Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model
Abstract It has been well known that tumor progression is dependent on secreted factors not only from tumor cells but also from other surrounding non-tumor cells. In the current study, we investigated the role of cholangiocytes during hepatocarcinogenesis following induction of oncogenic kras V12 ex...
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2021
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oai:doaj.org-article:0700a23680934a129bde399f453f74c52021-12-02T15:23:00ZStimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model10.1038/s41598-020-80621-62045-2322https://doaj.org/article/0700a23680934a129bde399f453f74c52021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80621-6https://doaj.org/toc/2045-2322Abstract It has been well known that tumor progression is dependent on secreted factors not only from tumor cells but also from other surrounding non-tumor cells. In the current study, we investigated the role of cholangiocytes during hepatocarcinogenesis following induction of oncogenic kras V12 expression in hepatocytes using an inducible transgenic zebrafish model. Upon induction of carcinogenesis in hepatocytes, a progressive cell proliferation in cholangiocytes was observed. The proliferative response in cholangiocytes was induced by enhanced lipogenesis and bile acids secretion from hepatocytes through activation of Sphingosine 1 phosphate receptor 2 (S1pr2), a known cholangiocyte receptor involving in cholangiocyte proliferation. Enhancement and inhibition of S1pr2 could accelerate or inhibit cholangiocyte proliferation and hepatocarcinogenesis respectively. Gene expression analysis of hepatocytes and cholangiocytes showed that cholangiocytes stimulated carcinogenesis in hepatocytes via an inflammatory cytokine, Il17a/f1, which activated its receptor (Il17ra1a) on hepatocytes and enhanced hepatocarcinogenesis via an ERK dependent pathway. Thus, the enhancing effect of cholangiocytes on hepatocarcinogenesis is likely via an inflammatory loop.Mohamed HelalChuan YanZhiuyan GongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
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Medicine R Science Q Mohamed Helal Chuan Yan Zhiuyan Gong Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
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Abstract It has been well known that tumor progression is dependent on secreted factors not only from tumor cells but also from other surrounding non-tumor cells. In the current study, we investigated the role of cholangiocytes during hepatocarcinogenesis following induction of oncogenic kras V12 expression in hepatocytes using an inducible transgenic zebrafish model. Upon induction of carcinogenesis in hepatocytes, a progressive cell proliferation in cholangiocytes was observed. The proliferative response in cholangiocytes was induced by enhanced lipogenesis and bile acids secretion from hepatocytes through activation of Sphingosine 1 phosphate receptor 2 (S1pr2), a known cholangiocyte receptor involving in cholangiocyte proliferation. Enhancement and inhibition of S1pr2 could accelerate or inhibit cholangiocyte proliferation and hepatocarcinogenesis respectively. Gene expression analysis of hepatocytes and cholangiocytes showed that cholangiocytes stimulated carcinogenesis in hepatocytes via an inflammatory cytokine, Il17a/f1, which activated its receptor (Il17ra1a) on hepatocytes and enhanced hepatocarcinogenesis via an ERK dependent pathway. Thus, the enhancing effect of cholangiocytes on hepatocarcinogenesis is likely via an inflammatory loop. |
format |
article |
author |
Mohamed Helal Chuan Yan Zhiuyan Gong |
author_facet |
Mohamed Helal Chuan Yan Zhiuyan Gong |
author_sort |
Mohamed Helal |
title |
Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
title_short |
Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
title_full |
Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
title_fullStr |
Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
title_full_unstemmed |
Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model |
title_sort |
stimulation of hepatocarcinogenesis by activated cholangiocytes via il17a/f1 pathway in kras transgenic zebrafish model |
publisher |
Nature Portfolio |
publishDate |
2021 |
url |
https://doaj.org/article/0700a23680934a129bde399f453f74c5 |
work_keys_str_mv |
AT mohamedhelal stimulationofhepatocarcinogenesisbyactivatedcholangiocytesviail17af1pathwayinkrastransgeniczebrafishmodel AT chuanyan stimulationofhepatocarcinogenesisbyactivatedcholangiocytesviail17af1pathwayinkrastransgeniczebrafishmodel AT zhiuyangong stimulationofhepatocarcinogenesisbyactivatedcholangiocytesviail17af1pathwayinkrastransgeniczebrafishmodel |
_version_ |
1718387306670325760 |