PUBLICATION

Leptin induces muscle wasting in kras-driven hepatocellular carcinoma (HCC) model in zebrafish

Authors

Yang, Q., Yan, C., Wang, X., Gong, Z.

ID

ZDB-PUB-190206-5

Date

2019

Source

Disease models & mechanisms 12(2): (Journal)

Registered Authors

Gong, Zhiyuan, Wang, Xu

Keywords

Cancer cachexia, Leptin, Leptin receptor (Lepr), Liver cancer, Muscle wasting, Zebrafish

MeSH Terms

Leptin/metabolism*
Receptors, Leptin/metabolism
Humans
Up-Regulation
Disease Models, Animal
Muscular Atrophy/pathology*
Proto-Oncogene Proteins p21(ras)/metabolism*
Carcinoma, Hepatocellular/genetics
Carcinoma, Hepatocellular/pathology*
Zebrafish Proteins/metabolism*
Fatty Liver/pathology
Zebrafish/metabolism*
Carcinogenesis/pathology
Male
Signal Transduction
Gene Knockout Techniques
Liver Neoplasms/genetics
Liver Neoplasms/pathology*
Feeding Behavior
Mutation/genetics
Animals

(all 21)

PubMed

30718259 Full text @ Dis. Model. Mech.

Abstract

Cancer cachexia affects up to 80% of the patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish HCC model driven by oncogenic kras^G12V , we observed a progressive muscle wasting phenotype in adult zebrafish, characterized by significant loss of body weight and muscle fibers. By differential feeding, we observed that overfeeding caused fatty liver, accelerated carcinogenesis and muscle wasting. Interestingly, leptin, an obesity hormone, was upregulated in oncogenic hepatocytes and overfeeding groups. We also found a progressively increased leptin expression during human liver disease progression. By using leptin receptor (lepr) knockout fish, we found that tumor fish in the lepr mutant background had a higher survival rate and significantly lower muscle wasting level after tumor induction than the tumor fish in the wildtype background. Chemical inhibitors targeting leptin signaling also alleviated muscle wasting phenotype, indicating that the leptin signaling may be a new therapeutic target for cancer patients with muscle wasting.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
gz32Tg	chemical treatment by environment: doxycycline	Adult	male organism liver	RTPCR	Fig. 3
gz32Tg	increased food availability, chemical treatment by environment: doxycycline	Adult	male organism liver	RTPCR	Fig. 3
gz32Tg	chemical treatment by environment: doxycycline, limited food availability	Adult	male organism liver	RTPCR	Fig. 3
gz32Tg	chemical treatment by environment: doxycycline	Adult	male organism liver	RTPCR	Fig. 3
gz32Tg	increased food availability, chemical treatment by environment: doxycycline	Adult	male organism liver	RTPCR	Fig. 3
gz32Tg	chemical treatment by environment: doxycycline, limited food availability	Adult	male organism liver	RTPCR	Fig. 3
lepr^zf3068/+	standard conditions	Adult	male organism liver	RTPCR	Fig. 4
lepr^{zf3068/zf3068}	standard conditions	Adult	male organism liver	RTPCR	Fig. 4
WT	standard conditions	Adult	male organism liver	RTPCR	Fig. 4
gz32Tg	increased food availability, chemical treatment by environment: doxycycline	Adult	male organism liver	RTPCR	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	increased food availability	Adult	male organism skeletal muscle decreased mass, abnormal	Fig. 2
WT	limited food availability	Adult	male organism decreased weight, abnormal	Fig. 2
gz32Tg	chemical treatment by environment: EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, chemical treatment by environment: doxycycline	Adult	hepatocyte cell population proliferation increased occurrence, abnormal	Fig. 6
gz32Tg	chemical treatment by environment: EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, chemical treatment by environment: doxycycline	Adult	male organism decreased weight, ameliorated	Fig. 6
gz32Tg	chemical treatment by environment: EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, chemical treatment by environment: doxycycline	Adult	male organism hepatocellular carcinoma increased amount, abnormal	Fig. 6
gz32Tg	chemical treatment by environment: EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, chemical treatment by environment: doxycycline	Adult	male organism liver neoplastic, abnormal	Fig. 6
gz32Tg	chemical treatment by environment: EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, chemical treatment by environment: doxycycline	Adult	male organism skeletal muscle decreased mass, ameliorated	Fig. 6
gz32Tg	chemical treatment by environment: doxycycline	Adult	hepatocyte cell population proliferation increased occurrence, abnormal	Fig. 2
gz32Tg	chemical treatment by environment: doxycycline	Adult	hepatocyte cell population proliferation increased occurrence, abnormal	Fig. 5
gz32Tg	chemical treatment by environment: doxycycline	Adult	hepatocyte cell population proliferation increased occurrence, abnormal	Fig. 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz32Tg	Tg(fabp10a:RTTA) Tg(TETRE:EGFP-kras_G12V)	Transgenic Insertion
zf3068		Small Deletion	lepr

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
hepatocellular carcinoma	WT	chemical treatment by environment: doxycycline	TAS

Sequence Targeting Reagents

Fish

Fish
gz32Tg
lepr^zf3068/+
lepr^zf3068/+; gz32Tg
lepr^{zf3068/zf3068}
lepr^{zf3068/zf3068}; gz32Tg
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab2-lepa	polyclonal			Rabbit
Ab5-pcna	polyclonal		IgG	Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Yang et al., 2019 ZDB-PUB-190206-5 PMID:30718259

Leptin induces muscle wasting in kras-driven hepatocellular carcinoma (HCC) model in zebrafish

Yang et al., 2019

ZDB-PUB-190206-5
PMID:30718259