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Article: LANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress

TitleLANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress
Authors
Issue Date7-Aug-2023
PublisherLippincott, Williams & Wilkins
Citation
Hepatology, 2023 How to Cite?
Abstract

Background & Aims: 

HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC T initiation.

Approach & Results: 

Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells.

Conclusions: 

Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.


Persistent Identifierhttp://hdl.handle.net/10722/337375
ISSN
2023 Impact Factor: 12.9
2023 SCImago Journal Rankings: 5.011

 

DC FieldValueLanguage
dc.contributor.authorHuang, Hongyang-
dc.contributor.authorTsui, Yu-Man-
dc.contributor.authorHo, Daniel Wai-Hung-
dc.contributor.authorChung, Clive Yik-Sham-
dc.contributor.authorSze, Karen Man-Fong-
dc.contributor.authorLee, Eva-
dc.contributor.authorCheung, Gary Cheuk-Hang-
dc.contributor.authorZhang, Vanilla Xin-
dc.contributor.authorWang, Xia-
dc.contributor.authorLyu, Xueying-
dc.contributor.authorNg, Irene Oi-Lin-
dc.date.accessioned2024-03-11T10:20:24Z-
dc.date.available2024-03-11T10:20:24Z-
dc.date.issued2023-08-07-
dc.identifier.citationHepatology, 2023-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/337375-
dc.description.abstract<h3>Background & Aims: </h3><p>HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC T initiation.</p><h3>Approach & Results: </h3><p>Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells.</p><h3>Conclusions: </h3><p>Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.</p>-
dc.languageeng-
dc.publisherLippincott, Williams & Wilkins-
dc.relation.ispartofHepatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleLANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1097/HEP.0000000000000523-
dc.identifier.eissn1527-3350-
dc.identifier.issnl0270-9139-

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