4.6
CiteScore
2.2
Impact Factor
- ISSN 1674-8301
- CN 32-1810/R
4.6
2.2
| 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
|
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.
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.
| [1] |
Lim IIP, Bondoc AJ, Geller JI, et al. Hepatoblastoma-the evolution of biology, surgery, and transplantation[J]. Children, 2018, 6(1): 1. doi: 10.3390/children6010001
|
| [2] |
Kehm RD, Osypuk TL, Poynter JN, et al. Do pregnancy characteristics contribute to rising childhood cancer incidence rates in the United States?[J]. Pediatr Blood Cancer, 2018, 65(3): e26888. doi: 10.1002/pbc.26888
|
| [3] |
Herzog CE, Andrassy RJ, Eftekhari F. Childhood cancers: hepatoblastoma[J]. Oncologist, 2000, 5(6): 445–453. doi: 10.1634/theoncologist.5-6-445
|
| [4] |
Feng J, Polychronidis G, Heger U, et al. Incidence trends and survival prediction of hepatoblastoma in children: a population-based study[J]. Cancer Commun, 2019, 39(1): 1–9. doi: 10.1186/s40880-018-0346-4
|
| [5] |
Kremer N, Walther AE, Tiao GM. Management of hepatoblastoma: an update[J]. Curr Opin Pediatr, 2014, 26(3): 362–369. doi: 10.1097/MOP.0000000000000081
|
| [6] |
Warmann SW, Fuchs J. Drug resistance in hepatoblastoma[J]. Curr Pharm Biotechnol, 2007, 8(2): 93–97. doi: 10.2174/138920107780487456
|
| [7] |
Arzumanian VA, Kiseleva OI, Poverennaya EV. The curious case of the HepG2 cell line: 40 years of expertise[J]. Int J Mol Sci, 2021, 22(23): 13135. doi: 10.3390/ijms222313135
|
| [8] |
López-Terrada D, Cheung SW, Finegold MJ, et al. Hep G2 is a hepatoblastoma-derived cell line[J]. Hum Pathol, 2009, 40(10): 1512–1515. doi: 10.1016/j.humpath.2009.07.003
|
| [9] |
Clapham DE. Calcium signaling[J]. Cell, 2007, 131(6): 1047–1058. doi: 10.1016/j.cell.2007.11.028
|
| [10] |
Yang Z, Yue Z, Ma X, et al. Calcium homeostasis: a potential vicious cycle of bone metastasis in breast cancers[J]. Front Oncol, 2020, 10: 293. doi: 10.3389/fonc.2020.00293
|
| [11] |
Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival[J]. Nat Rev Cancer, 2008, 8(5): 361–375. doi: 10.1038/nrc2374
|
| [12] |
Prevarskaya N, Skryma R, Shuba Y. Calcium in tumour metastasis: new roles for known actors[J]. Nat Rev Cancer, 2011, 11(8): 609–618. doi: 10.1038/nrc3105
|
| [13] |
Liu Z, Wang L, Xu H, et al. Heterogeneous responses to mechanical force of prostate cancer cells inducing different metastasis patterns[J]. Adv Sci, 2020, 7(15): 1903583. doi: 10.1002/advs.201903583
|
| [14] |
Liberzon A, Birger C, Thorvaldsdottir H, et al. The molecular signatures database hallmark gene set collection[J]. Cell Syst, 2015, 1(6): 417–425. doi: 10.1016/j.cels.2015.12.004
|
| [15] |
Yang N, Tang Y, Wang F, et al. Blockade of store-operated Ca2+ entry inhibits hepatocarcinoma cell migration and invasion by regulating focal adhesion turnover[J]. Cancer Lett, 2013, 330(2): 163–169. doi: 10.1016/j.canlet.2012.11.040
|
| [16] |
Easley IV CA, Brown CM, Horwitz AF, et al. CaMK-II promotes focal adhesion turnover and cell motility by inducing tyrosine dephosphorylation of FAK and paxillin[J]. Cell Motil Cytoskeleton, 2008, 65(8): 662–674. doi: 10.1002/cm.20294
|
| [17] |
Patergnani S, Danese A, Bouhamida E, et al. Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer[J]. Int J Mol Sci, 2020, 21(21): 8323. doi: 10.3390/ijms21218323
|
| [18] |
Marchi S, Giorgi C, Galluzzi L, et al. Ca2+ fluxes and cancer[J]. Mol Cell, 2020, 78(6): 1055–1069. doi: 10.1016/j.molcel.2020.04.017
|
| [19] |
Roberts-Thomson SJ, Chalmers SB, Monteith GR. The calcium-signaling toolkit in cancer: remodeling and targeting[J]. Cold Spring Harb Perspect Biol, 2019, 11(8): a035204. doi: 10.1101/cshperspect.a035204
|
| [20] |
Wu L, Lian W, Zhao L. Calcium signaling in cancer progression and therapy[J]. FEBS J, 2021, 288(21): 6187–6205. doi: 10.1111/febs.16133
|
| [21] |
Koivisto AP, Belvisi MG, Gaudet R, et al. Advances in TRP channel drug discovery: from target validation to clinical studies[J]. Nat Rev Drug Discov, 2022, 21(1): 41–59. doi: 10.1038/s41573-021-00268-4
|
| [22] |
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646–674. doi: 10.1016/j.cell.2011.02.013
|
| [23] |
Monteith GR, Prevarskaya N, Roberts-Thomson SJ. The calcium-cancer signalling nexus[J]. Nat Rev Cancer, 2017, 17(6): 373–380. doi: 10.1038/nrc.2017.18
|
| [24] |
Gupta SC, Singh R, Asters M, et al. Regulation of breast tumorigenesis through acid sensors[J]. Oncogene, 2016, 35(31): 4102–4111. doi: 10.1038/onc.2015.477
|
| [25] |
Joeckel E, Haber T, Prawitt D, et al. High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor[J]. Mol Cancer, 2014, 13: 42. doi: 10.1186/1476-4598-13-42
|
| [26] |
Zhivotovsky B, Orrenius S. Calcium and cell death mechanisms: a perspective from the cell death community[J]. Cell Calcium, 2011, 50(3): 211–221. doi: 10.1016/j.ceca.2011.03.003
|
| [27] |
Sukumaran P, Da Conceicao VN, Sun Y, et al. Calcium signaling regulates autophagy and apoptosis[J]. Cells, 2021, 10(8): 2125. doi: 10.3390/cells10082125
|
| [28] |
Ding LS, Sun XY, You YP, et al. Expression of focal adhesion kinase and phosphorylated focal adhesion kinase in human gliomas is associated with unfavorable overall survival[J]. Transl Res, 2010, 156(1): 45–52. doi: 10.1016/j.trsl.2010.05.001
|
| [29] |
Teutschbein J, Schartl M, Meierjohann S. Interaction of Xiphophorus and murine Fyn with focal adhesion kinase[J]. Comp Biochem Physiol C Toxicol Pharmacol, 2009, 149(2): 168–174. doi: 10.1016/j.cbpc.2008.09.013
|
| [30] |
Peng JM, Tseng RH, Shih TC, et al. CAMK2N1 suppresses hepatoma growth through inhibiting E2F1-mediated cell-cycle signaling[J]. Cancer Lett, 2021, 497: 66–76. doi: 10.1016/j.canlet.2020.10.017
|
| [31] |
Chen W, An P, Quan X, et al. Ca2+/calmodulin-dependent protein kinase II regulates colon cancer proliferation and migration via ERK1/2 and p38 pathways[J]. World J Gastroenterol, 2017, 23(33): 6111–6118. doi: 10.3748/wjg.v23.i33.6111
|
| [32] |
Lu KK, Armstrong SE, Ginnan R, et al. Adhesion-dependent activation of CaMKII and regulation of ERK activation in vascular smooth muscle[J]. Am J Physiol Cell Physiol, 2005, 289(5): C1343–C1350. doi: 10.1152/ajpcell.00064.2005
|
| [33] |
Wang Y, Liu Y, Liu Y, et al. A polymeric prodrug of cisplatin based on pullulan for the targeted therapy against hepatocellular carcinoma[J]. Int J Pharm, 2015, 483(1–2): 89–100. doi: 10.1016/j.ijpharm.2015.02.027
|
| [34] |
Huang C, Chen JYF, Wu J, et al. Ling-Zhi polysaccharides potentiate cytotoxic effects of anticancer drugs against drug-resistant urothelial carcinoma cells[J]. J Agric Food Chem, 2010, 58(15): 8798–8805. doi: 10.1021/jf1020158
|
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