WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy

Chia-Ying Hou; Chung-Yung Ma; Yu-Ju Lin; Chou-Long Huang; Horng-Dar Wang; Chiou-Hwa Yuh

doi:10.3390/ijms232012100

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WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy

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WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy

Chia-Ying Hou, Chung-Yung Ma, Yu-Ju Lin, Chou-Long Huang, Horng-Dar Wang and Chiou-Hwa Yuh

International journal of molecular sciences, Vol.23(20), p.12100

10/11/2022

DOI: 10.3390/ijms232012100

PMCID: PMC9602556

PMID: 36292952

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Abstract

Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b ( osr1b ) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb . In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [ tert x p53 −/− ] and [ HBx,src,p53 −/− ,RPIA ], while ppp2r1bb is downregulated in [ tert x p53 −/− ]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [ HBx,src,p53 −/− ,RPIA ] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1β expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated β-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1–OSR1–PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1–OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1–OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy.

hepatocellular carcinoma (HCC)

lysine-deficient protein kinase-1 (WNK1)

oxidative stress responsive 1 (OSR1)

Protein Phosphatase 2A (PP2A)

tumor-induced angiogenesis

Details

Title: Subtitle: WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy
Creators: Chia-Ying Hou - National Health Research Institutes
Chung-Yung Ma - Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 300044, Taiwan Department of Life Science, National Tsing Hua University, Hsinchu 300044, Taiwan Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Yu-Ju Lin - Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 300044, Taiwan Department of Life Science, National Tsing Hua University, Hsinchu 300044, Taiwan Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Chou-Long Huang - University of Iowa
Horng-Dar Wang - University of Iowa
Chiou-Hwa Yuh - University of Iowa
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.23(20), p.12100
DOI: 10.3390/ijms232012100
PMID: 36292952
PMCID: PMC9602556
NLM abbreviation: Int J Mol Sci
ISSN: 1422-0067
eISSN: 1422-0067
Publisher: MDPI
Grant note: MG-109-PP-06; 110-2320-B-007-003-; NIH DK111542 / National Health Research Institutes 105-2319-B-400-001 / MOST 108-2320-B-400-005-MY3 / Taiwan National Science and Technology Council
Language: English
Date published: 10/11/2022
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984359938402771

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