[1]陈建丽,张永喜,马国靖,等.乳腺癌组织中Notch1、Pim1及信号转导和转录激活因子3表达与患者生存的关系[J].新乡医学院学报,2021,38(8):751-756.[doi:10.7683/xxyxyxb.2021.08.011]
　CHEN Jianli,ZHANG Yongxi,MA Guojing,et al.Correlation between the expression of Notch1,Pim1 and signal transducer and activator of transcription 3 in breast cancer tissues and survival of patients[J].Journal of Xinxiang Medical University,2021,38(8):751-756.[doi:10.7683/xxyxyxb.2021.08.011]
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乳腺癌组织中Notch1、Pim1及信号转导和转录激活因子3表达与患者生存的关系
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《新乡医学院学报》[ISSN:1004-7239/CN:41-1186/R]

卷:
38
期数:
2021年8
页码:
751-756
栏目:
临床研究
出版日期:
2021-08-05

文章信息/Info

Title:
Correlation between the expression of Notch1,Pim1 and signal transducer and activator of transcription 3 in breast cancer tissues and survival of patients
作者:
陈建丽1; 张永喜1; 马国靖1; 吴　华2; 陈晓文2; 陈余英3; 蒋宇杰4
（1.新乡医学院第三附属医院肿瘤内三科，河南　新乡　453003；2.广东医科大学附属医院肿瘤中心，广东　湛江　524000；3.广东医科大学附属第二医院肿瘤科，广东　湛江　524000；4.广东农垦中心医院检验科，广东　湛江　524000）
Author(s):
CHEN Jianli1; ZHANG Yongxi1; MA Guojing1; WU Hua2; CHEN Xiaowen2; CHEN Yuying3; JIANG Yujie4
(1.Department of Oncology,the Third Affiliated Hospital of Xinxiang Medical University,Xinxiang 453003,Henan Province,China2.Oncology Center,Affiliated Hospital of Guangdong Medical University,Zhanjiang 524000,Guangdong Province,China3.Department of Oncology,the Second Affiliated Hospital of Guangdong Medical University,Zhanjiang 524000,Guangdong Province,China4.Department of Laboratory Medicine,Guangdong Agricultural Reclamation Central Hospital,Zhanjiang 524000,Guangdong Province,China)
关键词:
Notch1; 信号转导和转录激活因子3; Pim1; 乳腺癌; 生存
Keywords:
Notch1signal transducer and activator of transcription 3Pim1breast cancersurvival
分类号:
R737.9
DOI:
10.7683/xxyxyxb.2021.08.011
文献标志码:
A
摘要:
目的　探讨乳腺癌组织中Notch1、Pim1及信号转导和转录激活因子3（STAT3）表达与临床病理资料及预后的关系。方法　选择2013年1月至2014年12月新乡医学院第三附属医院和广东医科大学附属医院收治的80例乳腺癌患者为研究对象。通过患者病历资料和原始病理报告收集可能影响乳腺癌进展及预后的临床和病理学参数，包括年龄、组织学分级、淋巴结转移、TNM分期、雌激素受体（ER）状态、孕激素受体（PR）状态、人表皮生长因子受体2（HER2）状态以及辅助治疗方法。采用免疫组织化学染色法检测乳腺癌组织和癌旁组织中Notch1、STAT3和Pim1蛋白表达水平。采用Spearman等级相关分析乳腺癌组织中Notch1、STAT3与Pim1蛋白表达的相关性，采用Kaplan-Meier法分析Pim1、Notch1、STAT3蛋白表达水平与乳腺癌患者生存期的关系，采用Cox回归分析临床病理特征及Notch1、Pim1和STAT3表达对生存期的影响。结果　Notch1和STAT3蛋白主要表达于细胞质中，Pim1蛋白主要表达于细胞核和（或）细胞质中；乳腺癌组织中 Notch1、STAT3和Pim1蛋白高表达率均显著高于低表达率（P<0.05）；癌旁组织中Notch1、STAT3和Pim1蛋白高表达率均显著低于低表达率（P<0.05）；乳腺癌组织中Notch1、STAT3和Pim1高表达率显著高于癌旁组织（P<0.05）。乳腺癌组织中STAT3蛋白表达水平与患者是否发生淋巴结转移有关（P<0.05）；乳腺癌组织中Notch1、STAT3、Pim1蛋白表达水平与患者的ER状态有关（P<0.05）；乳腺癌组织中Notch1、STAT3、Pim1蛋白表达水平与患者的年龄、TNM分期、组织学分级、PR状态、HER2状态、辅助治疗方法无关（P>0.05）；乳腺癌组织中Notch1、Pim1表达水平与患者是否发生淋巴结转移无关（P>0.05）。乳腺癌组织中Notch1与Pim1、STAT3与Pim1、Notch1与Pim1蛋白表达水平均呈显著正相关（P<0.05）。Pim1高表达和低表达患者的中位生存期分别为61、62个月，Notch1高表达和低表达患者的中位生存期分别为58、61个月，STAT3高表达和低表达患者的中位生存期分别为57、70个月；Pim1、Notch1高表达与低表达患者的中位生存期比较差异无统计学意义（P＞0.05），STAT3高表达患者的中位生存期显著低于STAT3低表达患者（P<0.05）。Cox多因素回归分析显示，年龄、组织学分级、TNM分期、淋巴结状态、ER、PR、Her-2状态及Notch1、Pim1、 STAT3蛋白表达水平与乳腺癌患者的生存期无相关性（P＞0.05）。结论　Pim1与Notch1在乳腺癌发生及发展的过程中存在协同的促进作用，ER及STAT3可能是二者间发生关联的关键因子。Notch1、STAT3和Pim1联合检测在长期评估乳腺癌患者生存中的预测价值得关注。
Abstract:
Objective　To investigate the relationship between the expression of Notch1,Pim1 and signal transducer and activator of transcription 3 (STAT3) and clinicopathological data and prognosis in breast cancer tissues. Methods　Eighty breast cancer patients admitted to the Third Affiliated Hospital of Xinxiang Medical University and the Affiliated Hospital of Guangdong Medical University from January 2013 to December 2014 were selected as the research objects.Clinical and pathological parameters that might affect breast cancer progression and prognosis were collected through patient medical records and original pathology reports,including age,histological grade,lymph node metastasis,TNM staging,estrogen receptor (ER) status,progesterone receptor body (PR) status,human epidermal growth factor receptor 2 (HER2) status and methods of adjuvant therapy.The expression levels of Notch1,STAT3 and Pim1 protein in breast cancer tissues and paracancerous tissues were detected by immunohistochemical staining.The correlation of Notch1,STAT3 and Pim1 protein expression in breast cancer tissues was analyzed by Spearman rank correlation.The relationship between the expression levels of Pim1,Notch1,STAT3 protein and the survival time of patients was analyzed by the Kaplan-Meier method.The effect of clinical pathological characteristics and the influence of Notch1,Pim1 and STAT3 expression on survival was analyzed by Cox regression.Results　Notch1 and STAT3 protein were mainly expressed in the cytoplasm,and Pim1 protein was mainly expressed in the nucleus and/or cytoplasm.In breast cancer tissues,the high expression rates of Notch1,STAT3 and Pim1 protein were significantly higher than the low expression rates (P<0.05)in paracancerous tissues,the high expression rates of Notch1,STAT3 and Pim1 protein were significantly lower than the low expression rates (P<0.05)the high expression rates of Notch1,STAT3 and Pim1 protein in breast cancer tissues were significantly higher than those in adjacent tissues (P<0.05).The expression level of STAT3 in breast cancer tissue was related to whether the patient had lymph node metastasis (P<0.05)the expression level of Notch1,STAT3 and Pim1 protein in breast cancer tissue was related to the patient′s ER status (P<0.05)the expression levels of Notch1,STAT3 and Pim1 protein in breast cancer tissues had no relationship with the patient′s age,TNM stage,histological grade,PR status,HER2 status and adjuvant treatment methods (P>0.05)the expression level of Notch1 and Pim1 protein in breast cancer tissue had relationship with whether the patient had lymph node metastasis (P>0.05).There were positively correlations between the expression levels of Notch1 and Pim1,STAT3 and Pim1,Notch1 and Pim1 in breast cancer tissues (P<0.05).The median survival periods of patients with high and low expression of Pim1 were 61,62 months,respectivelythe median survival periods of patients with high and low expression of Notch1 were 58,61 months,respectivelythe median survival periods of patients with high and low expression of STAT3 were 57,70 months,respectively.There was no significant difference in median survival periods between patients with high and low expression of Pim1 and Notch1 (P>0.05)the median survival periods of patients with high STAT3 expression was significantly lower than that of patients with low STAT3 expression (P<0.05).Cox multivariate regression analysis showed that age,histological grade,TNM staging,lymph node status,ER,PR,HER2 status and Notch1,Pim1,STAT3 protein expression levels were not correlated with the survival periods of breast cancer patients (P>0.05).Conclusion　Pim1 and Notch1 have a synergistic effect on the occurrence and development of breast cancer.ER and STAT3 may be the key factors in the relationship between Pim1 and Notch1.The predictive value of the combined detection of Notch1,STAT3 and Pim1 in the long-term assessment of the prognosis of breast cancer patients is worthy of attention.

参考文献/References:

［1］　DONG X B,JI C Y,MA D X,et al.Notch signaling in human breast cancer［J］.Chin J Oncol,2007,29(6):425-428.
［2］　WEIJZEN S,RIZZO P,BRAID M,et al.Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells［J］.Nat Med,2002,8(9):979-986.
［3］　SPEISER J,FOREMAN K,DRINKA E,et al.Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer［J］.Int J Surg Pathol,2012,20(2):139-145
［4］　SUMAN S,DAS T P,DAMODARAN C.Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells［J］.Br J Cancer,2013,109(10):2587-2596.
［5］　JIMNEZ-GARCA M P,LUCENA-CACACE A,ROBLES-FRíAS M J,et al.Inflammation and stem markers association to PIM1/PIM2 kinase-induced tumors in breast and uterus［J］.Oncotarget,2017,8(35)：58872-58886.
［6］　BANERJEE K,RESAT H.Constitutive activation of STAT3 in breast cancer cells:a review［J］.Int J Cancer,2016,138(11):2570-2578.
［7］　ZHANG X,ZHAO X,SHAO S,et al.Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role［J］.Int J Oncol,2015,46(3):1141-1148.
［8］　PENG D,TANIKAWA T,LI W,et al.Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling［J］.Cancer Res,2016,76(11):3156-3165.
［9］　BLANCO-APARICIO C,CARNERO A.Pim kinases in cancer:diagnostic,prognostic and treatment opportunities［J］.Biochem Pharmacol,2013,85(5):629-643.
［10］　BELLON M,LU L,NICOT C.Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia［J］.Blood,2016,127(20):2439-2450.
［11］　XIE Y,XU K,DAI B,et al.The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX andprotects human prostate cancer cells from apoptosis induced by chemotherapeuticdrugs［J］.Oncogene,2016,25(1):70-78.
［12］　WU M,WEI W,XIAO X,et al.Expression of SIRT1 is associated with lymph node metastasis and poor prognosis in both operable triple-negative and non-triple-negative breast cancer［J］.Med Oncol,2012,29(5):3240-3249.
［13］　DIVART A,BEAULIEU N,JOLICOEUR P,et al.Involvement of Notch1 in the development of mouse mammary tumors［J］.Oncogene,1999,18(44):5973-5981.
［14］　YUAN X,ZHANG M,WU H,et al.Expression of Notch1 correlates with breast cancer progression and prognosis［J］.PLoS One,2015,10(6):e0131689.
［15］　MA D,DONG X,ZANG S,et al.Aberrant expression and clinical correlation of Notch signaling mole-cules in breast cancer of Chinese population［J］.Asia Pac J Clin Oncol,2011,7(4):385-391.
［16］　NATARAJAN K,BHULLAR J,SHUKLA S,et al.The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms［J］.Biochem Pharmacol,2013,85(4):514-524.
［17］　MOODY S E,SCHINZEL A C,SINGH S,et al.PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling［J］.Oncogene,2015,34(16):2061-2071.
［18］　ZHANG G,LIU Z,CUI G,et al.MicroRNA-486-5p targeting PIM-1 suppresses cell proliferation in breast cancer cells［J］.Tumour Biol,2014,35(11):11137-11145.
［19］　ZHAO W,QIU R,LI P,et al.PIM1:a promising target in patients with triple-negative breast cancer［J］.Med Oncol,2017,34(8):142.
［20］　SANTIO N M,LANDOR S K,VAHTERA L,et al.Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells［J］.Oncotarget,2016,7(28):43220-43238.
［21］　HAO L,RIZZO P,OSIPO C,et al.Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells［J］.Oncogene,2010,29(2):201-213.
［22］　SOARES R,BALOGH G,GUO S,et al.Evidence for the notch signaling pathway on the role of estrogen in angiogenesis［J］.Mol Endocrinol,2004,18(9):2333-2343.
［23］　MALINEN M,JSKELINEN T,PELKONEN M,et al.Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors［J］.Mol Cell Endocrinol,2013,365(2):270-276.

相似文献/References:

[1]张松峰,王永玲.Notch1 在胃癌组织中的表达及意义 [J].新乡医学院学报,2012,29(10):754.

更新日期/Last Update: 2021-08-05