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2021 Volume 46 Issue 4
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LYU Di, SHANG Yao, LI Xiao-biao, et al. Effects of Moderate Intensity Aerobic Exercise on Tumor Growth in 4T1 Breast Cancer Mice by nhibiting Excessively Activated NF-κB Pathway[J]. Journal of Southwest China Normal University(Natural Science Edition), 2021, 46(4): 53-60. doi: 10.13718/j.cnki.xsxb.2021.04.011
Citation: LYU Di, SHANG Yao, LI Xiao-biao, et al. Effects of Moderate Intensity Aerobic Exercise on Tumor Growth in 4T1 Breast Cancer Mice by nhibiting Excessively Activated NF-κB Pathway[J]. Journal of Southwest China Normal University(Natural Science Edition), 2021, 46(4): 53-60. doi: 10.13718/j.cnki.xsxb.2021.04.011
shu

Effects of Moderate Intensity Aerobic Exercise on Tumor Growth in 4T1 Breast Cancer Mice by nhibiting Excessively Activated NF-κB Pathway

  • 1.

    School of Physical Education, Southwest University, Chongqing 400715, China

  • 2.

    Chengdu Sport University, Chengdu 610041, China

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  • Corresponding author: LI Jing-wen
  • Received Date: 09/06/2020
    Available Online: 20/04/2021

  • MSC: G804.5; K737.9

  • Researches have been done to observe the effect of moderate-intensity aerobic exercise on tumor growth in orthotopically transplanted 4T1 breast cancer mouse model and to explore its related mechanism. Forty female 6-week-old Balb/C mice were randomly divided into normal control group (NC, n=10), exercise control group (NCE, n=10), tumor control group(TC, n=10) and exercise group with tumor(TCE, n=10). The mice in TC and TCE groups were inoculated with 4T1 cells. And those in the NCE and TCE groups, were given the intensity of intervention for 10m/min, 60min/time, and 5times/week and lasted 28 days. Forty-eight hours after the last exercise, mouse serum and tumors were collected, and the tumor volume and tumor weight were recorded. Serum interleukin-1β (IL-1β) and estradiol (estradiol, E2) contents were detected by ELISA method, and the expression of NF-κBP65 and IκBα proteins in mouse tumor tissues were analyzed through Western blot. Results show that, After 4 weeks of aerobic exercise intervention, the tumor volume and tumor weight of mice in the TCE group were significantly smaller than those in the TC group (p < 0.05). Compared with the TC group, IL-1β (p < 0.05) and E2 content (p < 0.01) in the TCE group were significantly reduced. Compared with the TC group, aerobic exercise intervention significantly reduced the expression of NF-κBP65 and IκBα proteins in tumor tissues of the TCE group (p < 0.01). It is concluded that intervention of moderate-intensity aerobic exercise could inhibit the growth of 4T1 breast cancer tumors. The possible mechanism is that aerobic exercise down-regulates the inflammatory factor IL-1β content, decreases the activation of IκBα protein to reduce the entry of NF-κBP65 into the nucleus, delays the occurrence of the transcription process, and thus inhibits the excessive activation of the NF-κB signaling pathway.
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  • [1] 段骄楠, 李小龙, 陈首英, 等. 女性乳腺癌危险因素研究新进展[J]. 中国妇幼保健, 2016, 31(12): 2571-2573.

    Google Scholar

    [2] CUMMINGS S R, TICE J A, BAUER S, et al. Prevention of Breast Cancer in Postmenopausal Women: Approaches to Estimating and Reducing Risk [J]. Journal of the National Cancer Institute, 2009, 101(6): 384-398. doi: 10.1093/jnci/djp018

    CrossRef Google Scholar

    [3] FRIEDENREICH C M, ORENSTEIN M R. Physical Activity and Cancer Prevention: Etiologic Evidence and Biological Mechanisms [J]. The Journal of Nutrition, 2002, 132(11 Suppl): 3456-3464.

    Google Scholar

    [4] HARRISS D J, ATKINSON G, BATTERHAM A M, et al. Lifestyle Factors and Colorectal Cancer Risk (2): a Systematic Review and Meta-analysis of Associations with Leisure-time Physical Activity[J]. Colorectal Disease, 2009, 11(7): 689-701. doi: 10.1111/j.1463-1318.2009.01767.x

    CrossRef Google Scholar

    [5] CAMPBELL K L, MCTIERNAN A, LI S S, et al. Effect of a 12-Month Exercise Intervention on the Apoptotic Regulating Proteins Bax and BCL-2 in Colon Crypts: a Randomized Controlled Trial [J]. Cancer Epidemiology, Biomarkers & Prevention, 2007, 16(9): 1767-1774.

    Google Scholar

    [6] HAWKINS V N, FOSTER-SCHUBERT K, CHUBAK J, et al. Effect of Exercise on Serum Sex Hormones in Men: a 12-Month Randomized Clinical Trial [J]. Medicine and Science in Sports and Exercise, 2008, 40(2): 223-233. doi: 10.1249/mss.0b013e31815bbba9

    CrossRef Google Scholar

    [7] BROWN J K, BYERS T, DOYLE C, et al. Nutrition and Physical Activity during and after Cancer Treatment: an American Cancer Society Guide for Informed Choices [J]. CA: a Cancer Journal for Clinicians, 2003, 53(5): 268-291. doi: 10.3322/canjclin.53.5.268

    CrossRef Google Scholar

    [8] HOLICK C N, NEWCOMB P A, TRENTHAM-DIETZ A, et al. Physical Activity and Survival after Diagnosis of Invasive Breast Cancer [J]. Cancer Epidemiology, Biomarkers & Prevention, 2008, 17(2): 379-386.

    Google Scholar

    [9] IRWIN M L, SMITH A W, MCTIERNAN A, et al. Influence of Pre- and Postdiagnosis Physical Activity on Mortality in Breast Cancer Survivors: The Health, Eating, Activity, and Lifestyle Study[J]. Journal of Clinical Oncology, 2008, 26(24): 3958-3964. doi: 10.1200/JCO.2007.15.9822

    CrossRef Google Scholar

    [10] BETOF A S, DEWHIRST M W, JONES L W, et al. Effects and Potential Mechanisms of Exercise Training on Cancer Progression: a Translational Perspective[J]. Brain Behavior and Immunity, 2013, 30: 75-87. doi: 10.1016/j.bbi.2012.05.001

    CrossRef Google Scholar

    [11] WORKMAN P, ABOAGYE E O, BALKWILL F, et al. Guidelines for the Welfare and Use of Animals in Cancer Research [J]. British Journal of Cancer, 2010, 102(11): 1555-1577. doi: 10.1038/sj.bjc.6605642

    CrossRef Google Scholar

    [12] Yanagita S, Amemiya S, Suzuki S, et al. Effects of Spontaneous and Forced Running on Activation of Hypothalamic Corticotropin-releasing Hormone Neurons in Rats[J]. Life Sciences, 2007, 80(4): 356-363. doi: 10.1016/j.lfs.2006.09.027

    CrossRef Google Scholar

    [13] 费占洋, 李凯明, 李登科, 等. 运动及运动强度对荷瘤小鼠移植肿瘤生长的影响[J]. 中国康复医学杂志, 2019, 34(8): 895-901. doi: 10.3969/j.issn.1001-1242.2019.08.004

    CrossRef Google Scholar

    [14] 王斌, 许诗雨, 刘嘉欣, 等. 黄连总生物碱联合运动通过阻滞细胞周期G1/S转换抑制原位移植4T1乳腺癌小鼠荷瘤生长的研究[J]. 中国中药杂志, 2019, 44(8): 1635-1641.

    Google Scholar

    [15] 陈薇薇, 陈嘉勤, 朱敬生, 等. PI3K/Akt/mTOR信号通路相关细胞因子在小鼠H22肝癌增殖及运动与药物干预中的差异表达[J]. 中国运动医学杂志, 2013, 32(12): 1074-1081.

    Google Scholar

    [16] 王玉. 游泳运动对结直肠癌荷瘤小鼠肿瘤生长影响的研究[J]. 成都体育学院学报, 2007, 33(6): 90-93. doi: 10.3969/j.issn.1001-9154.2007.06.025

    CrossRef Google Scholar

    [17] HOESEL B, SCHMID J A. The Complexity of NF-κB Signaling in Inflammation and Cancer [J]. Molecular Cancer, 2013, 12(1): 86. doi: 10.1186/1476-4598-12-86

    CrossRef Google Scholar

    [18] 徐林, 蒋正刚, 李宝华, 等. 小鼠乳腺癌实验动物模型中CD4+CD25+调节性T细胞的变化及意义[J]. 复旦学报(医学版), 2006, 33(6): 736-740. doi: 10.3969/j.issn.1672-8467.2006.06.006

    CrossRef Google Scholar

    [19] FERNANDO P, BONEN A, HOFFMAN-GOETZ L. Predicting Submaximal Oxygen Consumption during Treadmill Running in Mice [J]. Canadian Journal of Physiology and Pharmacology, 1993, 71(10-11): 854-857. doi: 10.1139/y93-128

    CrossRef Google Scholar

    [20] 靳肖寒. ACT001通过抑制NFκB信号通路逆转乳腺癌他莫昔芬耐药的机制研究[D]. 天津: 天津医科大学, 2018.

    Google Scholar

    [21] RASHID O M, TAKABE K. Animal Models for Exploring the Pharmacokinetics of Breast Cancer Therapies [J]. Expert Opinion on Drug Metabolism & Toxicology, 2015, 11(2): 221-230.

    Google Scholar

    [22] 李素萍, 矫玮. 运动联合紫杉醇对小鼠乳腺癌移植模型荷瘤生长影响的研究[J]. 中国体育科技, 2013, 49(5): 139-144. doi: 10.3969/j.issn.1002-9826.2013.05.021

    CrossRef Google Scholar

    [23] 朱敬生, 陈嘉勤, 陈薇薇, 等. 有氧运动联合雷氏蛛毒对小鼠H22肝肿瘤的干预研究[J]. 武汉体育学院学报, 2014, 48(1): 96-100. doi: 10.3969/j.issn.1000-520X.2014.01.019

    CrossRef Google Scholar

    [24] 沈政洁, 程海波, 沈卫星, 等. 肿瘤炎性微环境与"癌毒"病机相关性探讨[J]. 北京中医药大学学报, 2015, 38(1): 14-17. doi: 10.3969/j.issn.1006-2157.2015.01.003

    CrossRef Google Scholar

    [25] 陈小英, 曾晏萍, 刘汉儒, 等. 太子参须多糖粗提物对小鼠免疫功能的调节作用[J]. 西南大学学报(自然科学版), 2020, 42 (4): 56-64.

    Google Scholar

    [26] SHANG D, LI Z, ZHU Z, et al. Baicalein Suppresses 17-β-estradiol-induced Migration, Adhesion and Invasion of Breast Cancer Cells via the G Protein-coupled Receptor 30 Signaling Pathway[J]. Oncology Reports, 2015, 33(4): 2077-2085. doi: 10.3892/or.2015.3786

    CrossRef Google Scholar

    [27] BROLINSON P G, ELLIOTT D. Exercise and the Immune System [J]. Clinics in Sports Medicine, 2007, 26(3): 311-319. doi: 10.1016/j.csm.2007.04.011

    CrossRef Google Scholar

    [28] 王玉. 早期运动干预对二甲基苯蒽诱导大鼠乳腺癌发生影响的研究[J]. 现代预防医学, 2008, 35(14): 2728-2729. doi: 10.3969/j.issn.1003-8507.2008.14.051

    CrossRef Google Scholar

    [29] KARIN M, CAO Y, GRETEN F R, et al. NF-κB in cancer: from Innocent Bystander to Major Culprit[J]. Nature Reviews Cancer, 2002, 2(4): 301-310. doi: 10.1038/nrc780

    CrossRef Google Scholar

    [30] REMICK D G, CALL D R, EBONG S J, et al. Combination Immunotherapy with Soluble Tumor Necrosis Factor Receptors Plus Interleukin 1 Receptor Antagonist Decreases Sepsis Mortality [J]. Critical Care Medicine, 2001, 29(3): 473-481. doi: 10.1097/00003246-200103000-00001

    CrossRef Google Scholar

    [31] Silvia Gaspar Pereira, Fiona Oakley. Nuclear factor-κB1: Regulation and function[J]. International Journal of Biochemistry and Cell Biology, 2007, 40(8): 1425-1430.

    Google Scholar

    [32] SCHEIDEREIT C. IkappaB Kinase Complexes: Gateways to NF-kappaB Activation and Transcription [J]. Oncogene, 2006, 25(51): 6685-6705. doi: 10.1038/sj.onc.1209934

    CrossRef Google Scholar

    [33] SILVERMAN N, MANIATIS T. NF-kappaB Signaling Pathways in Mammalian and Insect Innate Immunity [J]. Genes & Development, 2001, 15(18): 2321-2342.

    Google Scholar

    [34] PIVA R, BELARDO G, SANTORO M G. NF-kappaB: a Stress-Regulated Switch for Cell Survival [J]. Antioxidants & Redox Signaling, 2006, 8(3-4): 478-486.

    Google Scholar

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Effects of Moderate Intensity Aerobic Exercise on Tumor Growth in 4T1 Breast Cancer Mice by nhibiting Excessively Activated NF-κB Pathway

    Corresponding author: LI Jing-wen
  • Received Date: 09/06/2020
  • Available Online: 20/04/2021

Abstract: Researches have been done to observe the effect of moderate-intensity aerobic exercise on tumor growth in orthotopically transplanted 4T1 breast cancer mouse model and to explore its related mechanism. Forty female 6-week-old Balb/C mice were randomly divided into normal control group (NC, n=10), exercise control group (NCE, n=10), tumor control group(TC, n=10) and exercise group with tumor(TCE, n=10). The mice in TC and TCE groups were inoculated with 4T1 cells. And those in the NCE and TCE groups, were given the intensity of intervention for 10m/min, 60min/time, and 5times/week and lasted 28 days. Forty-eight hours after the last exercise, mouse serum and tumors were collected, and the tumor volume and tumor weight were recorded. Serum interleukin-1β (IL-1β) and estradiol (estradiol, E2) contents were detected by ELISA method, and the expression of NF-κBP65 and IκBα proteins in mouse tumor tissues were analyzed through Western blot. Results show that, After 4 weeks of aerobic exercise intervention, the tumor volume and tumor weight of mice in the TCE group were significantly smaller than those in the TC group (p < 0.05). Compared with the TC group, IL-1β (p < 0.05) and E2 content (p < 0.01) in the TCE group were significantly reduced. Compared with the TC group, aerobic exercise intervention significantly reduced the expression of NF-κBP65 and IκBα proteins in tumor tissues of the TCE group (p < 0.01). It is concluded that intervention of moderate-intensity aerobic exercise could inhibit the growth of 4T1 breast cancer tumors. The possible mechanism is that aerobic exercise down-regulates the inflammatory factor IL-1β content, decreases the activation of IκBα protein to reduce the entry of NF-κBP65 into the nucleus, delays the occurrence of the transcription process, and thus inhibits the excessive activation of the NF-κB signaling pathway.

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  • 癌症已发展为影响人类健康的3大疾病之一，仅次于心血管病. 根据国家疾病中心数据显示，在2016年内，中国乳腺癌发病为273 000例，高居女性恶性肿瘤之首[1]，因而研究如何防治乳腺癌已成为临床医学的主要任务之一.

    流行病学调查显示，定期进行中等强度的体育锻炼与降低多种癌症的风险相关，其中包括乳腺癌、结肠癌和子宫内膜癌等[2-4]. 有规律的运动可以显著降低癌症高风险人群中的癌症危险生物标志物[5-6]，同时，有氧运动可以改善患癌后生活质量，并可使特定癌症死亡率和全因死亡率降低30%~50%[7-9]. 尽管有氧运动能够降低患癌风险和改善预后，但少有研究关注有氧运动干预对肿瘤生长的影响[10]. 有氧运动干预抑制肿瘤生长的效果受动物品系、运动方式、运动时间和强度等多种因素的影响[11-16].

    细胞凋亡是细胞基本生理活动之一，与肿瘤的发生和发展密切相关. 肿瘤“微环境”中存在的炎症因子可使NF-κB信号通路过度激活，抑制凋亡蛋白的表达，影响癌症正常细胞凋亡，进而加速肿瘤生长[17]. 因此，寻找抑制NF-κB信号通路过度激活的方法和药物成为肿瘤学研究的重要内容.

    本实验以原位移植4T1乳腺癌细胞的Balb/C小鼠为模型，研究了中等强度有氧运动对肿瘤生长的影响，并通过观察肿瘤组织内NF-κB通路关键蛋白变化进行机制探索.

1.   材料与方法

    1.1.   动物与细胞株

  • SPF级Balb/C小鼠，雌性，6~8周龄，体质量(18±2) g，购于重庆瀚东实验动物公司，动物合格证号SCXK(京)2017-0003. 小鼠饲养于西南大学药学院动物实验中心，每笼5只群养，自由饮食、饮水，室温23~24 ℃，湿度(50±10)%，人工12 h/12 h昼夜节律光照. 每2 d更换一次鼠料及清理饲养笼具. 4T1小鼠乳腺癌细胞购于中国科学院上海细胞库，根据常规贴壁细胞的方式培养.

    • 1.2.   主要仪器

  • DB030型六道动物实验跑台，北京智鼠多宝生物科技有限公司；TGL-16C台式离心机，美国Sigma公司；AJC-0501-P纯水仪，WH-2微型漩涡混合器，美国安胜；TL-420D水浴，姜堰市天利医疗设备有限公司；Rt2100c酶标检测仪，Rayto.

    • 1.3.   主要试剂

  • 1640培养基，BCA蛋白定量检测试剂盒(G2026)购于Servicebio；蛋白Marker(26616)购于Therm(Fermentas)；GAPDH (GB12002)购于Servicebio；MouseIL-1β ELISA kit(EK201B1/2)，Enzyme-linked Immunosorbent Assay Kit For Estradiol(CEA461Ge)购于武汉优尔生科技股份有限公司.

    • 1.4.   造模

  • 将4T1小鼠乳腺癌细胞放置在含有10%胎牛血清的1640培养基中，于5%-CO2，37 ℃条件培养箱中. 取对数期细胞用胰蛋白酶消化，PBS清洗并改变细胞浓度为1×106个/mL. 于小鼠右腋下皮下注射4T1乳腺癌细胞悬液0.2 mL，自然生长7 d后测量肿瘤大于2 mm×2 mm时，判断造模成功[18].

    • 1.5.   分组及运动干预方案

  • 接种前，将小鼠随机分成正常对照(NC)组10只，运动对照(NCE)组10只，模型组20只. 造模成功后，分模型运动组(TCE)与模型对照组(TC)各10只. 各组正常进食饮水，对20只NCE和TCE组小鼠进行中等强度有氧运动干预[19]. 干预方式：设置跑台速度10 m/min，0坡度，60 min/次，5次/周(周1至周5，晚间6：00-7：30)，持续28 d. 为消除噪声干扰，将NC和TC组小鼠放在跑步机旁边但不运动.

    • 1.6.   动物体质量与瘤质量检测

  • 造模成功后，每3 d记录一次小鼠体质量和瘤体积(V)，后者测量方式：分别用游标卡尺测量肿瘤长度和宽度，然后使用公式V=0.5×W2×L(W是瘤宽，L是瘤长)计算. 30 d后，将小鼠处死并收集肿瘤，称质量，做好记录并于－80 ℃条件存放.

    • 1.7.   血清内IL-1β，E2指标检测

  • 30 d后，在处死小鼠前，从眼睑取血，离心收集血清，－80 ℃条件下存放. 严格按照ELISA试剂盒步骤分别测量IL-1β和E2质量浓度.

    • 1.8.   Western blot检测小鼠瘤组织中蛋白表达

  • 用组织匀浆器和组织蛋白裂解液对小鼠肿瘤组织进行破碎，离心并收集蛋白样品. BAC法测定蛋白浓度后，进行SDS-PAGE电泳. 转膜、封闭，洗膜后加入1∶1 000稀释的一抗(NF-κBP65，IκBα，GAPDH)，4 ℃孵育过夜. TBST洗膜后加入1∶2 000稀释的HRP标记的二抗，室温孵育2 h后洗膜，ECL化学发光液显色，凝胶成像系统拍照，Image J软件进行灰度处理.

    • 1.9.   统计学处理

  • 所得数据由Spss 19.0软件中的单因素方差分析进行处理，用x±s进行表示，并用Origin 8.0软件作图.

2.   结果

    2.1.   有氧运动干预对小鼠肿瘤生长的影响

  • 运动干预结束后48 h，迅速完成取材，并将肿瘤组织拍照(部分有破损，每组取8个完整肿瘤组织来拍照). 较TC组，经有氧运动干预后TCE组小鼠肿瘤体积增长曲线更为平缓(图 1)，且体积明显变小(图 2). 结合表 1，TCE组最后1次测量的瘤体积及瘤质量均小于TC组，差异有统计学意义(p＜0.05). 由此可见，中等强度有氧运动对4T1乳腺癌肿瘤生长有显著的抑制作用.

    • 2.2.   有氧运动干预对小鼠血清IL-1β，E2指标的影响

  • 血清中E2和IL-1β质量浓度同乳腺癌的出现两者密切相关，肿瘤能够刺激机体产生炎症反应，而IL-1β是重要的炎症调节因子. 图 3显示，TC组和TCE组的IL-1β水平明显高于NC组(p＜0.01). 而与TC组相比，中等强度有氧运动干预的TCE组小鼠体内的IL-1β质量浓度明显下降了16%，并达到统计学意义(p＜0.05). 说明中等强度有氧运动干预能够明显改善4T1乳腺癌小鼠体内IL-1β质量浓度，减轻炎症反应.

    图 4显示，与NC组相比，NCE，TC，TCE组小鼠体内E2质量浓度分别下降了44%，50%，97%，差异有统计学意义(p＜0.01). 经中等强度有氧运动干预后TCE组内E2质量浓度比TC组下降了94%，差异有统计学意义(p＜0.01). E2是体内重要的雌激素，较高的表达水平会促进乳腺癌的发展，此结果表明中等强度有氧运动干预可以显著降低E2的质量浓度，从而抑制乳腺癌的发生.

    • 2.3.   中等强度有氧运动干预对小鼠肿瘤组织NF-κB信号通路相关蛋白的影响

  • 在乳腺肿瘤组织中普遍存在NF-κB激活现象，NF-κB在乳腺癌的发生、发展及转移中具有重要作用[20]，其中，NF-κBP65，IκBα蛋白可以减少NF-κB入核和抑制转录过程的发生，从而抑制NF-κB通路的过度激活. 本实验利用Western blot检测小鼠瘤组织中NF-κBP65，IκBα蛋白表达变化(图 5).

    图 6显示，TCE组小鼠肿瘤组织内NF-κBP65蛋白表达比TC组下调了34%，差异有统计学意义(p < 0.01). 结合图 7，较TC组，TCE组小鼠肿瘤组织中IκBα蛋白表达显著下调了39%，差异有统计学意义(p < 0.01). 结果表明，中等强度有氧运动干预能够显著降低NF-κBP65和IκBα蛋白表达，抑制NF-κB信号通路过度激活.

3.   讨论

  • 乳腺癌对于女性来说是最致命的恶性肿瘤之一，全球乳腺癌发病率呈现快速增长的趋势，因而探寻新的治疗手段对人类具有重要的意义.

    目前，已开发出自发性、诱发性、移植性、远处转移和转基因等乳腺癌小鼠模型用作实验研究. 4T1乳腺癌细胞形成肿瘤具有血管丰富、免疫原性低、早期就可发生远处易感器官转移等特点，其生长特性与人类乳腺癌相似度极高. 有证据表明，4T1小鼠乳腺癌细胞系移植入免疫功能正常的同品系小鼠体内，从而模拟人乳腺癌发展和转移情况，此种方法比将人乳腺癌细胞系(异种移植物)移植入免疫功能缺陷小鼠体内来观察肿瘤发展和转移情况更加有效，并得到了广泛认可[21]. 因此，本研究采用4T1细胞原位移植模型，于小鼠右腋下皮下注射4T1乳腺癌细胞悬液0.2 mL，所有小鼠在7 d后均检测到肿瘤体积大于2 mm×2 mm，显示此次实验造模成功.

    有氧运动干预可以显著降低多种乳腺癌的患病风险、改善生活质量，但有氧运动干预对乳腺癌成瘤后的影响研究相对较少，且效果并不明显，其可能与单次有氧运动干预时间相关. 王斌等的研究发现经30 min/次单纯有氧运动干预后原位接种4T1细胞的Balb/C小鼠其荷瘤体积反而较大[14]. 李素萍等采用了17 m/min，30 min/次的有氧运动干预对乳腺癌小鼠体内乳腺癌细胞的作用并不明显，而是通过促进小鼠对紫杉醇的吸收从而抑制肿瘤生长[22]. 而在几项运动联合药物干预研究中，其运动干预时间均为60 min，可抑制乳腺癌肿瘤的生长[15, 23]. 因此，我们将有氧运动方案设置为10 m/min，60 min/次，5次/周，共干预4周，结果能明显抑制乳腺癌小鼠肿瘤的生长.

    瘤体积、瘤质量能够较好地反应4T1细胞原位移植乳腺癌模型小鼠肿瘤的生长情况. 至实验结束，TC组，TCE组平均瘤质量分别为1.69 g和0.98 g，显示有氧运动干预显著降低了瘤质量. 同时，根据最后瘤体积和生长曲线，中等强度有氧运动显著抑制了肿瘤的生长，且观察到TCE组小鼠精神状态明显好于TC组. 出于伦理道德和成本的考虑，本项实验有氧运动干预共进行了4周，未能进一步探讨各组小鼠最终存活时间，后续还需进一步实验.

    现代研究发现炎症参与了恶性肿瘤的发生、发展和转移的全过程，被称为恶性肿瘤的第七大生物学特征[24]. 体内高水平的IL-1β被证实能够促进乳腺癌的发生发展[25]. 本项研究中，TC，TCE组相较于NC，NCE组，小鼠血清IL-1β质量浓度显著上升，说明接种4T1乳腺癌形成肿瘤的过程中出现了炎症反应，而有氧运动具有降低IL-1β的作用，减轻小鼠体内的炎症反应，改善肿瘤“微环境”，一定程度上可以遏制肿瘤细胞的恶性增殖.

    内源、外源性雌激素质量浓度增多也会导致患乳腺癌风险增大，同乳腺癌相联系的各种危险因子均同雌激素有着一定关系且大多通过性激素有关路径产生影响. 雌二醇(E2)作为女性体内的重要性激素，病理条件下，将会导致乳腺癌细胞激增、转移、入侵等一系列行为的产生[26]. 人体和动物实验均显示，有氧运动干预可以降低E2质量浓度[27-28]. 本研究中，运动组相较于对照组，其E2质量浓度均出现了明显下降，表明无论是在正常小鼠或是乳腺癌模型小鼠中，有氧运动干预均可降低E2质量浓度，也支持了有氧运动可以降低患癌风险和抑制肿瘤生长的作用.

    细胞凋亡是细胞基本生理活动之一，与肿瘤的发生和发展密切相关. 肿瘤的生长与细胞增殖速度和凋亡速度两方面相关，凋亡过程受抑则会导致细胞的过度生长，从而促进肿瘤细胞群体的生存和扩增. 因此，如何促进细胞凋亡途径诱导细胞死亡成为肿瘤研究的重要方面. NF-κB信号通路在肿瘤细胞抗凋亡中至关重要，抑制NF-κB信号通路过度激活可以调控凋亡蛋白的表达[29]. NF-κB是在B淋巴细胞中发现的一种转录因子，参与免疫与炎症反应相关的基因调控. NF-κB的过度激活可以促进肿瘤细胞增殖，抑制肿瘤细胞凋亡，促进肿瘤血管生成，提高肿瘤转移力，因此在肿瘤的发生发展中起着重要作用，其中P65∶P50 (NF-κB)组成的异二聚体起着主要的调控作用[30-31]. NF-κB过度激活可上调c-IAP，c-FLIP以及Bcl-2家族蛋白Bcl-x L等凋亡抑制因子的表达，从而拮抗细胞的凋亡. 同时，NF-κB可以激活具有抑制细胞死亡能力的基因的转录，表明了NF-κB与细胞的凋亡呈现敌对状态. 本研究中，模型组小鼠体内IL-1β质量浓度增加，出现了明显的炎症反应，受IL-1β等炎症因子刺激，抑制蛋白IκBα从在细胞质中的NF-κB与IκBα结合的三聚体复合物中解离出来，磷酸化并降解，从而释放NF-κBP65，使其得以转位进入细胞核中，与核内DNA上的特异序列相结合，从而启动或增强相关基因的转录[32-34].

4.   结论

  • 中等强度有氧运动干预能够抑制4T1乳腺癌肿瘤的生长，其机制可能与有氧运动降低炎症因子IL-1β，减少IκBα蛋白的激活以降低NF-κBP65入核，抑制转录过程的发生，从而抑制NF-κB信号通路过度激活有关.

Figure (7)  Table (1) Reference (34)

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