Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis

Gastric cancer is one of the most common malignancies and leading cause of cancer-related death worldwide. Tremendous reports have demonstrated that a wide variety of receptor tyrosine kinases play a causal role in gastric cancers. Receptor tyrosine kinase MET, aka. hepatocyte growth factor receptor...

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Main Author: Sim, Kae Hwan
Other Authors: Sze Siu Kwan
Format: Theses and Dissertations
Language:English
Published: 2016
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Online Access:https://hdl.handle.net/10356/66452
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-664522023-02-28T18:34:07Z Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis Sim, Kae Hwan Sze Siu Kwan School of Biological Sciences DRNTU::Science::Biological sciences Gastric cancer is one of the most common malignancies and leading cause of cancer-related death worldwide. Tremendous reports have demonstrated that a wide variety of receptor tyrosine kinases play a causal role in gastric cancers. Receptor tyrosine kinase MET, aka. hepatocyte growth factor receptor (HGFR), has been frequently found dysregulated in gastric carcinomas. MET is a single-pass receptor tyrosine kinase localizing on plasma membrane and specific for hepatocyte growth factor/scatter factor (HGF/SF)1. Activation of MET/HGF regulates many cellular processes, such as proliferation, survival, motility, angiogenesis and morphogenesis. In gastric cancer, aberrant MET/HGF signaling pathway has been found dysregulate cell proliferation, contributing to angiogenesis, oncogenesis, tumor cell invasion and metastasis, and also protection from apoptosis in cancer cells. Therapeutic strategies targeting MET/HGF thus hold promise for gastric cancer. Handful of studies on MET signaling in gastric cancer have looked into the underlying mechanisms of dysregulated MET signaling in gastric oncogenesis. Recently it was reported that several RTKs including MET can translocalize into mitochondria of cancer cells. An important role of mtMET (the mitochondrial-localized MET receptor is referred to as mtMET) in cancers is suggested. In this study, we aim to understand the function and substrate of mtMET of SNU5 gastric cancer cell line. Based on preliminary data from qualitative profiling of mitochondrial proteome, we identified different components of endocytosis pathway. Functional assays using different endocytic inhibitors coupled with immunofluorescence staining approach were applied to study the translocalization of MET into mitochondria. Abundance and phosphorylation of MET in mitochondria were severely disrupted when endocytosis was inhibited. We proposed that MET is activated and endocytosed, followed by translocation of a portion of MET into mitochondria of cancer cells. Moreover, our findings have suggested the participation of other mechanisms in the mitochondrial translocalization of MET. Co-immunoprecipitation and TMT-based high-throughput quantitative proteomic approach were also adopted to identify the potential substrates of mtMET in mitochondria. Among the proteins which were identified at high confidence level, a major fraction is involved in catalytic activity and metabolic process in mitochondria. Proximity ligation assays have revealed that mtMET has direct protein-protein interaction with two novel substrates, HMGA1 and PKM2. Taken together, this report suggested a novel functional role of mtMET in regulation of energy metabolism in mitochondria. The present study has disclosed a novel paradigm of mtMET signaling in gastric cancer cells and thus contributed to the ongoing efforts to therapeutically target aberrant RTK activities in human cancers. DOCTOR OF PHILOSOPHY (SBS) 2016-04-07T05:58:54Z 2016-04-07T05:58:54Z 2016 Thesis Sim, K. H. (2016). Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/66452 10.32657/10356/66452 en 197 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Sim, Kae Hwan
Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
description Gastric cancer is one of the most common malignancies and leading cause of cancer-related death worldwide. Tremendous reports have demonstrated that a wide variety of receptor tyrosine kinases play a causal role in gastric cancers. Receptor tyrosine kinase MET, aka. hepatocyte growth factor receptor (HGFR), has been frequently found dysregulated in gastric carcinomas. MET is a single-pass receptor tyrosine kinase localizing on plasma membrane and specific for hepatocyte growth factor/scatter factor (HGF/SF)1. Activation of MET/HGF regulates many cellular processes, such as proliferation, survival, motility, angiogenesis and morphogenesis. In gastric cancer, aberrant MET/HGF signaling pathway has been found dysregulate cell proliferation, contributing to angiogenesis, oncogenesis, tumor cell invasion and metastasis, and also protection from apoptosis in cancer cells. Therapeutic strategies targeting MET/HGF thus hold promise for gastric cancer. Handful of studies on MET signaling in gastric cancer have looked into the underlying mechanisms of dysregulated MET signaling in gastric oncogenesis. Recently it was reported that several RTKs including MET can translocalize into mitochondria of cancer cells. An important role of mtMET (the mitochondrial-localized MET receptor is referred to as mtMET) in cancers is suggested. In this study, we aim to understand the function and substrate of mtMET of SNU5 gastric cancer cell line. Based on preliminary data from qualitative profiling of mitochondrial proteome, we identified different components of endocytosis pathway. Functional assays using different endocytic inhibitors coupled with immunofluorescence staining approach were applied to study the translocalization of MET into mitochondria. Abundance and phosphorylation of MET in mitochondria were severely disrupted when endocytosis was inhibited. We proposed that MET is activated and endocytosed, followed by translocation of a portion of MET into mitochondria of cancer cells. Moreover, our findings have suggested the participation of other mechanisms in the mitochondrial translocalization of MET. Co-immunoprecipitation and TMT-based high-throughput quantitative proteomic approach were also adopted to identify the potential substrates of mtMET in mitochondria. Among the proteins which were identified at high confidence level, a major fraction is involved in catalytic activity and metabolic process in mitochondria. Proximity ligation assays have revealed that mtMET has direct protein-protein interaction with two novel substrates, HMGA1 and PKM2. Taken together, this report suggested a novel functional role of mtMET in regulation of energy metabolism in mitochondria. The present study has disclosed a novel paradigm of mtMET signaling in gastric cancer cells and thus contributed to the ongoing efforts to therapeutically target aberrant RTK activities in human cancers.
author2 Sze Siu Kwan
author_facet Sze Siu Kwan
Sim, Kae Hwan
format Theses and Dissertations
author Sim, Kae Hwan
author_sort Sim, Kae Hwan
title Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
title_short Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
title_full Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
title_fullStr Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
title_full_unstemmed Elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
title_sort elucidating the role of mitochondrial-localized hepatocyte growth factor receptor in gastric oncogenesis
publishDate 2016
url https://hdl.handle.net/10356/66452
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