莪术醇通过JAK2/STAT3信号通路抑制非小细胞肺癌增殖和转移机制OA

Objective:To investigate the inhibitory effects of curcumol(Cur)on the proliferation and metastasis of non-small cell lung cancer(NSCLC)cells and to explore the underlying mechanisms.Methods:In vivo,a subcutaneous tumor xenograft model was established to evaluate the antiproliferative effect of Cur.In vitro,the cell counting kit-8(CCK-8)assay was used to assess the effects of Cur at concentrations of 0,60,120,240,360,480,600,720,840,960 μmol·L-1 on the viability of NCI-A549 and NCI-H23 cells,and to evaluate its inhibitory effect on the proliferation of human bronchial epithelial BEAS-2B cells.Wound healing and Transwell migration assays were conducted to assess changes in cell migratory capacity following Cur treatment.Immunohistochemistry(IHC-P)was used to investigate the regulatory effect of Cur on the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway in tumor tissues.Western blot was performed to determine the protein expression levels of phosphorylated JAK2(p-JAK2),phosphorylated STAT3(p-STAT3),proliferating cell nuclear antigen(PCNA),matrix metalloproteinase-2(MMP-2),matrix metalloproteinase-9(MMP-9),and vascular endothelial growth factor A(VEGFA)in tumor tissues and cells.To further verify the role of the JAK2/STAT3 signaling pathway in the pharmacological effects of Cur,rescue experiments were performed using the pathway agonist colivelin.Results:In vivo experiments showed that,compared with the model group,the tumor volumes of subcutaneous xenografts in nude mice in both low-and high-dose Cur groups were significantly reduced(P＜0.05),and the tumor inhibition rates were significantly increased(P＜0.05).The inhibitory effect in the high-dose group was comparable to that of the cisplatin group,and the body weight of mice in the Cur groups remained stable throughout the experiment.In vitro,compared with the control group,Cur at concentrations of 120 and 240 μmol·L-1 inhibited the proliferation of NCI-A549 and NCI-H23 cells in a concentration-dependent manner(P＜0.05),with a significant inhibitory effect observed at 360 μmol·L-1(P＜0.01),while no significant effect on the viability of BEAS-2B cells was observed.Migration assays demonstrated that,compared with the control group,Cur treatment significantly reduced the migration rates of both cell lines in a concentration-dependent manner(P＜0.05),with an inhibitory effect at 360 μmol·L-1 comparable to that of the cisplatin group.Mechanistic validation showed that,compared with the control group,the protein expression levels of p-JAK2 and p-STAT3 in tumor tissues and cells were significantly downregulated in the Cur groups(P＜0.01),and the expression levels of downstream proteins PCNA,MMP-2,MMP-9,and VEGFA were also significantly decreased with increasing Cur concentration(P＜0.05).In the rescue experiments,compared with the control group,colivelin pretreatment increased cell proliferation and migration rates(P＜0.05)and upregulated the expression of related proteins(P＜0.05).Compared with the Cur group,the colivelin+Cur group showed significantly increased proliferation and migration rates(P＜0.05),along with significantly upregulated protein expression levels(P＜0.05).Conclusion:Cur can significantly inhibit the proliferation and metastasis of NSCLC both in vivo and in vitro,and its mechanism of action is closely associated with the inhibition of JAK2/STAT3 signaling pathway activation.