2. Academic Validation
  3. Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression

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

  • Cancer Res. 2025 Jan 24. doi: 10.1158/0008-5472.CAN-24-2097.
Ran Chen 1,  Cuihong Ma 2,  Haoran Qian 3,  Xinyu Xie 4,  Yuxue Zhang 5,  Dayun Lu 6,  Shunjie Hu 7,  Mao Zhang 8,  Fen Liu 9,  Yunhao Zou 10,  Qiang Gao 8,  Hu Zhou 11,  Hailong Liu 12,  Moubin Lin 13,  Gaoxiang Ge 2,  Daming Gao 14
Affiliations

Affiliations

  • 1 Yangpu Hospital of Tongji University, Shanghai, China.
  • 2 Shanghai institute of Biochemistry and Cell Biology, Shanghai, China.
  • 3 Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, China.
  • 4 University of Chinese Academy of Sciences, Shanghai, China.
  • 5 Chinese Academy of Sciences, Shanghai, China.
  • 6 Nanjing University of Chinese Medicine,, China.
  • 7 Zhongshan Hospital, China.
  • 8 Zhongshan Hospital, Shanghai, China.
  • 9 Center for Excellence in Molecular Cell Science, shanghai, China.
  • 10 Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China.
  • 11 Shanghai Institute of Materia Medica, Shanghai, China.
  • 12 Yangpu Hospital of Tongji University, China.
  • 13 Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
  • 14 Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
PMID: 39854318 DOI: 10.1158/0008-5472.CAN-24-2097
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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