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LCN2 Promotes Proliferation and Glycolysis by Activating the JAK2/STAT3 Signaling Pathway in Hepatocellular Carcinoma

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Abstract

This study aimed to explore the molecular mechanism of LCN2 regulating aerobic glycolysis on abnormal proliferation of HCC cells. Based on the prediction of GEPIA database, the expression levels of LCN2 in hepatocellular carcinoma tissues were detected by RT-qPCR analysis, western blot, and immunohistochemical staining, respectively. In addition, CCK-8 kit, clone formation, and EdU staining were used to analyze the effect of LCN2 on the proliferation of hepatocellular carcinoma cells. Glucose uptake and lactate production were detected using kits. In addition, western blot was used to detect the expressions of aerobic glycolysis-related proteins. Finally, western blot was used to detect the expressions of phosphorylation of JAK2 and STAT3. We found LCN2 was upregualted in hepatocellular carcinoma tissues. CCK-8 kit, clone formation, and EdU staining results showed that LCN2 could promote the proliferation in hepatocellular carcinoma cells (Huh7 and HCCLM3 cells). Western blot results and kits confirmed that LCN2 significantly promotes aerobic glycolysis in hepatocellular carcinoma cells. Western blot results showed that LCN2 could significantly upregulate the phosphorylation of JAK2 and STAT3. Our results indicated that LCN2 activated the JAK2/STAT3 signaling pathway, promoted aerobic glycolysis, and accelerated malignant proliferation of hepatocellular carcinoma cells.

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References

  1. Torimura, T., & Iwamoto, H. (2021). Treatment and the prognosis of hepatocellular carcinoma in Asia. Liver International, 42(9), 2042.

    Article  Google Scholar 

  2. Sun, T., & Zhang, J. (2021). ETV4 mediates the Wnt/β-catenin pathway through transcriptional activation of ANXA2 to promote hepatitis B virus-associated liver hepatocellular carcinoma progression. Journal of biochemistry, 170(5), 663–673.

    Article  CAS  PubMed  Google Scholar 

  3. Wu, R., et al. (2019). Zn(II)-curcumin solid dispersion impairs hepatocellular carcinoma growth and enhances chemotherapy by modulating gut microbiota-mediated zinc homeostasis. Pharmacological Research, 150, 104454.

    Article  CAS  PubMed  Google Scholar 

  4. Ganapathy-Kanniappan, S. (2018). Molecular intricacies of aerobic glycolysis in cancer: Current insights into the classic metabolic phenotype. Critical Reviews In Biochemistry And Molecular Biology, 53(6), 667–682.

    Article  CAS  PubMed  Google Scholar 

  5. Qin, Y., et al. (2019). Homeodomain-interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer. Cell Proliferation, 52(3), e12603.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Li, Y., et al. (2019). The ubiquitination ligase SMURF2 reduces aerobic glycolysis and colorectal cancer cell proliferation by promoting ChREBP ubiquitination and degradation. The Journal Of Biological Chemistry, 294(40), 14745–14756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang, W., et al. (2022). LINC01605 promotes aerobic glycolysis through lactate dehydrogenase A in triple-negative breast cancer. Cancer Science, 113(8), 2484.

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, X., et al. (2018). lncRNA Ftx promotes aerobic glycolysis and tumor progression through the PPARγ pathway in hepatocellular carcinoma. International Journal Of Oncology, 53(2), 551–566.

    MathSciNet  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  9. Costa, D., et al. (2017). LCN2 overexpression in bone enhances the hematopoietic compartment via modulation of the bone marrow microenvironment. Journal Of Cellular Physiology, 232(11), 3077–3087.

    Article  CAS  PubMed  Google Scholar 

  10. Lim, D., Jeong, J., & Song, J. (2021). Lipocalin 2 regulates iron homeostasis, neuroinflammation, and insulin resistance in the brains of patients with dementia: Evidence from the current literature. CNS Neuroscience & Therapeutics, 27(8), 883–894.

    Article  CAS  Google Scholar 

  11. Yao, F., et al. (2021). A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature Communications, 12(1), 7333.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  12. Gao, J., Luo, T., & Wang, J. (2021). Gene interfered-ferroptosis therapy for cancers. Nature Communications, 12(1), 5311.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  13. Zhao, H., Ding, F., & Zheng, G. (2020). LncRNA TMPO-AS1 promotes LCN2 transcriptional activity and exerts oncogenic functions in ovarian cancer. The FASEB Journal, 34(9), 11382–11394.

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Y., et al. (2013). Lipocalin-2 negatively modulates the epithelial-to-mesenchymal transition in hepatocellular carcinoma through the epidermal growth factor (TGF-beta1)/Lcn2/Twist1 pathway. Hepatology (Baltimore, Md.), 58(4), 1349–1361.

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  15. Li, X., et al. (2022). Targeting long noncoding RNA-AQP4-AS1 for the treatment of retinal neurovascular dysfunction in diabetes mellitus. EBioMedicine, 77, 103857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fu, J., & Wang, H. (2018). Precision diagnosis and treatment of liver cancer in China. Cancer Letters, 412, 283–288.

    Article  CAS  PubMed  Google Scholar 

  17. Schröder, S., Pinoé-Schmidt, M., & Weiskirchen, R. (2022). Lipocalin-2 (LCN2) deficiency leads to cellular changes in highly metastatic human prostate cancer cell line PC-3. Cells, 11(2), 260.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu, J., et al. (2020). LCN2 Mediated by IL-17 affects the proliferation, migration, invasion and cell cycle of gastric cancer cells by targeting SLPI. Cancer Management And Research, 12, 12841–12849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barsoum, I., Elgohary, M., & Bassiony, M. (2020). Lipocalin-2: A novel diagnostic marker for hepatocellular carcinoma. Cancer Biomarkers, 28(4), 523–528.

    Article  CAS  PubMed  Google Scholar 

  20. Tseng, H., et al. (2022). A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α-mediated aerobic glycolysis. Molecular Oncology, 16(11), 2274–2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sun, K., et al. (2019). Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling. EBioMedicine, 41, 370–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, X., et al. (2015). Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells. Oncology Reports, 33(1), 157–162.

    Article  CAS  PubMed  Google Scholar 

  23. Liu, C., et al. (2021). Pharmacological targeting PTK6 inhibits the JAK2/STAT3 sustained stemness and reverses chemoresistance of colorectal cancer. Journal Of Experimental & Clinical Cancer Research : Cr, 40(1), 297.

    Article  PubMed Central  Google Scholar 

  24. Bao, X., et al. (2021). β-elemonic acid inhibits growth and triggers apoptosis in human castration-resistant prostate cancer cells through the suppression of JAK2/STAT3/MCL-1 and NF-ĸB signal pathways. Chemico-Biological Interactions, 342, 109477.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang, Q., et al. (2022). Peptide identification of hepatocyte growth-promoting factor and its function in cytoprotection and promotion of liver cell proliferation through the JAK2/STAT3/c-MYC pathway. European Journal Of Pharmacology, 920, 174832.

    Article  CAS  PubMed  Google Scholar 

  26. Lei, R., et al. (2017). IL-9 promotes proliferation and metastasis of hepatocellular cancer cells by activating JAK2/STAT3 pathway. International Journal Of Clinical And Experimental Pathology, 10(7), 7940–7946.

    PubMed  PubMed Central  Google Scholar 

  27. Li, L., et al. (2021). Circ_0072088 promotes progression of hepatocellular carcinoma by activating JAK2/STAT3 signaling pathway via miR-375. IUBMB Life, 73(9), 1153–1165.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Sichuan Mianyang 404 Hospital, Mianyang, China

    Baojun Han, Zhiming An, Teng Gong & Yu Pu

  2. General Surgery, Santai County Hospital of Traditional Chinese Medicine, Tongchuan Town, Santai County, Mianyang, 621100, Sichuan Province, China

    Ke Liu

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  1. Baojun Han
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  2. Zhiming An
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  3. Teng Gong
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  4. Yu Pu
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  5. Ke Liu
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Contributions

B.H.: writing, conceptualization, methodology, software

Z. A.: data curation, original draft preparation

T. G.: visualization, investigation

Y. P.: supervision, methodology, validation

K. L.: reviewing and editing, project management

Corresponding author

Correspondence to Ke Liu.

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This study was approved by the ethics committee of Sichuan Mianyang 404 Hospital and written consent approval was obtained from all participants.

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Han, B., An, Z., Gong, T. et al. LCN2 Promotes Proliferation and Glycolysis by Activating the JAK2/STAT3 Signaling Pathway in Hepatocellular Carcinoma. Appl Biochem Biotechnol 196, 717–728 (2024). https://doi.org/10.1007/s12010-023-04520-y

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  • DOI: https://doi.org/10.1007/s12010-023-04520-y

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