PUBLICATION

Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model

Authors

Helal, M., Yan, C., Gong, Z.

ID

ZDB-PUB-210116-5

Date

2021

Source

Scientific Reports 11: 1372 (Journal)

Registered Authors

Gong, Zhiyuan

Keywords

none

MeSH Terms

Carcinogenesis*/genetics
Carcinogenesis*/metabolism
Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism
Animals
Interleukin-17*/genetics
Interleukin-17*/metabolism
Hepatocytes/metabolism*
Animals, Genetically Modified
Liver Neoplasms, Experimental*/genetics
Liver Neoplasms, Experimental*/metabolism
Zebrafish*/genetics
Zebrafish*/metabolism
Proto-Oncogene Proteins p21(ras)*/genetics
Proto-Oncogene Proteins p21(ras)*/metabolism

(all 15)

PubMed

33446803 Full text @ Sci. Rep.

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.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
EGFP	gz32Tg/gz32Tg	chemical treatment by diet: cholesterol, chemical treatment by environment: doxycycline	Days 7-13	liver	IFL	Figure 4
EGFP	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline	Days 7-13	liver	IFL	Figure 4
EGFP	gz32Tg/gz32Tg	chemical treatment by diet: glucose, chemical treatment by environment: doxycycline	Days 7-13	liver	IFL	Figure 4
EGFP	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline, fasting	Days 7-13	liver	IFL	Figure 4
il17a/f1	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline, chemical treatment by environment: JTE-013	Days 7-13	cholangiocyte	RTPCR	Figure 5
il17a/f1	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline, chemical treatment by environment: taurocholic acid	Days 7-13	cholangiocyte	RTPCR	Figure 5
il17a/f1	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline	Days 7-13	cholangiocyte	RTPCR	Figure 5
il17a/f1	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline	Days 7-13	hepatocyte	RTPCR	Figure 5
il17a/f1	WT	standard conditions	Adult	cholangiocyte	RTPCR	Figure 5
il17ra1a	gz32Tg/gz32Tg	chemical treatment by environment: doxycycline	Days 7-13	cholangiocyte	RTPCR	Figure 5

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by diet: cholesterol	Days 7-13	cholangiocyte zn-8 labeling increased amount, abnormal	Figure 4
WT	chemical treatment by diet: cholesterol	Days 7-13	liver bile acid biosynthetic process increased process quality, abnormal	Figure 4
WT	chemical treatment by diet: cholesterol	Days 7-13	liver increased size, abnormal	Figure 4
WT	chemical treatment by diet: cholesterol	Days 7-13	liver proliferative region ab5-pcna labeling increased amount, abnormal	Figure 4
WT	chemical treatment by diet: cholesterol	Days 7-13	liver triglyceride-rich plasma lipoprotein particle increased amount, abnormal	Figure 4
WT	chemical treatment by environment: doxycycline	Days 7-13	cholangiocyte ERK1 and ERK2 cascade normal rate, normal	Figure 5
WT	chemical treatment by environment: doxycycline, chemical treatment by environment: taurocholic acid	Days 7-13	cholangiocyte ERK1 and ERK2 cascade increased rate, abnormal	Figure 5
WT	chemical treatment by diet: glucose	Days 7-13	liver bile acid biosynthetic process normal process quality, normal	Figure 4
WT	chemical treatment by diet: glucose	Days 7-13	liver normal size, normal	Figure 4
WT	chemical treatment by diet: glucose	Days 7-13	liver triglyceride-rich plasma lipoprotein particle normal amount, normal	Figure 4

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Mutations / Transgenics

Allele	Construct	Type
gl22Tg	Tg(mpeg1:EGFP)	Transgenic Insertion
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
gz32Tg	Tg(fabp10a:RTTA) Tg(TETRE:EGFP-kras_G12V)	Transgenic Insertion
nz50Tg	Tg(lyz:DsRed2)	Transgenic Insertion

1 - 4 of 4

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
il17a/f1	MO1-il17a/f1	MRPHLNO
il17a/f1	MO2-il17a/f1	MRPHLNO

Fish

Fish
gl22Tg
gl22Tg; gz32Tg
gl22Tg; gz32Tg + MO1-il17a/f1
gl22Tg + MO1-il17a/f1
gz32Tg/gz32Tg
gz32Tg; nz50Tg
gz32Tg; nz50Tg + MO1-il17a/f1
nz50Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
DsRed2	EFG	DsRed2
EGFP	EFG	EGFP

Mapping

Helal et al., 2021 ZDB-PUB-210116-5 PMID:33446803

Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model

Helal et al., 2021

ZDB-PUB-210116-5
PMID:33446803