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Frontiers of Medicine

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Front. Med.    2016, Vol. 10 Issue (1) : 41-51    https://doi.org/10.1007/s11684-016-0429-z
RESEARCH ARTICLE
Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer cell proliferation in vitro and in vivo
Lan Wang1,Jueheng Wu3,Jie Yuan3,Xun Zhu2,3,Hongmei Wu1,Mengfeng Li2,3,*()
1. Department of Microbiology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou 510006, China
2. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
3. Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
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Abstract

Midline2 (MID2) is an ubiquitin-conjugating E2 enzyme linked to tumor progression and a novel interacting partner of breast cancer 1, early-onset (BRCA1). However, the role of MID2 in breast cancer remains unknown. This study investigated the expression, prognostic value, and role of MID2 in breast cancer. The expression of MID2 mRNA and protein was significantly upregulated in breast cancer tissue and established cell lines compared with that in normal breast epithelial cells and paired adjacent non-tumor tissue (P<0.001). Immunohistochemical analysis demonstrated that MID2 was overexpressed in 272 of 284 (95.8%) paraffin-embedded, archived breast cancer tissue. Moreover, MID2 expression increased with advanced clinical stage (P<0.001). High MID2 expression was significantly associated with advanced clinical stages and T, N, and M staging (all P<0.05). Univariate and multivariate analyses indicated that high MID2 expression was an independent prognostic factor for poor overall survival in the entire cohort (93.73 vs. 172.1 months; P<0.001, log-rank test) and in subgroups with stages Tis+ I+ II and III+ IV. Furthermore, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide colony formation, and anchorage-independent growth ability assays were conducted. Results showed that siRNA silencing of MID2 expression significantly reduced MCF-7 and MDA-MB-231 cell proliferation in vitro and blocked the growth of MDA-MB-231 cell xenograft tumors in vivo (P<0.05). This study indicated that MID2 may be a novel prognostic marker and interventional target in breast cancer.
Keywords breast cancer      MID2      proliferation      overall survival      xenograft     
Corresponding Author(s): Mengfeng Li   
Just Accepted Date: 25 December 2015   Online First Date: 20 January 2016    Issue Date: 31 March 2016
 Cite this article:   
Lan Wang,Jueheng Wu,Jie Yuan, et al. Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer cell proliferation in vitro and in vivo[J]. Front. Med., 2016, 10(1): 41-51.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0429-z
https://academic.hep.com.cn/fmd/EN/Y2016/V10/I1/41
Characteristics Number MID2 Chi-square test P-value
???Low ???High
Age <45 104 ???46 ???58 0.9
≥45 180 ???81 ???99
Clinical stage Tis 23 ???23 ???0 <0.001
I 25 ???22 ???3
II 126 ???65 ???61
III 79 ???13 ???66
IV 31 ???4 ???27
T classification T1 63 ???46 ???17 <0.001
T2 144 ???72 ???72
T3 49 ???7 ???42
T4 28 ???2 ???26
N classification N0 129 ???83 ???46 <0.001
N1 101 ???32 ???69
N2 43 ???10 ???33
N3 11 ???2 ???9
Metastasis No 269 ???125 ???144 0.032
Yes 15 ???2 ???13
Histologic grade Low 59 ???50 ???9 <0.001
Intermediate 110 ???63 ???47
High 115 ???14 ???101
ER Negative 130 ???54 ???76 0.34
Positive 154 ???73 ???81
PR Negative 111 ???45 ???66 0.268
Positive 167 ???80 ???87
ErbB-2 Negative 36 ???13 ???23 0.562
Positive 116 ???50 ???66
Tab.1  Correlation between MID2 expression and clinicopathological characteristics of breast cancer patients
Fig.1  Analysis of MID2 protein and mRNA expression in breast cancer cells. (A) Western blot analysis of MID2 protein expressed in two normal breast epithelial cell lines (NBECs) and breast cancer cell lines. (B) Real-time PCR analysis of MID2 mRNA expression in NBECs and breast cancer cell lines. Data are expressed relative to GAPDH levels. * P<0.05.
Fig.2  Analysis of MID2 protein and mRNA expression in freshly isolated human primary breast cancer tissue specimens (T) and paired adjacent non-tumor tissue (ANT). (A) Western blot analysis of MID2 protein expression; β-actin was used as loading control. (B) Real-time PCR analysis of MID2 expression in the indicated tissue specimens; GAPDH was used as loading control. *P<0.05. (C) IHC staining for the MID2 protein in the indicated tissue. The images were obtained at 200× magnification.
Fig.3  Immunohistochemical analysis of MID2 expression in archived, paraffin-embedded normal human breast and breast cancer tissue. (A) Representative images of MID2 expression in normal breast tissue and different clinical stages of breast cancer. (B) Quantification of the average mean optical density (MOD) for MID2 in normal breast tissue and different clinical stages of breast cancer. (C) Kaplan-Meier overall survival curve (left) and disease-free survival curves (right) for 284 patients with breast cancer stratified by high and low expression of MID2. (D) Kaplan-Meier overall survival curves for subgroups of patients with different stages (left: low clinical stage; right: high clinical stage) of breast cancer stratified by high and low MID2 expression.
Characteristics All cases Mean survival (month) Median survival (month) P value Mean disease-free survival (month) Median disease-free survival (month) P value
Age <45 104 120.33 128 0.094 114.3 110 0.042
≥45 180 140.64 138 141.41 132
Clinical stage Tis 23 139.07 143 <0.001 139.08 143 <0.001
I 25 156.83 149 154.66 154
II 126 144.19 142 148.99 138
III 79 97.64 106 88 96
IV 31 92.96 89 76.98 84
T classification T1 63 141.92 144 <0.001 139.22 143 <0.001
T2 144 144.13 138 147.99 138
T3 49 102.16 118 89.02 100
T4 28 66.27 50 47.34 24
N classification N0 129 159 143 <0.001 155.81 143 <0.001
N1 101 119.75 126 120.68 110
N2 43 79.69 82 69.57 67
N3 11 111.48 126 88.56 96
Metastasis No 269 134.76 134 <0.001 135.58 130 <0.001
Yes 15 56.33 40 44.8 24
Histologic grade Low 59 179.34 172 <0.001 176.12 176 <0.001
Intermediate 110 151.17 140 175.09 175
High 115 72.4 68 62.24 62
MID2 expression Low 127 172.1 168 <0.001 178.19 166 <0.001
High 157 93.73 100 84.77 89
Tab.2  Clinical pathological parameters and MID2 expression for prognosis of 284 patients with breast cancer by univariate survival ?????analysis (log-rank test)
Variable Overall survival Disease-free survival
Relative risk 95% confidence interval P value Relative risk 95% confidence interval P value
MID2 2.825 1.744–4.576 0.013 1.938 1.221–3.076 0.005
T classification 1.752 1.407–2.182 <0.001 1.702 1.359–2.131 <0.001
N classification 1.559 1.21–2.01 0.009 1.457 1.146–1.853 0.002
Metastasis 4.463 2.429–8.203 0.031 3.178 1.705–5.923 <0.001
Histologic grade 7.535 4.994–11.367 <0.001 4.763 3.312–6.849 <0.001
Tab.3  Multivariate analysis of overall and disease-free survival (Cox regression model)
Fig.4  Knockdown of endogenous MID2 inhibits MCF-7 and MDA-MB-231 cell proliferation in vitro. (A) Western blot analysis of MID2 and Ki67 expression. (B) MTT assays of cell proliferation. (C) Representative micrographs and quantification of cell colonies stained with crystal violet in the colony formation assay. (D) Representative micrographs (left) and colony numbers in the anchorage-independent growth assay. Each bar represents the mean SEM of three independent experiments. *P<0.05.
Fig.5  Knockdown of endogenous MID2 inhibits the growth of breast cancer tumor xenografts in vivo. Five NOD/SCID mice were injected with vector-transfected and MID2-RNAi1-transfected cells. (A) Images of the excised tumors 35 d after injection. (B) Tumor growth curves; tumor volume was measured every 5 days. (C) Average weight of the excised tumors. (D) Western blot of MID2 expression in the excised xenograft tumors. (E) Representative images of MID2 and Ki67 expression in tumors after immunohistochemical staining. *P<0.05. Images were obtained at 200× (left) and 400× (right) magnifications.
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