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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 6  |  Page : 1032-1037

Expression of WW domain-containing protein 2 is correlated with pathological grade and recurrence of glioma


1 Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China
2 Institute of Nervous System Diseases, Lab of Neurosurgery, Xuzhou Medical College, Xuzhou 221002, China

Date of Web Publication13-Dec-2017

Correspondence Address:
Dr. Ru-Tong Yu
Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.176176

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 > Abstract 

Objective: WW domain-containing protein 2 (WWP2) is an E3 ubiquitin ligase, which belongs to the NEDD4-like protein family. Recently, it is reported to play a key role in tumorigenesis and development of tumors such as prostate and lung cancer. However, there has been not related report on glioma until now. The aim of this study is to detect the expression of WWP2 and analyze its correlation to the pathological grade and tumor recurrence in patients with glioma.
Materials and Methods: Western blot and immunohistochemistry were separately used to detect the expression of WWP2 protein in 31 brain glioma tissue samples and 80 brain glioma paraffin specimens. The method of Kaplan–Meier was used to analyze the correlation between the WWP2 expression and glioma recurrence.
Results: The protein expression level of WWP2 in glioma tissue was significantly higher than that in nontumorous brain tissue (P < 0.05), and the protein expression level of WWP2 in high-grade glioma (Grade III–IV) was significantly higher than that in low-grade glioma (Grade I–II) (P < 0.05). Kaplan–Meier analysis indicated that the patients with high WWP2 expression had significantly shorter tumor recurrence time than the patients with low WWP2 expression (P < 0.05).
Conclusion: Our study suggests that WWP2 may play a role in the genesis and development of glioma; it may be a potential biomarker to predict pathological grade and tumor recurrence in patients with glioma.

Keywords: Glioma, pathological grade, recurrence, WW domain-containing protein 2


How to cite this article:
Liang J, Qi WF, Xie S, Wang WF, Zhang XL, Zhou XP, QS, Hu JX, Yu RT. Expression of WW domain-containing protein 2 is correlated with pathological grade and recurrence of glioma. J Can Res Ther 2017;13:1032-7

How to cite this URL:
Liang J, Qi WF, Xie S, Wang WF, Zhang XL, Zhou XP, QS, Hu JX, Yu RT. Expression of WW domain-containing protein 2 is correlated with pathological grade and recurrence of glioma. J Can Res Ther [serial online] 2017 [cited 2020 Apr 2];13:1032-7. Available from: http://www.cancerjournal.net/text.asp?2017/13/6/1032/176176

Jun Liang and Wei-Feng Qi have contributed equally to this work.



 > Introduction Top


Glioma is considered to be the most common malignancies of the central nervous system, accounting for 44.69% approximately, characterized by rapid growth and recurrence, and with a mean survival time of 12 months.[1],[2],[3] The poor prognosis has been confusing us presently, though the current improvements in diagnostics and treatments.[4],[5],[6],[7] Now, our surgery may make an almost complete removal in majority of cases under a microscope, yet, it's very difficult to predict the tumor recurrence by using the conventional histological criteria alone. Hence, it is important to elucidate the mechanisms of glioma development and find the key molecular targets of effective therapies.

WW domain-containing protein 2 (WWP2), a C2-WW-HECT (homologous to E6-AP COOH terminus)-type ubiquitin (Ub) E3 ligase, is a small sub-group known as the NEDD4 family.[8],[9] It plays an important role in different cellular functions such as transcription, embryonic stem cell fate, cellular transport, T-cell activation, and apoptosis.[10],[11],[12],[13],[14],[15],[16],[17] Although WWP2 is reported as a potential oncogene that requires its E3 ligase activity, so far, only limited substrates such as PTEN and SMADs are implicated as functional substrates of WWP2 oncogene.[18],[19] In addition, p73 classified to the family of p53 is defined as a new target of WWP2 in a recent research.[20] Recent articles show that WWP2-N is significantly down-regulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and isolated example of full-length WWP2 and WWP2-C over-expression in early-stage breast cancer.[21] As far in glioma, the biological significance of WWP2 has been not reported. In this study, we find that WWP2 is over-expressed in glioma, and it is related to pathological grade and recurrence.


 > Materials and Methods Top


Patients and tissue specimens

To study the expression level of WWP2 in glioma tissue, a total of 31 human brain glioma tissue samples (surgical resection) and 10 nontumorous brain tissue samples (internal decompression in cerebral trauma) were used for Western blot analysis. Surgically removed tissue was sampled for histological diagnosis, and the remaining tissue was immediately frozen and stored in liquid nitrogen for analysis. Pathology was judged according to the World Health Organization (WHO) classification of tumors of the central nervous system.[22]

The paraffin-embedded sections for the immunohistochemistry were obtained from the pathology files of the Department of Pathology between June 2009 and October 2013, including 9 astrocytomas of WHO Grade I, 22 astrocytomas of WHO Grade II, 30 anaplastic astrocytomas of WHO Grade III, 19 glioblastomas of WHO Grade IV (clinical data: The tumor tissue was totally resected in operation, and 67 cases received radiotherapy and chemotherapy). Nontumorous brain specimens were obtained from 20 patients who underwent internal decompression for cerebral trauma.

Antibodies

Rabbit polyclonal anti-WWP2 (Novus); Mouse monoclonal anti-Ki67/MIB1 (Zhongshanjinqiao); Rabbit monoclonal anti-β-actin (Millipore).

Western blot

Total protein was extracted from nontumorous and glioma tissue collected after operation by using the radioimmunoprecipitation assay buffer (150 mM NaCl, 5 mM Ethylenediaminetetraacetic acid [EDTA], 1% Triton X-100, 1 mM sodium orthovanadate, 50 mM NaF, 1 mM phenylmethanesulfonyl fluoride, 1 mM aprotinin, 1 mM leupeptin, 5 mM dithiothreitol, and 10 mM Tris × HCl [pH 7.4]) in vitro. Protein lysate was concentrated by using the BCA Protein Assay Kit, and equal amount of protein lysate was subjected to 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis, then transferred to polyvinylidene difluoride membrane of 0.45 μm pore size, and probed with primary antibodies (WWP2 or β-actin) at 4°C overnight and secondary antibodies at room temperature for 2 h. Bound antibody was detected by the Pierce ECL Plus Western Blotting Substrate and exposed to X-ray films. Band density was quantified by using Image-Pro Plus software (Media Cybernetics), and the densitometric result was shown.

Immunohistochemistry

The glioma tissue specimens collected after surgery was made into paraffin-embedded tissue blocks, and then they were cut in a microtome to 4 μm and affixed to the slide. The tissue sections were baked at 60°C for about an hour before the experiment. Following that, the tissue sections were dewaxed in xylene and rehydrated through graded alcohol concentrations by using standard procedures. They were subsequently submerged in EDTA (pH 8.0) and autoclave at 121°C for 5 min to retrieve the antigenicity. The endogenous peroxidase was blocked by incubation in 3% hydrogen peroxide for 15 min at room temperature after washed in phosphate-buffered saline (PBS, 0.1 M, pH 7.4, 3 times for 5 min). Then, incubation with WWP2 antibody (Ki67/MIB1 antibody) diluted at 1:300 in PBS containing 0.5% bovine serum albumin was carried out overnight at 4°C, the bound antibody was detected by using the streptavidin-peroxidase kit. After finishing the steps above, the slides were counterstained with hematoxylin, dehydrated with ethanol and xylene, and covered with coverslips. The tissue sections stained without WWP2 antibody served as the negative control.

Immunohistochemical staining evaluation

Three independent, experienced pathologists who were blinded to clinicopathologic information and patient outcome evaluated the slides with bright-field light microscopy. WWP2 staining was mainly localized in the cytoplasm; the cell whose cytoplasm was stained brown was defined to be positive (Ki67/MIB1 staining was mainly localized in the nucleus). The sections were quantified using a visual grading system based on the extent of staining and the intensity of staining. The percentage of positively stained tumor cell was scored as follows: 0 (no positive tumor cells), 1 (≤25% positive tumor cells), 2 (26–50% positive tumor cells), 3 (51–75% positive tumor cells), and 4 (≥76% positive tumor cells). Staining intensity was scored as follows: 0 (no staining), 1 (very weak staining), 2 (weak staining), 3 (moderate staining), and 4 (strong staining). The final score was calculated by multiplying the high proportion score by the staining intensity score: 0–3 was considered as low expression and ≥4 was considered as high expression.

Analysis of tumor recurrence time

According to the intensity of immunohistochemical staining of WWP2, these patients were divided into high and low expression groups, and the times of tumor recurrence were collected and analyzed, the follow-up period of the patients was within 20 months.

Tumor recurrence rate of different WW domain-containing protein 2 expression in different glioma grades

The case number of tumor recurrence was counted in low and high WWP2 expression in different glioma grades; the tumor recurrence rate was calculated and compared.

The difference between WW domain-containing protein 2 and Ki67/MIB1 expression

The numbers of the low and high expression of WWP2 and Ki67/MIB1 in 80 paraffin-embedded glioma sections were counted and compared.

Statistical analyses

Statistical analysis was performed by using the SPSS software 13.0 (Statistical Product and Service Solutions, IBM, Chicago, USA). The one-way ANOVA was used for the comparison of protein expression between glioma and nontumorous brain tissues. The Chi-square test was used for comparison of clinical features and tumor recurrence rates between the low and high expression groups of WWP2. The recurrent curve was plotted by the Kaplan–Meier method and assessed by using log-rank test. P < 0.05 was considered statistically significant.


 > Results Top


Expression of WW domain-containing protein 2 protein analyzed by Western blot

Aiming at studying the possible role of WWP2 in the development of human brain glioma, we detected the expression of WWP2 protein in glioma samples and nontumorous brain tissue samples by Western blot [Figure 1]a. As a result, the expression level of WWP2 protein in glioma was significantly higher than that in nontumorous tissue, and the expression level of WWP2 protein in high-grade glioma (Grade III–IV) was significantly higher than that in low-grade glioma (Grade I–II) [Figure 1]b, P < 0.05].
Figure 1: Expression of WW domain-containing protein 2 protein in glioma tissues. (a) Representative Western blot analysis of the total extracts isolated from nontumorous brain tissues and glioma tissues (low-grade: World Health Organization Grade I–II, high-grade: World Health Organization Grade III–IV). (b) Quantitative analysis of the expression levels of WW domain-containing protein 2 protein normalized to those of β-actin. *P < 0.05 versus nontumorous

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Expression of WW domain-containing protein 2 protein analyzed by immunohistochemistry

To further investigate whether WWP2 protein level abnormality is contributed to the pathological grade of glioma and its location in cell, 80 paraffin-embedded specimens were subjected to immunohistochemical staining. The result showed that WWP2 protein was located in the cytoplasm [Figure 2]a, the percentages of positive cells in nontumor, low-grade and high-grade glioma were 0.12 ± 0.043%, 14.88 ± 1.63% and 45.34 ± 2.23%, respectively. Statistical analysis showed that the rate of WWP2 positive cells in glioma specimen was significantly higher than that in nontumorous tissue, and the rate in high-grade glioma (Grade III–IV) was significantly higher than that in low-grade glioma (Grade I–II) [Figure 2]b, P < 0.05]. The result of Ki67/MIB1 staining was similar with that of WWP2 [Figure 2]c, P < 0.05].
Figure 2: Immunohistochemical staining of WW domain-containing protein 2 and Ki67/MIB1 in glioma. (a) Representative immunohistochemistry analysis of USP22 and Ki67/MIB1 expression in nontumorous brain tissue and glioma specimens of each World Health Organization grades. (b) The histogram showed the quantitative analysis of the percentage of WW domain-containing protein 2 positive cells. **P < 0.01 versus nontumorous. (c) The histogram showed the quantitative analysis of the percentage of Ki67/MIB1 positive cells. **P < 0.01 versus nontumorous

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Correlation between the expression of WW domain-containing protein 2 and the time of patients' tumor recurrence

The prognostic value of WWP2 on tumor recurrence was also evaluated in the patients with glioma (there were not statistical differences in the preoperative clinical data [23] and postoperative treatment between the low and high WWP2 expression groups) [Table 1]. The Kaplan–Meier analysis and log-rank test showed that glioma patients with high WWP2 expression had a significantly shorter tumor recurrence time than that with low expression [Figure 3], P < 0.01].
Table 1: The clinical features and recurrence-free survival of the patients with different WW domain-containing protein 2 expression levels

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Figure 3: The recurrence-free survival of patients with glioma was estimated according to the WW domain-containing protein 2 expression levels in glioma tissue specimens with immunohistochemical staining (Kaplan–Meier method) (P < 0.01)

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Tumor recurrence rate of low and high WW domain-containing protein 2 expression in different glioma grades

The case number of tumor recurrence was counted in low and high WWP2 expression in different glioma grades [Table 2]. In low-grade glioma group, 4 cases highly expressed WWP2, and all of them occurred tumor recurrence, tumor recurrence rate was 100%, it was significantly higher than that of low WWP2 expression (P < 0.05). In high-grade glioma group, 13 cases lowly expressed WWP2, and all of them did not occur tumor recurrence, tumor recurrence rate was 0%, it was significantly lower than that of high WWP2 expression (P < 0.05). The result shows WWP2 expression is more sensitive than WHO grade for prognosis of glioma.
Table 2: Tumor recurrence rates of different WW domain-containing protein 2 expression in different glioma grades

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The difference between WW domain-containing protein 2 and Ki67 expression

The cases of the commonly high expression of WWP2 and Ki67/MIB1 was 37, the cases of the commonly low expression of WWP2 and Ki67/MIB1 was 35, statistics showed there was not the difference between WWP2 and Ki67/MIB1 expression (P > 0.05) [Table 3].
Table 3: The correlation between WW domain-containing protein 2 and Ki67/MIB1 expression in glioma

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 > Discussion Top


Studies have demonstrated that posttranslational modification of cellular protein by Ub regulates diverse biological processes ranging from protein degradation, endocytosis of membrane protein, protein-protein interaction from signal transduction to cell cycle progression, gene transcription, apoptosis, and immune response.[24],[25],[26],[27],[28] For the reason, the Ub-proteasome system plays an important role in various cellular processes.[8] WWP2, a recently identified Ub E3 ligase, has been proved to be a multifunctional gene by degrading a series of targets via Ub-dependent proteasome system, including PETN, Smads, Oct4, RpbI, and so on.[11],[13],[19],[29],[30],[31] Present researches show that WWP2 plays a role in stem cells and immune system, and is also implicated in regulating the turnover of the epithelial sodium channel, divalent metal-ion transporter 1, the large subunit of RNA polymerase II (Rpb1) and ADAR2.[32] The roles of WWP2 involved in cancer also come to our eyes along with the discoveries of the targets such as PETN, Smads, and Oct4. There have been also a few researches on the roles of WWP2 in tumors to be reported, for instance, prostate cancer and lung adenocarcinoma. However, there has been not related report on glioma yet.

Glioma is considered to be the most common malignancies of the central nervous system, because of its incurability, the researches are focused on gene therapy.[33] Based on above literature, it is speculated that WWP2 is probably a novel target to glioma treatment. Then, how is the expression of WWP2 in glioma and what is the correlation between WWP2 and the pathological grade and the recurrence of glioma? With these doubts, the clinical significance of WWP2 expression in glioma is revealed in this study.

First, we used Western blot to detect the protein expression of WWP2 quantitatively. The results showed that the protein level of WWP2 in glioma tissue was significantly higher than that in nontumorous, moreover, with the increase of glioma pathological grade, the expression level of WWP2 protein was also gradually increased. To further observe the location and expression intensity of WWP2 in glioma cell, 80 brain glioma paraffin specimens were stained by immunohistochemistry, we got an identical result that the positive expression rate of glioma cell was higher than that of nontumorous, and the high-grade glioma had a higher rate than the low-grade. For pathological grade is determined by tumor cell density and nuclear division degree, it reflects the proliferation velocity and malignancy degree of glioma cell. These results suggested that WWP2 can promote the progression of glioma and its detection may help judge pathological grade.

According to the intensity of immunohistochemical staining of WWP2, these patients were divided into high and low expression groups, through analyzing their tumor recurrence time, we found that the patients with the higher WWP2 expression occurred tumor recurrence in a shorter period within 20 months, but the patients with the lower WWP2 expression had less tumor recurrence rate, the difference was obviously significant. The result prompted, from clinical manifestations, that WWP2 protein could promote the growth of glioma cells and lead to rapid tumor recurrence; it is an oncogene in glioma.

Besides, from the tumor recurrence rate in different glioma grades, we found that all the patients with high WWP2 expression occurred tumor recurrence in low-grade glioma and all the patients with low WWP2 expression did not occur tumor recurrence in high-grade glioma, the result shows WWP2 expression is more sensitive than WHO grade for prognosis of glioma.

Ki67/MIB1 is a recognized biomarker for proliferation, then, is there a difference between WWP2 and Ki67/MIB1 expression in glioma. We counted the cases of the commonly low and high expression of WWP2 and Ki67/MIB1; statistics showed there was not the difference between WWP2 and Ki67/MIB1 expression, this indicates WWP2 may also serve as a malignant tumor biomarker like Ki67/MIB1.


 > Conclusions Top


In summary, the data from the current study has shown that WWP2 is over-expressed in glioma; its detection may assist to determine the glioma pathological grade and estimate the time of glioma recurrence. WWP2 may be served as a significant biomarker to predict prognosis of patients with glioma. The possible mechanism will be further explored.

Financial support and sponsorship

This study was supported by the National Natural Science Foundation of China (No. 81072072) and a grant from Xuzhou Medical College (No. 09KJZ18).

Conflicts of interest

There are no conflicts of interest.

 
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