Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that targe...

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Autores principales:	Tianfeng Yang, Jian Huo, Rui Xu, Qi Su, Wenjuan Tang, Dongdong Zhang, Man Zhu, Yingzhuan Zhan, Bingling Dai, Yanmin Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	C‐MET/STAT3 HCC PLAGL2 selenium sulfide Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/769b517ae0a34af99893265a8d4ff97b
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spelling	oai:doaj.org-article:769b517ae0a34af99893265a8d4ff97b2021-11-11T12:06:40ZSelenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma2001-132610.1002/ctm2.536https://doaj.org/article/769b517ae0a34af99893265a8d4ff97b2021-09-01T00:00:00Zhttps://doi.org/10.1002/ctm2.536https://doaj.org/toc/2001-1326Abstract Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.Tianfeng YangJian HuoRui XuQi SuWenjuan TangDongdong ZhangMan ZhuYingzhuan ZhanBingling DaiYanmin ZhangWileyarticleC‐MET/STAT3HCCPLAGL2selenium sulfideMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 9, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	C‐MET/STAT3 HCC PLAGL2 selenium sulfide Medicine (General) R5-920
spellingShingle	C‐MET/STAT3 HCC PLAGL2 selenium sulfide Medicine (General) R5-920 Tianfeng Yang Jian Huo Rui Xu Qi Su Wenjuan Tang Dongdong Zhang Man Zhu Yingzhuan Zhan Bingling Dai Yanmin Zhang Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
description	Abstract Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.
format	article
author	Tianfeng Yang Jian Huo Rui Xu Qi Su Wenjuan Tang Dongdong Zhang Man Zhu Yingzhuan Zhan Bingling Dai Yanmin Zhang
author_facet	Tianfeng Yang Jian Huo Rui Xu Qi Su Wenjuan Tang Dongdong Zhang Man Zhu Yingzhuan Zhan Bingling Dai Yanmin Zhang
author_sort	Tianfeng Yang
title	Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
title_short	Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
title_full	Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
title_fullStr	Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
title_full_unstemmed	Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
title_sort	selenium sulfide disrupts the plagl2/c‐met/stat3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/769b517ae0a34af99893265a8d4ff97b
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Selenium sulfide disrupts the PLAGL2/C‐MET/STAT3‐induced resistance against mitochondrial apoptosis in hepatocellular carcinoma

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