致癌蛋白CIP2A在乳腺导管上皮恶变中的作用及预测浸润性导管癌患者预后的能力

doi:10.6040/j.issn.1671-7554.0.2016.1471

山东大学学报（医学版） ›› 2017, Vol. 55 ›› Issue (3): 100-106.doi: 10.6040/j.issn.1671-7554.0.2016.1471

致癌蛋白CIP2A在乳腺导管上皮恶变中的作用及预测浸润性导管癌患者预后的能力

林家香¹,郭子嘉²,苏鹏³,王晓¹,郭雅欣⁴,吴晓娟¹,相磊¹,周志强¹, 王妍¹,崔秀杰¹,潘爱凤¹,郭成浩¹

1. 山东大学医学院病理学教研室, 山东济南250012;2. 山东中医药大学第一临床医学院中医妇科, 山东济南 250012;3. 山东大学齐鲁医院病理科, 山东济南 250012;4. 山东大学公共卫生学院, 山东济南 250012

收稿日期:2016-11-09 出版日期:2017-03-10 发布日期:2017-03-10
通讯作者: 郭成浩. E-mail:chenghaoguo@sdu.edu.cn E-mail:chenghaoguo@sdu.edu.cn
基金资助:
中国博士后科学基金(2014M560560);山东省自然科学基金(ZR2012HQ002)

The role of CIP2A in the transformation of breast ductal epithelium and prognosis of invasive breast cancer

LIN Jiaxiang¹, GUO Zijia², SU Peng³, WANG Xiao¹, GUO Yaxin⁴, WU Xiaojuan¹, XIANG Lei¹, ZHOU Zhiqiang¹, WANG Yan¹, CUI Xiujie¹, PAN Aifeng¹, GUO Chenghao¹

1. Department of Pathology, School of Medicine, Shandong University, Jinan 250012, Shandong, China;
2. Department of Gynecology of Chinese Medicine, First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250012, Shandong, China;
3. Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China;
4. School of Public Health, Shandong University, Jinan 250012, Shandong, China

Received:2016-11-09 Online:2017-03-10 Published:2017-03-10

摘要/Abstract

摘要： 目的探讨蛋白磷酸酶2A的癌性抑制因子(CIP2A)在乳腺导管上皮的恶性转化过程中的作用及其预测浸润性导管癌患者预后的能力。方法收集乳腺正常导管上皮(正常对照)、普通型增生(UDH)、不典型增生(ADH)、导管内癌(DCIS)及浸润性导管癌(IDC)的石蜡标本322例,采用免疫组织化学染色法检测其中CIP2A的表达。通过χ2检验分析各组间CIP2A的表达差异,并验证CIP2A与DCIS及IDC患者临床病理学参数的关系。通过Kaplan-Meier生存分析及Cox比例风险回归模型分析CIP2A与IDC患者预后的关系。结果 CIP2A在正常对照组、UDH组、ADH组、DCIS组及IDC组的表达率分别为6.66%、5.13%、6.66%、32.35%及32.45%。 CIP2A分别在UDH组与DCIS组、UDH组与IDC组的表达差异有统计学意义(P=0.004 3、P=0.004 0)。 CIP2A表达与DCIS患者的高组织学分级及高Ki67指数呈显著相关性(P均<0.05)。在IDC患者中,CIP2A表达与CerbB2(Her-2)阳性、高Ki67指数、高TNM分期及淋巴结转移呈显著相关性(P均<0.05)。CIP2A阳性患者5年无病生存率和总生存率显著降低,且CIP2A可以作为一种独立的预后因子预测IDC患者预后。结论 CIP2A在乳腺导管上皮癌变过程中可能发挥重要作用。CIP2A有望用于监测导管上皮癌变,并预测IDC患者的预后。

关键词: 导管内癌, 浸润性导管癌, 普通型增生, 不典型增生, 癌性抑制因子, 预后, 蛋白磷酸酶2A

Abstract: Objective To explore the role of cancerous inhibitor of protein phosphatase 2A(CIP2A)in the malignant transformation of breast ductal epithelium and its association with the prognosis of breast ductal cancer. Methods Immunohistochemistry staining was used to detect CIP2A protein in 322 paraffin-embedded breast samples including normal breast duct, usual ductal hyperplasia(UDH), atypical ductal hyperplasia(ADH), ductal carcinoma in situ(DCIS)and invasive ductal carcinoma(IDC). Chi-square test was used to assess the difference of CIP2A expressions, and the correlation between CIP2A expression and the clinicopathologic characteristics. Kaplan-Meier method and Cox proportional hazard regression model were adopted to analyze the survival rate of patients. Results The expression rate 山东大学学报 (医学版)55卷3期 -林家香,等.致癌蛋白CIP2A在乳腺导管上皮恶变中的作用及预测浸润性导管癌患者预后的能力 \=-of CIP2A in of normal tissue, UDH, ADH, DCIS and IDC was 6.66%, 5.13%, 6.66%, 32.35% and 32.45%, respectively. There was significant difference between UDH and DCIS groups, and UDH and IDC groups(P=0.004 3, P=0.004 0). Furthermore, CIP2A expression was closely associated with high histological grade and Ki67 index in DCIS samples(both P<0.05). In IDC patients, CIP2A expression was significantly correlated with CerbB2(Her-2)positive expression, high Ki67 index, high TNM stage and lymph node metastasis(all P<0.05). Patients with positive CIP2A expression exhibited significantly shortened 5-year disease-free and overall survival rate. CIP2A could be an independent prognostic indicator for IDC. Conclusion CIP2A plays a key role in the transition from proliferative lesions to ductal carcinoma. It holds the potential to monitor the malignant transformation of breast duct epithelium, and to guide the prognosis and personal treatment of patients with breast cancer.

Key words: Usual ductal hyperplasia, Atypical ductal hyperplasia, Cancerous inhibitor of protein phosphatase 2A, Ductal carcinoma in situ, Prognosis, Invasive ductal cancer

中图分类号:

R737.9

林家香,郭子嘉,苏鹏,王晓,郭雅欣,吴晓娟,相磊,周志强, 王妍,崔秀杰,潘爱凤,郭成浩. 致癌蛋白CIP2A在乳腺导管上皮恶变中的作用及预测浸润性导管癌患者预后的能力[J]. 山东大学学报（医学版）, 2017, 55(3): 100-106.

LIN Jiaxiang, GUO Zijia, SU Peng, WANG Xiao, GUO Yaxin, WU Xiaojuan, XIANG Lei, ZHOU Zhiqiang, WANG Yan, CUI Xiujie, PAN Aifeng, GUO Chenghao. The role of CIP2A in the transformation of breast ductal epithelium and prognosis of invasive breast cancer[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(3): 100-106.

参考文献

[1] Huang Z, Wen W, Zheng Y, et al. Breast cancer incidence and mortality: trends over 40 years among women in Shanghai, China[J]. Ann Oncol, 2016, 27(6): 1129-1134.
[2] 庄婷, 薛梅, 房爱菊, 等. 黏蛋白(MUC1、MUC2、MUC5AC和MUC6)在乳腺浸润性导管癌中的表达及意义[J]. 山东大学学报(医学版), 2012, 50(5): 107-111. ZHUANG Ting, XUE Mei, FANG Aiju, et al. Expression of mucins(MUC1, MUC2, MUC5AC and MUC6)and their significance in invasive ductal breast carcinoma[J]. Journal of Shandong University(Health Sciences), 2012, 50(5): 107-111.
[3] 高永生, 王春健, 蔡淑萍, 等. Netrin-1在乳腺浸润性导管癌中的表达及与转移的相关性[J]. 山东大学学报(医学版), 2015, 53(7): 39-42. GAO Yongsheng, WANG Chunjian, CAI Shuping, et al. Expression of netrin-1 in invasive ductal breast cancer and its relationship with tumor metastasis [J]. Journal of Shandong University(Health Sciences), 2015, 53(7): 39-42.
[4] Sgroi DC. Preinvasive breast cancer [J]. Annu Rev Pathol, 2010,(5): 193-221.
[5] Tavassoli FA, Devilee P. Pathology and genetics: tumours of the breast and female genital organs [M]. Lyon, France, IARC Press, 2003.
[6] Junttila MR, Puustinen P, Niemel M, et al. CIP2A inhibits PP2A in human malignancies [J]. Cell, 2007, 130(1): 51-62.
[7] De P, Carlson J, Leyland-Jones B, et al. Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A(CIP2A): an oncoprotein with many hands [J]. Oncotarget, 2014, 5(13): 4581-4602.
[8] Ventelä S, Sittig E, Mannermaa L, et al. CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance [J]. Oncotarget, 2015, 6(1): 144-158.
[9] Wiegering A, Pfann C, Uthe FW, et al. CIP2A influences survival in colon cancer and is critical for maintaining Myc expression [J]. PLoS One, 2013, 8(10): 75292.
[10] Dong QZ, Wang Y, Dong XJ, et al. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis [J]. Ann Surg Oncol, 2011, 18(3): 857-865.
[11] Liu J, Wang X, Zhou G, et al. Cancerous inhibitor of protein phosphatase 2A is overexpressed in cervical cancer and upregulated by human papillomavirus 16 E7 oncoprotein [J]. Gynecol Oncol, 2011, 122(2): 430-436.
[12] Yu HC, Chen HJ, Chang YL, et al. Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma [J]. Biochem Pharmacol, 2013, 85(3): 356-366.
[13] Zhang W, Chen H, Chen Y, et al. Cancerous inhibitor of protein phosphatase 2A contributes to human papillomavirus oncoprotein E7-induced cell proliferation via E2F1 [J]. Oncotarget, 2015, 6(7): 5253-5262.
[14] Laine A, Sihto H, Come C, et al. Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1 [J]. Cancer Discov, 2013, 3(2): 182-197.
[15] Puustinen P, Jäättelä M. KIAA1524/CIP2A promotes cancer growth by coordinating the activities of MTORC1 and MYC [J]. Autophagy, 2014, 10(7): 1352-1354.
[16] Böckelman C, Hagström J, Mäkinen LK, et al. High CIP2A immunoreactivity is an independent prognostic indicator in early-stage tongue cancer [J]. Br J Cancer, 2011, 104(12): 1890-1895.
[17] Chen JS, Wu BB, Bao HL, et al. Relationship between CIP2A expression, and prognosis and MDR-related proteins in patients with advanced gastric cancer [J]. Int J Clin Exp Pathol, 2015, 8(11): 15007-15012.
[18] Li W, Ge Z, Liu C, et al. CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells [J]. Clin Cancer Res, 2008, 14(12): 3722-3728.
[19] Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update [J]. Clin Oncol, 2013, 31(31): 3997-4013.
[20] Mommers EC, Leonhart AM, Falix F, et al. Similarity in expression of cell cycle proteins between in situ and invasive ductal breast lesions of same differentiation grade [J]. J Pathol, 2001, 194(3): 327-333.
[21] Niemelä M, Kauko O, Sihto H, et al. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes [J]. Oncogene, 2012, 31(39): 4266-4278.
[22] Côme C, Laine A, Chanrion M, et al. CIP2A is associated with human breast cancer aggressivity [J]. Clin Cancer Res, 2009, 15(16): 5092-5100.
[23] Kim JS, Kim EJ, Oh JS, et al. CIP2A modulates cell-cycle progression in human cancer cells by regulating the stability and activity of Plk1 [J]. Cancer Res, 2013, 73(22): 6667-6678.
[24] Pallai R, Bhaskar A, Barnett-Bernodat N, et al. Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells [J]. Tumour Biol, 2015, 36(8): 6383-6390.
[25] Böckelman C, Lassus H, Hemmes A, et al. Prognostic role of CIP2A expression in serous ovarian cancer [J]. Br J Cancer, 2011, 105(7): 989-995.
[26] Flørenes VA, Emilsen E, Dong HP, et al. Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma [J]. Cancer Med, 2015, 4(6): 903-913.

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致癌蛋白CIP2A在乳腺导管上皮恶变中的作用及预测浸润性导管癌患者预后的能力

The role of CIP2A in the transformation of breast ductal epithelium and prognosis of invasive breast cancer

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