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

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

作者地址："[Yang, Zihan; Zhou, Li; Si, Tongxu; Ng, Kelvin Kaki; Wang, Zesheng; Liu, Guopan; Zhou, Xiaoyu; Zhang, Liang; Yang, Mengsu; Zhou, Zhihang] City Univ Hong Kong, Dept Biomed Sci, Kowloon, 83 Tat Chee Ave, Hong Kong, Peoples R China; [Yang, Zihan; Zhou, Li; Si, Tongxu; Ng, Kelvin Kaki; Wang, Zesheng; Liu, Guopan; Zhou, Xiaoyu; Zhang, Liang; Yang, Mengsu; Zhou, Zhihang] City Univ Hong Kong, Tung Biomed Sci Ctr, Kowloon, 83 Tat Chee Ave, Hong Kong, Peoples R China; [Yang, Zihan; Si, Tongxu; Ng, Kelvin Kaki; Wang, Zesheng; Liu, Guopan; Zhou, Xiaoyu; Zhang, Liang; Yang, Mengsu] City Univ Hong Kong, Dept Precis Diagnost & Therapeut Technol, Futian Res Inst, Shenzhen, Guangdong, Peoples R China; [Zhou, Li; Chen, Siyuan; Chen, Zhiji; Qiu, Chan; He, Song; Zhou, Zhihang] Chongqing Med Univ, Dept Gastroenterol, Affiliated Hosp 2, Chongqing, Peoples R China; [Liu, Chengxi; Yao, Zhongping] Hong Kong Polytech Univ, Res Inst Future Food, State Key Lab Chem Biol & Drug Discovery, Hung Hom,Kowloon, Hong Kong, Peoples R China; [Liu, Chengxi; Yao, Zhongping] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Hung Hom, Kowloon, Hong Kong, Peoples R China; [Wang, Qingliang] Chongqing Med Univ, Dept Pathol, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Yang, MS; Zhou, ZH (通讯作者)，City Univ Hong Kong, Dept Biomed Sci, Kowloon, 83 Tat Chee Ave, Hong Kong, Peoples R China.; Yang, MS; Zhou, ZH (通讯作者)，City Univ Hong Kong, Tung Biomed Sci Ctr, Kowloon, 83 Tat Chee Ave, Hong Kong, Peoples R China.; Yang, MS (通讯作者)，City Univ Hong Kong, Dept Precis Diagnost & Therapeut Technol, Futian Res Inst, Shenzhen, Guangdong, Peoples R China.; Zhou, ZH (通讯作者)，Chongqing Med Univ, Dept Gastroenterol, Affiliated Hosp 2, Chongqing, Peoples R China."

来源：MOLECULAR CANCER

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000926902200001

JCR分区：Q1

影响因子：27.7

年份：2023

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Confined migration; Lysyl Hydroxylase 1; Cancer metastasis; Septin2; Microfluidic chip

摘要："BackgroundExcessive 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.MethodsLC-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 mu m-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.ResultsLysyl 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.ConclusionsLH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization."

基金机构："National Natural Science Fund [81972285]; Hetao Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone Shenzhen Park Project [HZQB-KCZYZ-2021017]; Hong Kong Research Grant Council [CityU_11319516]; Research Impact Fund of the Hong Kong Research Grant Council [R1020-18F]; Natural Science Foundation of Chongqing (Chongqing, China) [CSTB2022NSCQ-MSX1038]; Senior Medical Talents Program of Chongqing for Young and Middle-aged and KuanrenTalents Program of the Second Affiliated Hospital of Chongqing Medical University [13-004-009]"

基金资助正文："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 KuanrenTalents Program of the Second Affiliated Hospital of Chongqing Medical University (13-004-009)."