Lee Hwan Hee, Kim Juhui, Park Eunbi, Kang Hyojeung, Cho Hyosun
College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.
Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.
Int J Mol Sci. 2025 May 20;26(10):4900. doi: 10.3390/ijms26104900.
Hypoxia, a low-oxygen state, is a common feature of solid tumors. MCP1 (CCL2) is a small cytokine that is closely related to hypoxia and has a positive effect on tumor development. Hypoxia causes resistance to various treatments for solid tumors and the evasion of cancer immune surveillance by lymphocytes. Natural killer (NK) cells are innate lymphocytes that play an important role in cancer development, particularly in the liver. First, it was found that the incubation of HCC in hypoxia (2-5% O) significantly increased the production of several inflammatory cytokines, including MCP1, compared to that of normal oxygen (20% O). Subsequently, blocking MCP1 with an anti-MCP1 antibody in HCC cultures inhibited the growth and migration of HCC cells in vitro and in vivo. This was associated with a decrease in the expression of HIF-1α/STAT3 in HCC under hypoxia. Furthermore, blocking MCP1 in HCC cell cultures under hypoxia significantly increased the chemotaxis and activation of NK-92 cells against HCC cells. MCP1 blockade in HCC cell cultures under hypoxia induced a shift in NK cells to the CD56 population and an increase in the expression of the activation receptors NKG2D and NKp44. In conclusion, modulation of MCP1 could enhance NK activity against hypoxic HCC cells.
缺氧，即低氧状态，是实体瘤的一个常见特征。单核细胞趋化蛋白1（MCP1，即CCL2）是一种与缺氧密切相关的小细胞因子，对肿瘤发展具有积极作用。缺氧会导致实体瘤对各种治疗产生抗性，并使淋巴细胞逃避癌症免疫监视。自然杀伤（NK）细胞是先天性淋巴细胞，在癌症发展中发挥重要作用，尤其是在肝癌中。首先，研究发现，与常氧（20%O₂）条件下培养的肝癌细胞相比，在缺氧（2-5%O₂）条件下培养肝癌细胞，几种炎性细胞因子（包括MCP1）的产生显著增加。随后，在肝癌细胞培养物中用抗MCP1抗体阻断MCP1，可在体外和体内抑制肝癌细胞的生长和迁移。这与缺氧条件下肝癌细胞中缺氧诱导因子-1α（HIF-1α）/信号转导和转录激活因子3（STAT3）表达的降低有关。此外，在缺氧条件下的肝癌细胞培养物中阻断MCP1，可显著增加NK-92细胞对肝癌细胞的趋化性和激活作用。在缺氧条件下的肝癌细胞培养物中阻断MCP1，可使NK细胞向CD56群体转变，并增加激活受体NKG2D和NKp44的表达。总之，调节MCP1可增强NK细胞对缺氧肝癌细胞的活性。
