A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction

Yeo Jun Yoon; Hyun Soo Shin; Jae Yol Lim

doi:10.1016/j.radonc.2019.05.012

A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction

Yeo Jun Yoon, Hyun Soo Shin, Jae Yol Lim

Department of Otorhinolaryngology

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Objective: Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. Materials and methods: Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. Results: We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. Conclusions: These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.

Original language	English
Pages (from-to)	9-16
Number of pages	8
Journal	Radiotherapy and Oncology
Volume	138
DOIs	https://doi.org/10.1016/j.radonc.2019.05.012
Publication status	Published - 2019 Sept

Bibliographical note

Funding Information:
This work is supported by the Stem Cell Research Project through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2017M3A9B4032053 ) and by the Basic Science Research Program through the NRF funded by the Ministry of Science and ICT ( NRF-2018R1A2B3004269 ), Republic of Korea.

Publisher Copyright:
© 2019 The Authors

All Science Journal Classification (ASJC) codes

Hematology
Oncology
Radiology Nuclear Medicine and imaging

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10.1016/j.radonc.2019.05.012

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title = "A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction",

abstract = "Objective: Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. Materials and methods: Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. Results: We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. Conclusions: These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.",

author = "Yoon, {Yeo Jun} and Shin, {Hyun Soo} and Lim, {Jae Yol}",

note = "Funding Information: This work is supported by the Stem Cell Research Project through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2017M3A9B4032053 ) and by the Basic Science Research Program through the NRF funded by the Ministry of Science and ICT ( NRF-2018R1A2B3004269 ), Republic of Korea. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = sep,

doi = "10.1016/j.radonc.2019.05.012",

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AU - Yoon, Yeo Jun

AU - Shin, Hyun Soo

AU - Lim, Jae Yol

N1 - Funding Information: This work is supported by the Stem Cell Research Project through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2017M3A9B4032053 ) and by the Basic Science Research Program through the NRF funded by the Ministry of Science and ICT ( NRF-2018R1A2B3004269 ), Republic of Korea. Publisher Copyright: © 2019 The Authors

PY - 2019/9

Y1 - 2019/9

N2 - Objective: Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. Materials and methods: Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. Results: We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. Conclusions: These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.

AB - Objective: Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. Materials and methods: Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. Results: We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. Conclusions: These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.

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A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction

Abstract

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