bränström, Robert; Larsson, Catharina; Caramuta, Stefano; Hansson, Johan
Issue date: 2020-09-09
Rights:
Publication year: 2020
ISBN: 978-91-7831-930-5
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