Expression level of membrane-associated proteins Numb in epithelial ovarian cancer and its relationship with drug resistance P-glycoprotein and multidrug resistance-associated protein 1

doi:10.3877/cma.j.issn.1673-5250.2015.03.008

Objective

To explore the expression level of membrane-associated protein Numb in epithelial ovarian cancer(EOC) and its relationship with drug resistance P-glycoprotein(P-gp) and multidrug resistance-associated protein(MRP)-1.

Methods

A total of 136 patients who had ovarian tumors and 22 patients who had hysterectomy and bilateral salpingooophorectomy only for the lesion in uterus from January 2012 to June 2014 in department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University were chosen as study subjects.According to the histopathologic examination results of ovaries tissues, they were divided into EOC group(n=92), borderline ovarian tumor(BOT) group(n=23), ovarian benign tumor group(n=21) and normal ovary group(n=22). Expression levels of Numb protein, P-gp and MRP-1 in ovarian tissues were detected by immunohistochemical SP method, the positive expression rates differences of Numb protein among 4 groups and in patients of different clinical characteristics in EOC group were analyzed statistically. The positive expression rates differences of these 3 kinds of protein and their correlation in EOC group, and the relationship with chemotherapy sensitive and chemotherapy resistance were analyzed statistically.This study was approved by the ethic committee of West China Second University Hospital, Sichuan University, and consent forms were signed by all the patients.There were no significant differences among 4 groups in general clinical data, such as age, body height and body mass, etc.(P>0.05).

Results

①The positive expression rate of Numb protein in EOC group was higher than that in benign tumor or normal ovary group, also Numb protein positive expression rate in BOT group was higher than that in normal ovary group, and the differences were statistically significant(P<0.05). However, there were no significant differences of Numb protein positive expression rates neither between EOC group and BOT group, nor between BOT group and ovarian benign tumor group, nor between ovarian benign tumor group and normal ovary group(P>0.05). ②Comparison of Numb protein positive expression rate in ovarian tissue in EOC group: the positive expression rate in FIGO stageⅠ-Ⅱ was lower than that in stage Ⅲ-Ⅳ, also the same in no lymph nodes metastasis compared with lymph nodes invasion, and the differences were statistically significant(P<0.05). While there were no significant differences among different age, clinical pathology types, pathological grades and residual tumor size(P>0.05). ③There was no significant difference between Numb protein and P-gp positive expression rate in EOC group(P>0.05), also there was no correlation between them(r=0.117, P=0.109). However, the positive expression rate of Numb protein was lower than that of MRP-1, and the difference was significant(P<0.05), also they were positively correlated(r=0.179, P=0.013). ④A total of 78 EOC patients were followed up successfully for chemoresistance, among them, 65 patients were chemotherapy sensitive and 13 patients were chemotherapy resistant.There were no significant differences between chemotherapy sensitive and resistant patients in positive expression rates of Numb protein, P-gp and MRP-1(P>0.05). Also, there was no significant difference of positive expression rate between any two of these 3 kinds of protein in chemotherapy sensitive or resistant patients(P>0.05).

Conclusions

Numb gene might be an oncogene in the development of ovarian neoplasms.Numb protein may be related with proliferation, invasion and metastasis of ovarian neoplasms tumor cell.The expression of Numb protein is correlated with the expression of MRP-1, but a further large sample research is needed to be done to certify whether Numb protein can act as a predictive parameter of chemotherapy sensation.

Key words: Ovarian neoplasms, Numb protein, human, P-glycoprotein, Multidrug resistance-associated protein 1, Immunohistochemistry, Drug resistance

图1 3种蛋白在上皮性卵巢癌中的表达（图1A：Numb蛋白；图1B：P-gp；图1C：MRP-1；DAB显色×400）

Figure 1 Expressions of 3 kinds of protein in epithelial ovarian carcer(Figure 1A:Numb protein;Figure 1B:P-gp;Figure 1C:MRP-1; DAB chromogenic×400)

表1 不同临床特征EOC组患者的Numb蛋白阳性表达率比较[n(%)]

Table 1 Comparison of positive expression rates of Numb proteins among patients of different clinical conditions in EOC group[n(%)]

临床特征		例数	Numb蛋白阳性表达率	χ²值	P值
年龄(岁)		?	?	0.523	0.470
?	≤40	16	9(56.2)	?	?
?	>40	76	50(65.8)	?	?
FIGO分期(期)		?	?	5.686	0.017
?	Ⅰ～Ⅱ	23	10(43.5)	?	?
?	Ⅲ～Ⅳ	69	49(71.0)	?	?
临床病理学类型		?	?	0.303	0.960
?	浆液性癌	55	35(63.6)	?	?
?	黏液性癌	10	7(70.0)	?	?
?	子宫内膜样癌	7	4(57.1)	?	?
?	透明细胞腺癌	6	4(66.7)	?	?
?	混合性腺癌	14	9(64.3)	?	?
组织病理分级		?	?	0.974	0.324
?	高分化	10	5(50.0)	?	?
?	中、低分化	82	54(65.8)	?	?
淋巴结转移		?	?	5.267	0.022
?	无	75	44(58.7)	?	?
?	有	17	15(88.2)	?	?
残留灶直径(cm)		?	?	0.557	0.455
?	≤2	86	56(65.1)	?	?
?	>2	6	3(50.0)	?	?

表1 不同临床特征EOC组患者的Numb蛋白阳性表达率比较[n(%)]

Table 1 Comparison of positive expression rates of Numb proteins among patients of different clinical conditions in EOC group[n(%)]

临床特征		例数	Numb蛋白阳性表达率	χ²值	P值
年龄(岁)		?	?	0.523	0.470
?	≤40	16	9(56.2)	?	?
?	>40	76	50(65.8)	?	?
FIGO分期(期)		?	?	5.686	0.017
?	Ⅰ～Ⅱ	23	10(43.5)	?	?
?	Ⅲ～Ⅳ	69	49(71.0)	?	?
临床病理学类型		?	?	0.303	0.960
?	浆液性癌	55	35(63.6)	?	?
?	黏液性癌	10	7(70.0)	?	?
?	子宫内膜样癌	7	4(57.1)	?	?
?	透明细胞腺癌	6	4(66.7)	?	?
?	混合性腺癌	14	9(64.3)	?	?
组织病理分级		?	?	0.974	0.324
?	高分化	10	5(50.0)	?	?
?	中、低分化	82	54(65.8)	?	?
淋巴结转移		?	?	5.267	0.022
?	无	75	44(58.7)	?	?
?	有	17	15(88.2)	?	?
残留灶直径(cm)		?	?	0.557	0.455
?	≤2	86	56(65.1)	?	?
?	>2	6	3(50.0)	?	?

表2 化疗敏感及耐药患者之间3种蛋白阳性表达率比较及3种蛋白在化疗敏感或耐药患者中阳性表达率比较[例数(%)]

Table 2 Comparison of positive expression rates of Numb，P-gp and MRP-1 between chemotherapy sensitive and chemotherapy resistance patients，and comparison of positive expression rates among these 3 kinds of protein in chemotherapy sensitive patients or chemotherapy resistant patients[case(%)]

化疗结果	例数	Numb蛋白阳性表达率	P-gp阳性表达率	MRP-1阳性表达率
化疗敏感	65	45(69.2)	49(75.4)	52(80.0)
化疗耐药	13	6(46.2)	9(69.2)	10(76.9)
χ²值	?	2.549	0.215	0.063
P值	?	0.110	0.643	0.802

表2 化疗敏感及耐药患者之间3种蛋白阳性表达率比较及3种蛋白在化疗敏感或耐药患者中阳性表达率比较[例数(%)]

化疗结果	例数	Numb蛋白阳性表达率	P-gp阳性表达率	MRP-1阳性表达率
化疗敏感	65	45(69.2)	49(75.4)	52(80.0)
化疗耐药	13	6(46.2)	9(69.2)	10(76.9)
χ²值	?	2.549	0.215	0.063
P值	?	0.110	0.643	0.802

[1]	Rhyu MS，Jan LY，Jan YN.Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells[J]．Cell，1994，76(3)：477–491.
[2]	Jan YN，Jan LY.Asymmetric cell division[J]．Nature，1998，392(6678)：775–778.
[3]	Katoh M，Katoh M．NUMB is a break of WNT-Notch signaling cycle[J]．Int J Mol Med，2006，18(3)：517–521.
[4]	万健，唐喜才，冯斌，等. 原发性肝癌中Numb和VEGF的表达及临床意义[J]. 中国普通外科杂志，2015，24(1)：335–339.
[5]	曾蕴林，绍喜明，李华顺. 膜相关蛋白Numb在结肠癌中的表达和意义[J]. 四川大学学报：医学版，2012，43(1)：326–330.
[6]	张晴晴，李连宏．细胞生长分化及肿瘤形成中Numb的作用[J]. 临床与实验病理学杂志，2012，28(11)：216–218.
[7]	陈小君，叶枫，陈怀增，等．细胞分裂方向的改变和Numb的表达增高在宫颈鳞癌中的作用[J]．实用癌症杂志，2005，20(5)：455–457.
[8]	Verdi JM，Bashirullah A，Goldhawk DE，et al.Distinct human NUMB isoforms regulate differentiation vs.proliferation in the neuronal lineage[J]. Proc Natl Acad Sci USA，1999，96(18)：10472–10476.
[9]	Shen Q，Zhong W，Jan YN，et al. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts[J]．Development，2002，129(20)：4843–4853.
[10]	Colaluca IN，Tosoni D，Nuciforo P，et al.NUMB controls p53 tumour suppressor activity[J]．Nature，2008，451(7174)：76–80.
[11]	Lowe SW，Ruley HE，Jacks T，et al.p53-dependent apoptosis modulates the cytotoxicity of anticancer agents[J]. Cell，1993，74(6)：957–967.
[12]	Sheng W，Dong M，Zhou J，et al. Cooperation among Numb，MDM2 and p53 in the development and progression of pancreatic cancer[J]．Cell Tissue Res，2013，354(2)：521–532.
[13]	Pece S，Serresi M，Santolini E，et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis[J]．J Cell Biol, 2004，167(2)：215–221.
[14]	Ma M，Wang X，Ding X，et al. Numb/Notch signaling plays an important role in cerebral ischemia-induced apoptosis[J]．Neurochem Res，2013，38(2)：254–261.
[15]	Carter S，Vousden KH.A role for Numb in p53 stabilization[J]．Genome Biol，2008，9(5)：221.
[16]	Kang Y，Ding M，Tian G，et al.Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma[J]．Oncol Rep，2013，30(1)：313–319.

[1]	Yang Zhao, Yingcong Xiao, Yan Ju, Xiaozhi Dang, Linli Cai, Wenxin Xue, Yang Li, Yao Xiao, Yuqi Guo, Hongping Song. Clinical value of automated breast ultrasound combined with immunohistochemistry in early prediction of pathological complete response to neoadjuvant chemotherapy in breast cancer[J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2024, 21(04): 361-369.
[2]	Lin Zhu, Tao Chen, Shen Zhang, Dong Xu. Changes of the structure and resistance of pathogenic bacteria in the department of infectious diseases of a tertiary hospital in central China in the past ten years[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2024, 18(02): 75-82.
[3]	Yongtao Wei, Songxia Wang, Aimei Su, Dongping Wang. Resistance and combination drug sensitivity test of carbapenem-resistant Pseudomonas aeruginosa[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2024, 18(01): 43-48.
[4]	Yifang Chen, Xiaohui Huang. Expression and clinical significance of paraoxonase 2 in hepatocellular carcinoma[J]. Chinese Archives of General Surgery(Electronic Edition), 2024, 18(03): 186-191.
[5]	Changqing Cao, Xinyan Guo, Yuan Gao, Cun Zhang, Haili Tang, Dong Fan, Xiaojun Yang, Song Zhang, Huadong Zhao. Research progress on the involvement of tumor microenvironment in mediating trastuzumab resistance in HER2-positive breast cancer[J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2024, 18(01): 90-95.
[6]	Ningning Hu, Yanrong Zhao, Dong Wang, Shengliang Wang, Yuan Guo. The correlation study between the expression of FMNL3 and prognosis in hepatocellular carcinoma liver transplant recipients[J]. Chinese Journal of Transplantation(Electronic Edition), 2024, 18(05): 283-288.
[7]	Qinliang Si, Shilong Bi, Huixiao Jiao, Shizhao Li, Zheyu Chen, Yudong Wu. Two cases of dedifferentiated liposarcoma of spermatic cord and literature review[J]. Chinese Journal of Endourology(Electronic Edition), 2024, 18(06): 585-590.
[8]	Jiayi Xing, Jiasheng Gong, Jiajia Zhu, Qun Lu. Analysis of pathogenic drug resistance and inflammatory factor changes in secondary pulmonary infection in chemotherapy patients with lung cancer[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(05): 714-718.
[9]	Hui Yang, Lijuan Guo, Xiaodan Feng, Jing LI, Chengmo Huang, Xingrui Cai, Yingjiao Qin, Yuanli Wang. Expression characteristics and prediction analysis of platinum-resistant mi RNA in non-small cell lung cancer[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(05): 719-724.
[10]	Jian Zhang, Conghua Lu, Jianghua Li, Caiyu Lin, Di Wu, Zhiguo Wang, Naifu Nie, Yong He, Li Li. Transcriptomics-based exploration of the mechanism of acquired resistance to Osimertinib[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(02): 195-200.
[11]	Lei Xing, Jingqi Shi, Rongyan Li, Jing Liu, Jianwei Liu, Ling Ye, Minghua Zhang, Jiao Fan. Mechanisms of drug resistance to the neddylation inhibitor MLN4924 in NCI-H460 cells based on transcriptome sequencing analysis[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(01): 1-10.
[12]	Xiangqian Wang, Qingfeng Li, Lei Chen, Wendan Qiu, Zhicheng Yao, Yi Li, Ronghuan Wu. Inhibitory effect of curcumin on sorafenib resistance in hepatocellular carcinoma and its regulatory mechanism[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2024, 13(05): 729-735.
[13]	Ruiyi Tan. Current advances and developments in diagnosis and treatment of small cell osteosarcoma[J]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(08): 781-784.
[14]	Yunyao Zhang, Jing Wang, Aijuan Fan, Haiping Mou. Meta-analysis of the clinical value of ultrasonography in the diagnosis of borderline ovarian tumors[J]. Chinese Journal of Diagnostics(Electronic Edition), 2024, 12(02): 85-89.
[15]	Jiajia Li, Linghua Li, Shiyun Lv, Kai Feng, Linshan Liu, Haidan Zhong, Chan Yan, Cong Liu. Characteristics of genotype drug resistance and influencing factors of HIV/AIDS patients with virology failure in Guangzhou[J]. Chinese Journal of Hygiene Rescue(Electronic Edition), 2024, 10(04): 207-212.

Viewed

Full text

Abstract

Please choose a citation manager

Content to export