Huang SS, Chen W, Vaishnani DK, Huang LJ, Li JZ, Huang SR, Li YZ, Xie QP. Leucine-rich repeat-containing protein 19 suppresses colorectal cancer by targeting cyclin-dependent kinase 6/E2F1 and remodeling the immune microenvironment. World J Gastroenterol 2025; 31(25): 107893 [PMID: 40656610 DOI: 10.3748/wjg.v31.i25.107893]
Corresponding Author of This Article
Qi-Peng Xie, MD, Deputy Director, Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109 Xueyuan West Road, Wenzhou 325000, Zhejiang Province, China. xieqipeng@wmu.edu.cn
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jul 7, 2025; 31(25): 107893 Published online Jul 7, 2025. doi: 10.3748/wjg.v31.i25.107893
Leucine-rich repeat-containing protein 19 suppresses colorectal cancer by targeting cyclin-dependent kinase 6/E2F1 and remodeling the immune microenvironment
Si-Si Huang, Wei Chen, Deep K Vaishnani, Li-Juan Huang, Ji-Zhen Li, Shi-Rui Huang, Yan-Zhen Li, Qi-Peng Xie
Si-Si Huang, Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Si-Si Huang, Li-Juan Huang, Ji-Zhen Li, Shi-Rui Huang, Qi-Peng Xie, Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Wei Chen, Yan-Zhen Li, School of General Practice, Renji College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Deep K Vaishnani, School of International Studies, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Author contributions: Huang SS and Chen W led the conceptualization and design of the study, focusing on the clinical applications of the research; Vaishnani DK conducted the data analyses and interpreted the findings; Huang LJ and Li JZ contributed to the methodology and patient data collection; Huang SR and Li JZ performed the statistical analyses and assisted with drafting the manuscript; Li YZ contributed to the literature review and provided critical insights on the clinical implications; Xie QP supervised the research, contributed to the theoretical framework, and reviewed the manuscript.
Supported by the Natural Science Foundation of Zhejiang Province, No. LY22H160005.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Wenzhou Medical University (Approval No. KY2024-R271).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of Wenzhou Medical University, No. XMS92021-0340.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Qi-Peng Xie, MD, Deputy Director, Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109 Xueyuan West Road, Wenzhou 325000, Zhejiang Province, China. xieqipeng@wmu.edu.cn
Received: March 31, 2025 Revised: May 20, 2025 Accepted: June 9, 2025 Published online: July 7, 2025 Processing time: 95 Days and 13.9 Hours
Abstract
BACKGROUND
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, primarily due to tumor heterogeneity and treatment resistance. The leucine-rich repeat-containing protein 19 (LRRC19) has been linked to immune regulation and tumor suppression, yet its specific role in CRC remains poorly understood.
AIM
To investigate the tumor-suppressive role of LRRC19 in CRC, focusing on cell cycle, immune microenvironment, and chemotherapy response.
METHODS
Bioinformatics analyses of Gene Expression Omnibus and The Cancer Genome Atlas databases identified differentially expressed genes in CRC. LRRC19 expression was validated in CRC tissues and cell lines by quantitative PCR, immunohistochemistry, and Western blotting. Functional assays, including proliferation, soft agar colony formation, flow cytometry, and xenograft models, assessed biological effects. Mechanistic studies with dual-luciferase reporter assays, molecular docking, and drug sensitivity testing explored LRRC19’s interaction with the cyclin-dependent kinase 6 (CDK6)/E2F1 axis and oxaliplatin (OXA) response. Single-cell sequencing and immune infiltration analyses assessed its impact on the immune microenvironment.
RESULTS
LRRC19 expression was significantly downregulated in CRC and associated with poor prognosis. Overexpression of LRRC19 inhibited CRC cell proliferation, induced G0/G1 phase arrest, and suppressed tumor growth in vivo. Mechanistically, LRRC19 suppressed CDK6 transcription by downregulating E2F1, leading to cell cycle arrest. Additionally, LRRC19 promoted immune cell infiltration, particularly B cells and CD4+ T cells, while decreasing immunosuppressive cells. LRRC19 also sensitized CRC cells to OXA, enhancing chemotherapy efficacy.
CONCLUSION
LRRC19 suppresses CRC by targeting the CDK6/E2F1 axis, modulating the immune microenvironment, and enhancing chemotherapy sensitivity, making it a promising therapeutic target for precision medicine in CRC.
Core Tip: Colorectal cancer (CRC) remains a major global health challenge due to tumor heterogeneity and treatment resistance. Leucine-rich repeat-containing protein 19 (LRRC19) is identified as a novel tumor suppressor in CRC, inhibiting the cyclin-dependent kinase 6/E2F1 axis to induce cell cycle arrest, remodeling the immune microenvironment by enhancing immune cell infiltration, and improving chemotherapy sensitivity to oxaliplatin. These findings provide new insights into the molecular mechanisms of CRC progression and suggest LRRC19 as a promising therapeutic target for precision medicine in CRC management.
