甘氨酸联合β-烯通过IL6/JAK2/STAT3信号通路抑制M2巨噬细胞极化以抑制癌症三阴性进展

摘要(中文译文)

三阴性乳腺癌（TNBC）是一种侵袭性强、预后差的亚型，与肿瘤免疫微环境失衡密切相关。肿瘤相关巨噬细胞（TAMs）在肿瘤进展中发挥关键作用。本研究旨在探讨甘氨酸联合β-榄香烯是否通过IL-6/JAK2/STAT3通路抑制M2型巨噬细胞极化，从而抑制TNBC进展。采用UPLC-Q-Exactive HRMS对甘氨酸和β-榄香烯进行鉴定。体外实验中，采用CCK-8法检测4T1细胞活力。将RAW264.7细胞极化为M2型巨噬细胞并与4T1细胞共培养。进行集落形成实验、划痕愈合实验和Transwell实验。采用Western blot和免疫组化检测蛋白表达。体外实验至少进行三次独立生物学重复。体内实验中，建立4T1异种移植小鼠模型（每组n=10）以评估抗肿瘤疗效。甘氨酸联合β-榄香烯显著抑制4T1细胞的增殖、集落形成和迁移。机制上，该联合用药通过下调IL-6、p-JAK2和p-STAT3抑制M2型巨噬细胞极化。体内实验中，该联合用药联合紫杉醇显示出最强的抗肿瘤效果，肿瘤体积和重量减小，Ki-67表达降低，M2型极化受到抑制。甘氨酸联合β-榄香烯通过抑制IL-6/JAK2/STAT3通路抑制M2型巨噬细胞极化，从而发挥抗TNBC作用。其与紫杉醇联合应用显示出协同抗肿瘤疗效。

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, closely associated with an imbalanced tumor immune microenvironment. Tumor-associated macrophages (TAMs) play a crucial role in tumor progression. This study aimed to investigate whether glycine combined with β-elemene inhibits TNBC progression by suppressing M2 macrophage polarization through the IL-6/JAK2/STAT3 pathway. UPLC-Q-Exactive HRMS was used to identify glycine and β-elemene. In vitro, 4T1 cell viability was determined by CCK-8 assay. RAW264.7 cells were polarized to M2 macrophages and co-cultured with 4T1 cells. Colony formation, wound healing, and Transwell assays were performed. Western blot and immunohistochemistry were used to detect protein expression. In vitro experiments were performed with at least three independent biological replicates. In vivo, 4T1 xenograft mouse models were established (n=10 per group) to evaluate anti-tumor efficacy. Glycine combined with β-elemene significantly suppressed proliferation, colony formation, and migration of 4T1 cells. Mechanistically, the combination inhibited M2 macrophage polarization by downregulating IL-6, p-JAK2, and p-STAT3. In vivo, the combination with paclitaxel showed the strongest anti-tumor effect, with reduced tumor volume and weight, decreased Ki-67 expression, and suppressed M2 polarization. Glycine combined with β-elemene inhibits M2 macrophage polarization by suppressing the IL-6/JAK2/STAT3 pathway, thereby exerting anti-TNBC effects. Its combination with paclitaxel demonstrates synergistic anti-tumor efficacy.

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