دورية أكاديمية
أعرض في EDS

Inhibition of KIF20A enhances the immunotherapeutic effect of hepatocellular carcinoma by enhancing c-Myc ubiquitination.

التفاصيل البيبلوغرافية
العنوان: Inhibition of KIF20A enhances the immunotherapeutic effect of hepatocellular carcinoma by enhancing c-Myc ubiquitination.
المؤلفون: Chen S; Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, 300211, China; Department of Hepatology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Zhao L; Department of Hepatology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Liu J; Department of Hepatology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Han P; Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, 300211, China; Department of Hepatology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Jiang W; Department of Liver Transplantation, Tianjin First Center Hospital, 2 West Baoshan Road, Xiqing District, Tianjin, 300392, China., Liu Y; Department of Pathology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Hou J; Department of Liver Surgery, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China., Wang F; Department of Hepatology and Gastroenterology, Tianjin First Center Hospital, 2 West Baoshan Road, Xiqing District, Tianjin, 300392, China. Electronic address: wangfengmei@tmu.edu.cn., Li J; Department of Hepatology, Tianjin Second People's Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, China. Electronic address: JiaLi_0503@tmu.edu.cn.
المصدر: Cancer letters [Cancer Lett] 2024 Aug 28; Vol. 598, pp. 217105. Date of Electronic Publication: 2024 Jul 04.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
مواضيع طبية MeSH: Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/immunology , Carcinoma, Hepatocellular*/pathology , Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/metabolism , Liver Neoplasms*/genetics , Liver Neoplasms*/pathology , Liver Neoplasms*/immunology , Liver Neoplasms*/drug therapy , Liver Neoplasms*/metabolism , Kinesins*/genetics , Kinesins*/antagonists & inhibitors , Kinesins*/metabolism , Proto-Oncogene Proteins c-myc*/genetics , Proto-Oncogene Proteins c-myc*/metabolism , Ubiquitination* , F-Box-WD Repeat-Containing Protein 7*/genetics , F-Box-WD Repeat-Containing Protein 7*/metabolism, Animals ; Humans ; Mice ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Cell Line, Tumor ; Mice, Knockout ; Xenograft Model Antitumor Assays ; Cell Proliferation ; Immunotherapy/methods ; Male ; Prognosis ; Gene Expression Regulation, Neoplastic
مستخلص: Immune therapy has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients, yet its efficacy remains limited, underscoring the urgency to identify new therapeutic targets and biomarkers. Here, we investigated the pathological and physiological roles of KIF20A and assess its potential in enhancing HCC treatment efficacy when combined with PD-1 inhibitors. We initially assess KIF20A's oncogenic function using liver-specific KIF20A knockout (Kif20a CKO) mouse models and orthotopic xenografts. Subsequently, we establish a regulatory axis involving KIF20A, FBXW7, and c-Myc, validated through construction of c-Myc splicing mutants. Large-scale clinical immunohistochemistry (IHC) analyses confirm the pathological relevance of the KIF20A-FBXW7-c-Myc axis in HCC. We demonstrate that KIF20A overexpression correlates with poor prognosis in HCC by competitively inhibiting FBXW7-mediated degradation of c-Myc, thereby promoting glycolysis and enhancing tumor proliferation. Conversely, KIF20A downregulation suppresses these effects, impairing tumor growth through c-Myc downregulation. Notably, KIF20A inhibition attenuates c-Myc-induced MMR expression, associated with improved prognosis in HCC patients receiving PD-1 inhibitor therapy. Furthermore, in Kif20a CKO HCC mouse models, we observe synergistic effects between Kif20a knockout and anti-PD-1 antibodies, significantly enhancing immunotherapeutic efficacy against HCC. Our findings suggest that targeting the KIF20A-c-Myc axis could identify HCC patients likely to benefit from anti-PD-1 therapy. In conclusion, we propose that combining KIF20A inhibitors with anti-PD-1 treatment represents a promising therapeutic strategy for HCC, offering new avenues for clinical development and patient stratification.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
فهرسة مساهمة: Keywords: FBXW7; Hepatocellular carcinoma; KIF20A; MMR; Metabolic reprogramming; PD-1; c-Myc
المشرفين على المادة: EC 3.6.4.4 (Kinesins)
0 (Proto-Oncogene Proteins c-myc)
0 (F-Box-WD Repeat-Containing Protein 7)
0 (KIF20A protein, human)
0 (Immune Checkpoint Inhibitors)
0 (FBXW7 protein, human)
0 (MYC protein, human)
تواريخ الأحداث: Date Created: 20240706 Date Completed: 20240815 Latest Revision: 20240815
رمز التحديث: 20240816
DOI: 10.1016/j.canlet.2024.217105
PMID: 38971490
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7980
DOI:10.1016/j.canlet.2024.217105