Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

Zihan Yang; Li Zhou; Tongxu Si; Siyuan Chen; Chengxi Liu; Kelvin Kaki Ng; Zesheng Wang; Zhiji Chen; Chan Qiu; Guopan Liu; Qingliang Wang; Xiaoyu Zhou; Liang Zhang; Zhongping Yao; Song He; Mengsu Yang; Zhihang Zhou

doi:10.1186/s12943-023-01727-9

Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

Zihan Yang, Li Zhou, Tongxu Si, Siyuan Chen, Chengxi Liu, Kelvin Kaki Ng, Zesheng Wang, Zhiji Chen, Chan Qiu, Guopan Liu, Qingliang Wang, Xiaoyu Zhou, Liang Zhang, Zhongping Yao, Song He, Mengsu Yang^*, Zhihang Zhou^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

20 Citations (Scopus)

96 Downloads (CityUHK Scholars)

Abstract

Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear.

Methods LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype.

Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis.

Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.

Original language	English
Article number	21
Journal	Molecular Cancer
Volume	22
Online published	31 Jan 2023
DOIs	https://doi.org/10.1186/s12943-023-01727-9
Publication status	Published - 31 Jan 2023

Funding

This work was supported by the National Natural Science Fund (No. 81972285), Hetao Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone Shenzhen Park Project (HZQB-KCZYZ-2021017), Hong Kong Research Grant Council (CityU_11319516), the Research Impact Fund of the Hong Kong Research Grant Council (R1020-18F), the Natural Science Foundation of Chongqing (Chongqing, China, CSTB2022NSCQ-MSX1038), Senior Medical Talents Program of Chongqing for Young and Middle-aged and Kuanren Talents Program of the Second Afliated Hospital of Chongqing Medical University (13–004-009)

Research Keywords

Confned migration
Lysyl Hydroxylase 1
Cancer metastasis
Septin2
Microfuidic chip

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12943-023-01727-9

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Yang, Z., Zhou, L., Si, T., Chen, S., Liu, C., Ng, K. K., Wang, Z., Chen, Z., Qiu, C., Liu, G., Wang, Q., Zhou, X., Zhang, L., Yao, Z., He, S., Yang, M., & Zhou, Z. (2023). Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network. Molecular Cancer, 22, Article 21. https://doi.org/10.1186/s12943-023-01727-9

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title = "Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network",

abstract = "Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear.Methods LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype.Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis.Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.{\textcopyright} The Author(s) 2023.",

keywords = "Confned migration, Lysyl Hydroxylase 1, Cancer metastasis, Septin2, Microfuidic chip",

author = "Zihan Yang and Li Zhou and Tongxu Si and Siyuan Chen and Chengxi Liu and Ng, {Kelvin Kaki} and Zesheng Wang and Zhiji Chen and Chan Qiu and Guopan Liu and Qingliang Wang and Xiaoyu Zhou and Liang Zhang and Zhongping Yao and Song He and Mengsu Yang and Zhihang Zhou",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = jan,

day = "31",

doi = "10.1186/s12943-023-01727-9",

language = "English",

volume = "22",

journal = "Molecular Cancer",

issn = "1476-4598",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

AU - Yang, Zihan

AU - Zhou, Li

AU - Si, Tongxu

AU - Chen, Siyuan

AU - Liu, Chengxi

AU - Ng, Kelvin Kaki

AU - Wang, Zesheng

AU - Chen, Zhiji

AU - Qiu, Chan

AU - Liu, Guopan

AU - Wang, Qingliang

AU - Zhou, Xiaoyu

AU - Zhang, Liang

AU - Yao, Zhongping

AU - He, Song

AU - Yang, Mengsu

AU - Zhou, Zhihang

PY - 2023/1/31

Y1 - 2023/1/31

N2 - Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear.Methods LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype.Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis.Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.© The Author(s) 2023.

AB - Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear.Methods LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype.Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis.Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.© The Author(s) 2023.

KW - Confned migration

KW - Lysyl Hydroxylase 1

KW - Cancer metastasis

KW - Septin2

KW - Microfuidic chip

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85147112581&origin=recordpage

U2 - 10.1186/s12943-023-01727-9

DO - 10.1186/s12943-023-01727-9

M3 - RGC 21 - Publication in refereed journal

C2 - 36721170

SN - 1476-4598

VL - 22

JO - Molecular Cancer

JF - Molecular Cancer

M1 - 21

ER -

Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

UN SDGs

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RIF: Development of an Integrated Microfluidics System for Multi-level High Content Screening of Anti-tumor Drugs

GRF: Development of an Integrated Microfluidic-Based System for Single Cell Mutation Analysis and Drug Sensitivity Test of Circulating Tumor Cells/Cell Clusters

Cite this

Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

UN SDGs

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

RIF: Development of an Integrated Microfluidics System for Multi-level High Content Screening of Anti-tumor Drugs

GRF: Development of an Integrated Microfluidic-Based System for Single Cell Mutation Analysis and Drug Sensitivity Test of Circulating Tumor Cells/Cell Clusters

Cite this