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[1]刘俊汝,郁春艳,郑小燕,等.富脂微环境通过PPARγ/ABCG2途径促进三阴性乳腺癌细胞的多药耐药[J].天津医科大学学报,2023,29(03):280.
　LIU Jun-ru,YU Chun-yan,ZHENG Xiao-yan,et al.The adipocyte-rich microenvironment promotes multidrug resistance in triple-negative breast cancer cells via the PPARγ/ABCG2 pathway[J].Journal of Tianjin Medical University,2023,29(03):280.
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富脂微环境通过PPARγ/ABCG2途径促进三阴性乳腺癌细胞的多药耐药(PDF)
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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:
29卷
期数:
2023年03期
页码:
280
栏目:
临床医学
出版日期:
2023-05-20

文章信息/Info

Title:
The adipocyte-rich microenvironment promotes multidrug resistance in triple-negative breast cancer cells via the PPARγ/ABCG2 pathway
文章编号:
1006－8147（2023）03-0280-08
作者:
刘俊汝; 郁春艳; 郑小燕; 刘子璇; 陈思琦; 邓为民
（天津医科大学基础医学院免疫学系，国家教育部免疫微环境与疾病重点实验室，天津 300070）
Author(s):
LIU Jun-ru;  YU Chun-yan;  ZHENG Xiao-yan; LIU Zi-xuan; CHEN Si-qi; DENG Wei-min
（Department of Immunology，School of Basic Medical Sciences，Tianjin Medical University，Key Laboratory of Diseases and Microenvironment of Ministry of Education of China， Tianjin 300070， China ）
关键词:
HATES; 三阴性乳腺癌; 多药耐药; PPARγ; ABCG2
Keywords:
HATES; triple-negative breast cancer; multidrug resistance; PPARγ; ABCG2
分类号:
R737.31
DOI:
-
文献标志码:
A
摘要:
目的：探讨富脂微环境（ARM）对三阴性乳腺癌（TNBC）细胞多药耐药（MDR）的影响及机制。方法：选择MDA-MB-231细胞作为研究模型，应用CCK-8检测过氧化物酶体增殖物激活受体（PPAR）γ拮抗剂GW9662、PPARγ激动剂曲格列酮和ABC转运蛋白G家族成员2（ABCG2）抑制剂KO143在时间和剂量效应下对细胞增殖的影响。应用油红O染色检测人脂肪组织提取液（HATES）对细胞脂滴积累的影响。利用HATES模拟ARM，应用顺铂（DDP）和紫杉醇（PTX）作为化疗药物，通过细胞形态、CCK-8及流式Annexin V-PE/7-AAD双染凋亡检测HATES对MDA-MB-231细胞MDR的影响。荧光素酶报告基因检测HATES、GW9662、曲格列酮对MDA-MB-231细胞ABCG2转录活性的影响。Western印迹检测HATES、GW9662对MDA-MB-231细胞PPARγ和ABCG2蛋白表达的影响。Western印迹、CCK-8及流式Annexin V-PE/7-AAD双染凋亡检测HATES对PPARγ-siRNA 瞬时转染MDA-MB-231细胞PPARγ及ABCG2蛋白表达、化疗时细胞增殖和凋亡的影响。CCK-8及流式Annexin V-PE/7-AAD双染凋亡检测HATES、GW9662、KO143对MDA-MB-231化疗时细胞增殖和凋亡的影响。结果：25 μmol/L GW9662、25 μmol/L 曲格列酮及10 μmol/L KO143处理细胞2 h均不影响细胞增殖，在此基础上进行后续实验。应用的HATES浓度可促进MDA-MB-231细胞脂滴形成且不影响MDA-MB-231细胞的形态、增殖及凋亡（均P＞0.05），但在化疗药物存在时可促进细胞增殖并减少细胞凋亡（均P＜0.05）。HATES可提高MDA-MB-231细胞的ABCG2转录活性，而阻断PPARγ可抑制该效应（P＜0.001）。HATES促进细胞的MDR，沉默PPARγ和使用GW9662及KO143减弱HATES对MDR的影响（均P＜0.001）。结论：HATES通过PPARγ/ABCG2途径促进MDA-MB-231细胞的MDR。
Abstract:
Objective： To investigate the effect and mechanism of adipocyte-rich microenvironment（ARM） on multidrug resistance（MDR） in triple-negative breast cancer（TNBC） cell. Methods：MDA-MB-231 cells were selected as the research model to detect the time and dose effects of peroxisome proliferator-activating receptor（PPAR）γ antagonist GW9662， PPARγ agonist troglitazone and ABC transporter G family member 2（ABCG2） inhibitor KO143 on cell proliferation. Oil red O staining was used to detect the effect of human adipose tissue extract（HATES） on cell lipid droplets accumulation. The effect of HATES on MDA-MB-231 cells was detected by cell morphology， CCK-8 and flow cytometry Annexin V-PE/7-AAD double-stained apoptosis by using HATES to simulate ARM， cisplatin（DDP） and paclitaxel（PTX） as chemotherapy drugs.Effect of luciferase reporter gene detection of HATES, GW9662, troglitazone on ABCG2 transcriptional activity in MDA-MB-231 cells. Western blotting examined the effects of HATES and GW9662 on the expression of PPARγ and ABCG2 proteins in MDA-MB-231 cells. Western blotting， CCK-8 and flow cytometry Annexin V-PE/7-AAD double-chromatic apoptosis detected by HATES on the expression of PPARγ and ABCG2 proteins in PPAR γ-siRNA transient transfection of MDA-MB-231 cells， cell proliferation and apoptosis during chemotherapy. CCK-8 and flow cytometry Annexin V-PE/7-AAD double-chromatic apoptosis detected by HATES， GW9662 and KO143 on cell proliferation and apoptosis during MDA-MB-231 chemotherapy. Results：In this experiment， 25 μmol/L GW9662， 25 μmol/L Trog and 10 μmol/L KO143 treated cells did not affect cell proliferation for 2 h， and subsequent experiments were carried out on this basis. The HATES concentration applied in this experiment promoted the formation of lipid droplets in MDA-MB-231 cells without affecting the morphology， proliferation and apoptosis of MDA-MB-231 cells（all P>0.05）， but promoted cell proliferation and reduced apoptosis（all P<0.05） in the presence of chemotherapy drugs. HATES increased the ABCG2 transcriptional activity of MDA-MB-231 cells， while blocking PPARγ inhibited this effect （P<0.001）. HATES promoted MDR in cells， silenced PPARγ and used GW9662 and KO143 to attenuate the effect of HATES on MDR（all P<0.001）. Conclusion：HATES promotes MDR in MDA-MB-231 cells through the PPARγ/ABCG2 pathway.

参考文献/References:

[1] BENVENUTO M，FOCACCETTI C，IZZI V，et al. Tumor antigens heterogeneity and immune response-targeting neoantigens in breast cancer[J]. Semin Cancer Biol，2021，72：65-75.
[2] LIU Y，TENG L，FU S，et al. Highly heterogeneous-related genes of triple-negative breast cancer：potential diagnostic and prognostic biomarkers[J]. BMC Cancer，2021，21（1）：644.
[3] GE J，ZUO W，CHEN Y，et al. The advance of adjuvant treatment for triple-negative breast cancer[J]. Cancer Biol Med，2021，19（2）：187-201.
[4] DEEPAK KGK，VEMPATI R，NAGARAJU G P，et al. Tumor microenvironment：challenges and opportunities in targeting metastasis of triple negative breast cancer[J]. Pharmacol Res，2020，153：104683.
[5] LIU Y，TIRUTHANI K，WANG M，et al. Tumor-targeted gene therapy with lipid nanoparticles inhibits tumor-associated adipocytes and remodels the immunosuppressive tumor microenvironment in triple-negative breast cancer[J]. Nanoscale Horiz，2021，6（4）：319-329.
[6] CHA Y J，KOO J S. Adipokines as therapeutic targets in breast cancer treatment[J]. Expert Opin Ther Targets，2018，22（11）：941-953.
[7] LI Y，YU C，DENG W. Roles and mechanisms of adipokines in drug resistance of tumor cells[J]. Eur J Pharmacol，2021，899：174019.
[8] LIU L，WU Y，ZHANG C，et al. Cancer-associated adipocyte-derived G-Csf promotes breast cancer malignancy via STAT3 signaling[J]. J Mol Cell Biol，2020，12（9）：723-737.
[9] KATHAWALA R J，GUPTA P，JR ASHBY C R，et al. The modulation of Abc transporter-mediated multidrug resistance in cancer：a review of the past decade[J]. Drug Resist Updat，2015，18：1-17.
[10] AMAWI H，SIM H M，TIWARI A K，et al. Abc transporter-mediated multidrug-resistant cancer[J]. Adv Exp Med Biol，2019，1141：549-580.
[11] KUKAL S，GUIN D，RAWAT C，et al. Multidrug efflux transporter Abcg2：expression and regulation[J]. Cell Mol Life Sci，2021，78（21/22）：6887- 6939.
[12] MARION-LETELLIER R，SAVOYE G，GHOSH S. Fatty acids， eicosanoids and ppar gamma[J]. Eur J Pharmacol，2016，785：44-49.
[13] SZATMARI I，VAMOSI G，BRAZDA P，et al. Peroxisome proliferator-activated receptor gamma-regulated Abcg2 expression confers cytoprotection to human dendritic cells[J]. J Biol Chem，2006， 281（33）：23812-23823.
[14] LIN Y，BIRCSAK K M，GORCZYCA L，et al. Regulation of the placental bcrp transporter by ppar gamma[J]. J Biochem Mol Toxicol，2017，31（5）：10.
[15] KIM C E，PARK H Y，WON H J，et al. Repression of ppargamma reduces the Abcg2-mediated efflux activity of M2 macrophages[J]. Int J Biochem Cell Biol，2021，130：105895.
[16] NIE J，ZHANG J，WANG L，et al. Adipocytes promote cholangiocarcinoma metastasis through fatty acid binding protein 4[J]. J Exp Clin Cancer Res，2017，36（1）：183.
[17] WON K A， SPRUCK C. Triple-negative breast cancer therapy：current and future perspectives（review）[J]. Int J Oncol，2020，57（6）：1245-1261.
[18] BAI X，NI J，BERETOV J，et al. Triple-negative breast cancer therapeutic resistance：where is the achilles′ heel?[J]. Cancer Lett，2021，497：100-111.
[19] NEDELJKOVIC M，DAMJANOVIC A. Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge[J]. Cells，2019，8（9）：957.
[20] CHOI J，CHA Y J，KOO J S. Adipocyte biology in breast cancer：from silent bystander to active facilitator[J]. Prog Lipid Res，2018，69：11-20.
[21] CAO Y. Adipocyte and lipid metabolism in cancer drug resistance[J]. J Clin Invest，2019，129（8）：3006-3017.
[22] ZHANG Y K，WANG Y J，GUPTA P，et al. Multidrug resistance proteins （Mrps） and cancer therapy[J]. AAPS J，2015，17（4）：802-812.
[23] HSU H H，CHEN M C，BASKARAN R，et al. Oxaliplatin resistance in colorectal cancer cells is mediated via activation of Abcg2 to alleviate er stress induced apoptosis[J]. J Cell Physiol，2018，233（7）：5458-5467.
[24] NIEMAN K M，KENNY H A，PENICKA C V，et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[J]. Nat Med，2011，17（11）：1498-1503.
[25] ZHANG M，DI MARTINO J S，BOWMAN R L，et al. Adipocyte-derived lipids mediate melanoma progression via fatp proteins[J]. Cancer Discov，2018，8（8）：1006-1025.
[26] LV S，WANG W，WANG H，et al. Ppargamma activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway[J]. BMC Cancer，2019，19（1）：204.
[27] YUAN X，ZHANG Z，GONG K，et al. Inhibition of reactive oxygen species/extracellular signal-regulated kinases pathway by pioglitazone attenuates advanced glycation end products-induced proliferation of vascular smooth muscle cells in rats[J]. Biol Pharm Bull，2011，34（5）：618-623.
[28] FLORI E， ROSATI E， CARDINALI G， et al. The alpha-melanocyte stimulating hormone/peroxisome proliferator activated receptor-gamma pathway down-pegulates proliferation in melanoma cell lines[J]. J Exp Clin Cancer Res，2017，36（1）：142.

相似文献/References:

[1]李勇莉,赵秀兰,张宁,等.RSRC2影响三阴性乳腺癌细胞增殖迁移及侵袭的初步研究[J].天津医科大学学报,2020,26(04):313.
　LI Yong-li,ZHAO Xiu-lan,ZHANG Ning,et al.A preliminary study on the effect of RSRC2 on the proliferation, migration and invasion of triple negative breast cancer cells[J].Journal of Tianjin Medical University,2020,26(03):313.

备注/Memo

备注/Memo:
基金项目 京津冀基础研究合作专项（20JCZXJC00140）；国家自然科学基金资助项目（82273340）
作者简介 刘俊汝（1997-），女，硕士在读，研究方向：肿瘤免疫；通信作者：邓为民，E-mail：dengweimin@tmu.edu.cn。
更新日期/Last Update: 1900-01-01