High expression of hexokinase 2 promotes proliferation,migration and invasion of colorectal cancer cells by activating the JAK/STAT pathway and regulating tumor immune microenvironment
QING Shunjie
SHEN Zhiyong
Abstract：Objective To explore the expression of hexokinase 2(HK2)in colorectal cancer(CRC)and its possible mechanisms for regulating tumor cell behaviors and tumor immune microenvironment.Methods We analyzed HK2 expression in CRC and its impact on patient prognosis and tumor immune microenvironment using public databases.HK2 expression was also examined in 8 CRC and paired adjacent tissues using immunohistochemistry,Western blotting and RT-qPCR.In cultured CRC cell lines CT26 and HCT116 with low HK2 expression,the effects of lentivirus-mediated HK2 overexpression and JAK/STAT3 inhibitors on cell proliferation,migration,and invasion were assessed using CCK-8 assay,colony formation assay and Transwell assay and in a subcutaneous tumor-bearing mouse model;the changes were also observed in MC38 and CACO2 cells with high HK2 expressions following treatment with HK2 inhibitor 3-BP.Western blotting was performed to verify the relationship between HK2 and JAK/STAT signaling pathway protein expressions.Results Informatics analyses suggested that HK2 expression was significantly higher in CRC tissues than in adjacent tissues(P<0.001),and patients with high HK2 expressions had worse prognosis(P=0.09).In the 8 clinical CRC tissues,HK2 expressions were significantly higher in the tumor tissues than in the adjacent tissues(P<0.01).In CT26 and HCT116 cells,HK2 overexpression significantly enhanced cell proliferation,migration and invasion,while in HK2-overexpressing MC38 and CACO2 cells,inhibiting HK2 with 3-BP strongly suppressed these changes.HK2 overexpression promoted STAT3 phosphorylation,and JAK/STAT3 inhibitors effectively suppressed tumor cell proliferation,migration and invasion.TIMER and MCPcounter analyses indicated correlations between HK2 and immune cells,and TCGA and GEO analyses suggested significant positive correlations between HK2 and the immune checkpoints including PDCD1.Conclusion HK2 is upregulated in CRC to promote tumor cell proliferation,migration and invasion possibly by activating the JAK-STAT signaling pathway and modulating tumor immune microenvironment.
Keywords：colorectal cancerhexokinase 2JAK-STAT signaling pathwayproliferationmigration and invasionimmune microenvironment
Publication Date：2025-03-20
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：12( 542-553 )