Role of insulin receptor substrates in the progression of hepatocellular carcinoma

Abstract Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yoshitaka Sakurai, Naoto Kubota, Iseki Takamoto, Atsushi Obata, Masahiko Iwamoto, Takanori Hayashi, Masakazu Aihara, Tetsuya Kubota, Hiroshi Nishihara, Takashi Kadowaki
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c5bd982e2a8f43ef86e9729852abb394
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c5bd982e2a8f43ef86e9729852abb394
record_format	dspace
spelling	oai:doaj.org-article:c5bd982e2a8f43ef86e9729852abb3942021-12-02T15:04:58ZRole of insulin receptor substrates in the progression of hepatocellular carcinoma10.1038/s41598-017-03299-32045-2322https://doaj.org/article/c5bd982e2a8f43ef86e9729852abb3942017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03299-3https://doaj.org/toc/2045-2322Abstract Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/β-catenin signaling is activated in HCC, we focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.Yoshitaka SakuraiNaoto KubotaIseki TakamotoAtsushi ObataMasahiko IwamotoTakanori HayashiMasakazu AiharaTetsuya KubotaHiroshi NishiharaTakashi KadowakiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yoshitaka Sakurai Naoto Kubota Iseki Takamoto Atsushi Obata Masahiko Iwamoto Takanori Hayashi Masakazu Aihara Tetsuya Kubota Hiroshi Nishihara Takashi Kadowaki Role of insulin receptor substrates in the progression of hepatocellular carcinoma
description	Abstract Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/β-catenin signaling is activated in HCC, we focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.
format	article
author	Yoshitaka Sakurai Naoto Kubota Iseki Takamoto Atsushi Obata Masahiko Iwamoto Takanori Hayashi Masakazu Aihara Tetsuya Kubota Hiroshi Nishihara Takashi Kadowaki
author_facet	Yoshitaka Sakurai Naoto Kubota Iseki Takamoto Atsushi Obata Masahiko Iwamoto Takanori Hayashi Masakazu Aihara Tetsuya Kubota Hiroshi Nishihara Takashi Kadowaki
author_sort	Yoshitaka Sakurai
title	Role of insulin receptor substrates in the progression of hepatocellular carcinoma
title_short	Role of insulin receptor substrates in the progression of hepatocellular carcinoma
title_full	Role of insulin receptor substrates in the progression of hepatocellular carcinoma
title_fullStr	Role of insulin receptor substrates in the progression of hepatocellular carcinoma
title_full_unstemmed	Role of insulin receptor substrates in the progression of hepatocellular carcinoma
title_sort	role of insulin receptor substrates in the progression of hepatocellular carcinoma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c5bd982e2a8f43ef86e9729852abb394
work_keys_str_mv	AT yoshitakasakurai roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT naotokubota roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT isekitakamoto roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT atsushiobata roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT masahikoiwamoto roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT takanorihayashi roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT masakazuaihara roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT tetsuyakubota roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT hiroshinishihara roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma AT takashikadowaki roleofinsulinreceptorsubstratesintheprogressionofhepatocellularcarcinoma
_version_	1718388981462204416

Role of insulin receptor substrates in the progression of hepatocellular carcinoma

Ejemplares similares