PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation

Background & Aims: Phosphatidylinositides-3 kinases (PI3Ks) are promising drug targets for cancer therapy, but blockage of PI3K-AKT signalling causes hyperglycaemia, hyperinsulinaemia, and liver damage in patients, and hepatocellular carcinoma (HCC) in mice. There are 4 PI3Ks: PI3Kα, PI3Kβ,...

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Autores principales:	Barbara Becattini, Ludovic Breasson, Claudia Sardi, Fabio Zani, Giovanni Solinas
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	NAFLD NASH Insulin AKT mTOR Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/0fe2adb7ba684bfba3441a0071b78ab9
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spelling	oai:doaj.org-article:0fe2adb7ba684bfba3441a0071b78ab92021-11-20T05:11:41ZPI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation2589-555910.1016/j.jhepr.2021.100359https://doaj.org/article/0fe2adb7ba684bfba3441a0071b78ab92021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S258955592100135Xhttps://doaj.org/toc/2589-5559Background & Aims: Phosphatidylinositides-3 kinases (PI3Ks) are promising drug targets for cancer therapy, but blockage of PI3K-AKT signalling causes hyperglycaemia, hyperinsulinaemia, and liver damage in patients, and hepatocellular carcinoma (HCC) in mice. There are 4 PI3Ks: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. The role of PI3Kγ in HCC is unknown. Methods: We performed histopathological, metabolic, and molecular phenotyping of mice with genetic ablation of PI3Kγ using models where HCC was initiated by the carcinogen diethylnitrosamine (DEN) and promoted by dietary or genetic obesity (ob/ob). The role of PI3Kγ in leucocytes was investigated in mice lacking PI3Kγ in haematopoietic and endothelial cells. Results: Loss of PI3Kγ had no effects on the development of DEN-induced HCC in lean mice. However, in mice injected with DEN and placed on an obesogenic diet, PI3Kγ ablation reduced tumour growth, which was associated with reduced insulinaemia, steatosis, and expression of inflammatory cytokines. ob/ob mice lacking PI3Kγ, and mice with diet-induced obesity lacking PI3Kγ in leucocytes and endothelial cells did not display improved insulin sensitivity, steatosis, metabolic inflammation, or reduced tumour growth. However, these mice showed a reduced number of tumours, reduced liver infiltration by neutrophils, and reduced hepatocyte proliferation acutely induced by DEN. Conclusions: Loss of PI3Kγ reduces tumour development in obesity-promoted HCC through multiple cell types and mechanisms that include improved insulinaemia, steatosis, and metabolic inflammation as well as the regulation of acute neutrophil infiltration and compensatory hepatocyte proliferation. PI3Kγ-selective inhibition may represent a novel therapeutic approach to reduce HCC initiation and slow HCC progression. Lay summary: Class-1 phosphatidylinositides-3 kinases (PI3Ks) are critical targets in cancer therapy, but complete inhibition of all isoforms causes liver damage, hyperglycaemia, and insulinaemia. Here we show that selective ablation of the PI3Kγ isoform dampens tumour initiation and growth in a mouse model of carcinogen-initiated and obesity-promoted hepatocellular carcinoma (HCC). The effect of PI3Kγ ablation on reduced tumour growth was explained by reduced tumour cell proliferation, which was associated with reduced insulin levels, liver lipids, and reduced expression of tumour-promoting cytokines. PI3Kγ ablation in leucocytes of obese mice had no effects on tumour size. However, it reduced tumour number in association with reduced carcinogen-induced neutrophil infiltration and hepatocyte proliferation in livers of obese mice. Inhibition of PI3Kγ may thus reduce HCC initiation and growth in obese subjects by a mechanism involving reduced metabolic stress and insulinaemia and reduced carcinogen-induced neutrophil infiltration to the fatty liver.Barbara BecattiniLudovic BreassonClaudia SardiFabio ZaniGiovanni SolinasElsevierarticleNAFLDNASHInsulinAKTmTORDiseases of the digestive system. GastroenterologyRC799-869ENJHEP Reports, Vol 3, Iss 6, Pp 100359- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NAFLD NASH Insulin AKT mTOR Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	NAFLD NASH Insulin AKT mTOR Diseases of the digestive system. Gastroenterology RC799-869 Barbara Becattini Ludovic Breasson Claudia Sardi Fabio Zani Giovanni Solinas PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
description	Background & Aims: Phosphatidylinositides-3 kinases (PI3Ks) are promising drug targets for cancer therapy, but blockage of PI3K-AKT signalling causes hyperglycaemia, hyperinsulinaemia, and liver damage in patients, and hepatocellular carcinoma (HCC) in mice. There are 4 PI3Ks: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. The role of PI3Kγ in HCC is unknown. Methods: We performed histopathological, metabolic, and molecular phenotyping of mice with genetic ablation of PI3Kγ using models where HCC was initiated by the carcinogen diethylnitrosamine (DEN) and promoted by dietary or genetic obesity (ob/ob). The role of PI3Kγ in leucocytes was investigated in mice lacking PI3Kγ in haematopoietic and endothelial cells. Results: Loss of PI3Kγ had no effects on the development of DEN-induced HCC in lean mice. However, in mice injected with DEN and placed on an obesogenic diet, PI3Kγ ablation reduced tumour growth, which was associated with reduced insulinaemia, steatosis, and expression of inflammatory cytokines. ob/ob mice lacking PI3Kγ, and mice with diet-induced obesity lacking PI3Kγ in leucocytes and endothelial cells did not display improved insulin sensitivity, steatosis, metabolic inflammation, or reduced tumour growth. However, these mice showed a reduced number of tumours, reduced liver infiltration by neutrophils, and reduced hepatocyte proliferation acutely induced by DEN. Conclusions: Loss of PI3Kγ reduces tumour development in obesity-promoted HCC through multiple cell types and mechanisms that include improved insulinaemia, steatosis, and metabolic inflammation as well as the regulation of acute neutrophil infiltration and compensatory hepatocyte proliferation. PI3Kγ-selective inhibition may represent a novel therapeutic approach to reduce HCC initiation and slow HCC progression. Lay summary: Class-1 phosphatidylinositides-3 kinases (PI3Ks) are critical targets in cancer therapy, but complete inhibition of all isoforms causes liver damage, hyperglycaemia, and insulinaemia. Here we show that selective ablation of the PI3Kγ isoform dampens tumour initiation and growth in a mouse model of carcinogen-initiated and obesity-promoted hepatocellular carcinoma (HCC). The effect of PI3Kγ ablation on reduced tumour growth was explained by reduced tumour cell proliferation, which was associated with reduced insulin levels, liver lipids, and reduced expression of tumour-promoting cytokines. PI3Kγ ablation in leucocytes of obese mice had no effects on tumour size. However, it reduced tumour number in association with reduced carcinogen-induced neutrophil infiltration and hepatocyte proliferation in livers of obese mice. Inhibition of PI3Kγ may thus reduce HCC initiation and growth in obese subjects by a mechanism involving reduced metabolic stress and insulinaemia and reduced carcinogen-induced neutrophil infiltration to the fatty liver.
format	article
author	Barbara Becattini Ludovic Breasson Claudia Sardi Fabio Zani Giovanni Solinas
author_facet	Barbara Becattini Ludovic Breasson Claudia Sardi Fabio Zani Giovanni Solinas
author_sort	Barbara Becattini
title	PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
title_short	PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
title_full	PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
title_fullStr	PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
title_full_unstemmed	PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
title_sort	pi3kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0fe2adb7ba684bfba3441a0071b78ab9
work_keys_str_mv	AT barbarabecattini pi3kgpromotesobesityassociatedhepatocellularcarcinomabyregulatingmetabolismandinflammation AT ludovicbreasson pi3kgpromotesobesityassociatedhepatocellularcarcinomabyregulatingmetabolismandinflammation AT claudiasardi pi3kgpromotesobesityassociatedhepatocellularcarcinomabyregulatingmetabolismandinflammation AT fabiozani pi3kgpromotesobesityassociatedhepatocellularcarcinomabyregulatingmetabolismandinflammation AT giovannisolinas pi3kgpromotesobesityassociatedhepatocellularcarcinomabyregulatingmetabolismandinflammation
_version_	1718419524760371200

PI3Kγ promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation

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