Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression

IF 12.5 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-01-24 DOI:10.1158/0008-5472.can-24-2097

Ran Chen, Cuihong Ma, Haoran Qian, Xinyu Xie, Yuxue Zhang, Dayun Lu, Shunjie Hu, Mao Zhang, Fen Liu, Yunhao Zou, Qiang Gao, Hu Zhou, Hailong Liu, Moubin Lin, Gaoxiang Ge, Daming Gao

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引用次数: 0

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy affecting the liver and biliary system. Enhanced understanding of the pathogenic mechanisms underlying iCCA tumorigenesis and the discovery of appropriate therapeutic targets are imperative to improve patient outcomes. Here, we investigated the functions and regulations of solute carrier family 16 member 3 (SLC16A3), which has been reported to be a biomarker of poor prognosis in iCCA. High SLC16A3 expression was enriched in KRAS-mutated iCCA tumors, and mutant KRAS elevated SLC16A3 expression via the PI3K/AKT/mTORC1/HIF1α pathway. SLC16A3 not only enhanced glycolysis but also induced epigenetic reprogramming to regulate iCCA progression. Phosphorylation of SLC16A3 at S436 (p-S436) was vital for its oncogenic function and was linked to iCCA progression. Casein kinase 2 (CK2) directly phosphorylated SLC16A3 at S436, and CK2 inhibition with CX-4945 (silmitasertib) reduced the growth of KRAS-mutated iCCA tumor xenografts and patient-derived organoids. Together, this study provides valuable insights into the diverse functions of SLC16A3 in iCCA and comprehensively elucidates the upstream regulatory mechanisms, providing potential therapeutic strategies for iCCA patients with KRAS mutations.

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.