Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression
文献类型：期刊论文
| 作者 | Chen, Ran2,3; Ma, Cuihong4,5; Qian, Haoran4,5; Xie, Xinyu4,5; Zhang, Yuxue6; Lu, Dayun1; Hu, Shunjie7; Zhang, Mao7; Liu, Fen4,5; Zou, Yunhao4,5 |
| 刊名 | CANCER RESEARCH
 |
| 出版日期 | 2025-04-03 |
| 卷号 | 85期号:7页码:1253-1269 |
| ISSN号 | 0008-5472 |
| DOI | 10.1158/0008-5472.CAN-24-2097 |
| 英文摘要 | 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. In this study, 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 viral oncogene homolog-mutated iCCA tumors, and mutant KRAS elevated SLC16A3 expression via the PI3K-AKT-mTORC1-HIF1 alpha pathway. SLC16A3 not only enhanced glycolysis but also induced epigenetic reprogramming to regulate iCCA progression. Phosphorylation of SLC16A3 at 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 patients with iCCA with KRAS mutations.Significance: Characterization of the oncogenic function and regulators of SLC16A3 in intrahepatic cholangiocarcinogenesis revealed the potential of CK2 inhibitors as a promising treatment for KRAS-mutated tumors. |
| WOS关键词 | TRANSPORTER MCT4 ; CANCER ; LACTATE ; GROWTH ; GENES ; CD147 ; LIFE |
| 资助项目 | National Key Research and Development Program of China (NKPs)[81925029] ; National Key Research and Development Program of China (NKPs)[82230098] ; National Key Research and Development Program of China (NKPs)[32221002] ; National Key Research and Development Program of China (NKPs)[82372665] ; National Key Research and Development Program of China (NKPs)[32070789] ; National Key Research and Development Program of China (NKPs)[32370755] ; National Key Research and Development Program of China (NKPs)[82303237] ; National Natural Science Foundation of China[2020YFA0803203] ; National Natural Science Foundation of China[2019YFA0802102] ; National Key Research and Development Program of China[YSBR-014] ; Chinese Academy of Sciences (CAS) Project for Young Scientists in Basic Research ; Shanghai Municipal Science and Technology Major Project[2023M732647] ; China Postdoctoral Science Foundation ; Cell Analysis Technology Platform of CAS Center for Excellence in Molecular Cell Science ; Experimental Animal Center of CAS Center for Excellence in Molecular Cell Science |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:001458551100011 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316899]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Lin, Moubin; Ge, Gaoxiang; Gao, Daming |
| 作者单位 | 1.Nanjing Univ Chinese Med, Jiangsu Key Lab Drug Target & Drug Degenerat Dis, Nanjing, Peoples R China 2.Tongji Univ, Yangpu Hosp, Ctr Clin Res & Translat Med, Sch Med, Shanghai, Peoples R China 3.Tongji Univ, Yangpu Hosp, Sch Med, Dept Gen Surg, 450 Tengyue Rd, Shanghai 200090, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Key Lab Multicell Syst, 320 Yueyang Rd, Shanghai 200031, Peoples R China 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Shanghai Jiao Tong Univ, Sch Med, Shanghai Chest Hosp, Dept Thorac Surg, Shanghai, Peoples R China 7.Fudan Univ, Zhongshan Hosp, Dept Hepatobiliary Surg & Transplantat, Liver Canc Inst ,Key Lab Carcinogenesis & Canc Inv, Shanghai, Peoples R China 8.Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China 9.Fudan Univ, State Key Lab Genet Engn, Shanghai, Peoples R China 10.Chinese Acad Sci, Dept Analyt Chem, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Ran,Ma, Cuihong,Qian, Haoran,et al. Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression[J]. CANCER RESEARCH,2025,85(7):1253-1269. |
| APA | Chen, Ran.,Ma, Cuihong.,Qian, Haoran.,Xie, Xinyu.,Zhang, Yuxue.,...&Gao, Daming.(2025).Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression.CANCER RESEARCH,85(7),1253-1269. |
| MLA | Chen, Ran,et al."Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression".CANCER RESEARCH 85.7(2025):1253-1269. |
入库方式： OAI收割
来源：上海药物研究所
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