GSTP1调控肿瘤相关巨噬细胞在乳腺癌耐药中的作用及机制研究

The resistance of breast cancer cells to chemotherapeutic drugs is the main cause of chemotherapy failure. Glutathione S-transferase P1 (GSTP1) expression is increased during drug resistance in breast cancer cells. However, the relationship between GSTP1 and breast cancer cell resistance is still unclear. Tumor-associated macrophages (TAMs) in the tumor microenvironment can promote tumor cell resistance by secreting IL-6. Our previous studies showed that GSTP1 increased autophagy to promote breast cancer cell resistance, regulate hepatocyte IGF-1 release, and regulate macrophage HMGB1 release. It suggests that GSTP1 may affect breast cancer resistance by regulating the release of cytokines. This study is to investigate the regulation of IL-6 release in TAMs by GSTP1; the effect of GSTP1 on ADR resistance in breast cancer; The regulation of GSTP1 expression in breast cancer cells by TAMs released IL-6 and the effect of enhanced GSTP1 protein on MCF-7 drug resistance; Verification of the effects of TAMs released IL-6 on MCF-7 drug-resistance in vivo. This study correlates GSTP1 with TAMs and tumor resistance, allowing us to understand the role of GSTP1 in ADR resistance in breast cancer cells from a new perspective.

乳腺癌细胞对化疗药物产生耐药性是造成化疗失败的主要原因。乳腺癌细胞耐药过程中谷胱甘肽S-转移酶P1（GSTP1）表达增加。但是目前GSTP1与乳腺癌细胞耐药的关系尚未明确。肿瘤微环境中的肿瘤相关巨噬细胞（TAMs）可通过分泌细胞因子促进肿瘤细胞耐药。前期研究表明：GSTP1提高自噬促进乳腺癌细胞耐药、调控肝细胞IGF-1的释放、调控巨噬细胞HMGB1的释放。提示GSTP1可能通过调控细胞因子释放等方式影响乳腺癌耐药。本课题拟研究：GSTP1调控TAMs中IL-6表达释放及具体机制；GSTP1调控TAMs对乳腺癌ADR耐受的影响；TAMs释放的IL-6对乳腺癌细胞中GSTP1表达的调控及表达增加的GSTP1对MCF-7耐药的影响；在体验证TAMs释放的IL-6对MCF-7耐药的作用。本研究将GSTP1与TAMs及肿瘤耐药相关联，使我们从全新角度认识GSTP1在乳腺癌细胞ADR耐受中的作用。

谷胱甘肽s -转移酶P1 (GSTP1)是一种在多种肿瘤细胞中过表达的II期解毒酶，在乳腺癌耐药过程中发挥重要作用。肿瘤相关巨噬细胞(Tumor-associated macrophages, TAMs)，代表实体肿瘤中大部分的白细胞群，参与癌细胞对化疗的耐受性。虽然GSTP1存在于TAMs中，但GSTP1在TAMs中是否促进耐药性尚不清楚。在目前的研究中，我们发现了一种新的机制，即TAMs中的GSTP1有助于乳腺癌细胞耐药。GSTP1在化疗后乳腺癌组织的TAMs中比未化疗时异常表达。阿霉素(Adriamycin, ADR)时间依赖性地诱导TAMs中GSTP1的表达。TAMs条件培养基显著抑制ADR诱导的MCF-7乳腺癌细胞死亡。同时，在TAMs中过表达GSTP1促进白细胞介素-6 (Interleukin-6, IL-6)的表达和释放，而这与ADR诱导的乳腺细胞死亡相关，使用IL-6中和抗体可逆转这一变化。GSTP1在机制上与核因子κB激酶β抑制剂(Inhibitor of nuclear factor kappa-B kinase subunit beta, IKKβ)相互作用，激活核因子-κB (nuclear factor kappa-B, NF-κB)，诱导IL-6在TAMs中的表达和释放。IL-6通过c-Jun进一步上调GSTP1，最终介导MCF-7细胞耐药。本项目研究证明了TAMs中的GSTP1通过调节IL-6的释放来促进乳腺癌对ADR耐药。