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  • ISSN 1674-8301
  • CN 32-1810/R
Volume 37 Issue 5
Sep.  2023
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Haozhe Xu, Yiming Zhou, Jing Guo, Tao Ling, Yujie Xu, Ting Zhao, Chuanxin Shi, Zhongping Su, Qiang You. Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity[J]. The Journal of Biomedical Research, 2023, 37(5): 340-354. DOI: 10.7555/JBR.37.20230067
Citation: Haozhe Xu, Yiming Zhou, Jing Guo, Tao Ling, Yujie Xu, Ting Zhao, Chuanxin Shi, Zhongping Su, Qiang You. Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity[J]. The Journal of Biomedical Research, 2023, 37(5): 340-354. DOI: 10.7555/JBR.37.20230067
shu

Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity

  • 1.

    Department of Geriatrics, Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China

  • 2.

    Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, Guangdong 510095, China

  • 3.

    Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

  • 4.

    Division of General Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China

  • 5.

    Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, Jiangsu 210029, China

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  • Corresponding author:

    Zhongping Su, Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, 300 Guangzhou Road, Gulou District, Nanjing, Jiangsu 210029, China. Tel: +86-25-68303236, E-mail: suzhping@163.com

    Qiang You, Department of Biotherapy, the Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan Road, Gulou District, Nanjing, Jiangsu 210011, China. Tel: +86-25-58509620, E-mail: qiang.you@njmu.edu.cn

  • ΔThese authors contributed equally to this work.

  • Received Date: February 02, 2023
  • Revised Date: April 27, 2023
  • Accepted Date: May 04, 2023
  • Available Online: September 09, 2023
  • Published Date: September 09, 2023
    Graphical Abstract
    • Abstract

  • Hepatoblastoma is the most frequent liver malignancy in children. HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture. Intriguingly, we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells. The calcium signal is in connection with a series of processes critical in the tumorigenesis. Here, we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells. Mechanistically, calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase (FAK), protein kinase B, and p38 mitogen-activated protein kinase. The inhibitor of FAK or Ca2+/calmodulin-dependent kinase Ⅱ (CaMKⅡ) reversed the Ca2+-induced effects on HepG2 cells, including cell proliferation and migration, epithelial-mesenchymal transition protein expression levels, and phosphorylation levels of FAK and protein kinase B. Moreover, calcium ions decreased HepG2 cells' sensitivity to cisplatin. Furthermore, we found that the expression levels of FAK and CaMKⅡ were increased in hepatoblastoma. The group with high expression levels of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8+ T and NK cells. The expression of CaMKⅡ was positively correlated with that of PDCD1 and LAG3. Correspondingly, the expression of FAK was negatively correlated with that of TNFSF9, TNFRSF4, and TNFRSF18. Collectively, extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡ and enhances cisplatin resistance. FAK and CaMKⅡ shape immune cell infiltration and responses in tumor microenvironments, thereby serving as potential targets for hepatoblastoma.

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  • None.

    This research was funded by the Jiangsu Medical Scientific Research Project of Jiangsu Health Commission (to Q.Y.), the 789 Outstanding Talent Program of SAHNMU (Grant No. 789ZYRC202070102 to Q.Y.), the Guangzhou Key Medical Discipline Construction Project (to Q.Y.), and the National Natural Science Foundation of China (Grant Nos. 81870409 and 81671543 to Q.Y.).

    CLC number: R735.7, Document code: A

    The authors reported no conflict of interests.

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