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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 553-559

Elevated β-catenin and C-myc promote malignancy, relapse, and indicate poor prognosis in patients with relapsed glioma


1 Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong Province, P. R. China
2 Department of Neurosurgery, Jining No. 1 People's Hospital, Jining, Shandong Province, P. R. China
3 Department of Neurosurgery, Dezhou People's Hospital, 1166 Dongfanghong West Road, Dezhou, Shandong, P. R. China
4 Department of Neurosurgery, Yidu Central Hospital of Weifang, No. 4138 Linglongshan South Road, Qingzhou, Shandong, P. R. China
5 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, P. R. China
6 Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, P. R. China

Date of Submission20-Feb-2021
Date of Decision21-Jan-2022
Date of Acceptance06-Apr-2022
Date of Web Publication20-May-2022

Correspondence Address:
Dexiang Wang
Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Street, Jinan, Shandong Province - 250012
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_246_22

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 > Abstract 


Context: Extensive studies have shown that β-catenin and C-myc have been linked to a number of human cancers. However, the role of β-catenin and C-myc in relapse glioma remains unclear.
Aims: The aims of this study were to investigate the role of β-catenin and C-myc in relapsed glioma patients and to explore the possible impact of malignancy, relapse, and prognosis.
Materials and Methods: We collected surgical samples of 100 patients with primary and relapsed glioma treated at our institution. Immunohistochemistry (IHC) staining was used to evaluate the expressions of β-catenin and C-myc. The impact of the differences on disease-free interval (DFI), initial overall survival (iOS), and overall survival from the time of glioma relapse (rOS) of the patients was analyzed. Kaplan–Meier survival functions were used to plot survival time, and a log-rank test was used for analyzing statistical significance. Cox multivariate regression analysis was used to determine independent prognostic parameters.
Results: Compared to primary tumors, relapsed gliomas had higher expressions of β-catenin and C-myc (P < 0.05). Furthermore, the expressions of β-catenin and C-myc were significantly correlated with glioma grade (P < 0.05). These changes in expression at the time of relapse were independent of radiotherapy use. In multivariate Cox analysis, we found that β-catenin and C-myc were independent prognostic factors for rOS (P < 0.05).
Conclusions: Elevated β-catenin and C-myc promote malignancy, relapse, and indicate poor prognosis in patients with relapsed glioma. The elevated levels of β-catenin and c-myc in relapsed glioma were not affected by radiation therapy. The results of this study may provide a new therapeutic target for patients with relapsed glioma.

Keywords: β-catenin, C-myc, glioma, malignancy, prognosis, relapse


How to cite this article:
Yu X, Xiao F, Wei Y, Miao L, Zhang W, Zhang X, Wang D. Elevated β-catenin and C-myc promote malignancy, relapse, and indicate poor prognosis in patients with relapsed glioma. J Can Res Ther 2022;18:553-9

How to cite this URL:
Yu X, Xiao F, Wei Y, Miao L, Zhang W, Zhang X, Wang D. Elevated β-catenin and C-myc promote malignancy, relapse, and indicate poor prognosis in patients with relapsed glioma. J Can Res Ther [serial online] 2022 [cited 2022 Sep 30];18:553-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/553/345540

Xuejuan Yu and Fengxia Xiao contributed equally to this work, they are both the first authors.





 > Introduction Top


Glioma is the most common primary brain tumor with high mortality in adults. Despite advances in treatment, there remains a high mortality rate from high grade glioma (HGG) s and inevitably relapses. Thus, there is an urgent need to find the mechanism of relapsed glioma. Extensive studies have shown that aberrant Wnt/β-catenin signaling has been linked to several human cancers. The canonical Wnt/β-catenin pathway governs a myriad of biological processes involved in the development and maintenance of adult tissue homeostasis, including the regulation of stem cell proliferation, differentiation, self-renewal, and apoptosis.[1],[2] This disassembly of the β-catenin destruction complex allows for the cytoplasmic protein β-catenin to enter the nucleus and modulate transcription.[3] β-catenin plays an important role in mediating the genes that control cell proliferation and metabolism, including the oncogene C-myc.[4] Furthermore, dysregulated C-myc activity is a common alteration reported in human malignancy.[5]

The modulations of β-catenin and C-myc can occur through multiple factors such as extracellular, cytoplasmic, microRNAs, and nuclear regulators.[6],[7],[8],[9],[10] Perturbations in β-catenin and C-myc promote human degenerative diseases and many cancers such as breast, colorectal, melanoma, prostate, lung cancers, and glioma.[11],[12],[13],[14],[15] Therefore, the important function of β-catenin and C-myc has attracted numerous studies on glioma in the past decade. Extensive in vitro studies have shown that aberrant β-catenin and C-myc influences glioma development,[16] including cell proliferation, apoptosis, and invasion.[17],[18],[19] Therefore, more attention is required on the knowledge of β-catenin and C-myc in glioma patients, especially its role in glioma relapse.

As we all know, radiotherapy is widely used as a standard treatment for glioma. Recent studies have reported that irradiation paradoxically promotes the malignant glioma cell phenotypes, leading to relapse after treatment.[2] However, mechanisms underlying the harmful effects of radiation are not well understood. In a review by Yang et al.,[20] it was noted that the Wnt/β-catenin pathway participates in radiation resistance by affecting tumor cell cycle, cell proliferation, DNA damage repair, and cell apoptosis and invasion. Here, we also investigated the role of β-catenin and C-myc in glioma relapse and whether radiation could affect the pathway at relapse.


 > Subjects and Methods Top


Patient samples

Hundred glioma patients' samples from Qilu Hospital of Shandong University from January 1, 1995 to December 31, 2015. These patients received surgery twice for both primary and relapsed glioma in our hospital. The date of the last follow-up was April 30, 2019. None of the patients showed evidence of any malignancy other than glioma at the time of diagnosis. The inclusion criteria were as follows: (1) patients' primary and relapsed surgeries should be completed in Qilu Hospital affiliated to Shandong University; (2) each incidence must be a solitary lesion; (3) the postoperative follow-up contrast-enhanced magnetic resonance imaging (MRI) can find new enhanced lesions, or an increase of 25% or more than the previous time; and (4) a Karnofsky score (KPS) of >60. Patients with radiation necrosis who were analyzed by magnetic resonance spectroscopy combined with the changes in clinical symptoms were excluded from the study.

Our study complied with national regulations and was approved by the Ethics and Investigation Committee of our institution with the No. KYLL-2015(KS)-068. None of the patients showed evidence of any malignancy other than glioma at the time of diagnosis.

Immunohistochemistry

Formalin-fixed, paraffin-embedded (FFPE) tissue slides were prepared from surgical glioma tissue. The FFPE slides were inserted in sodium citrate buffer (10 mmol/L, pH 6.0) for antigen retrieval and heated at 95°C for 30 min. Next, goat serum was used for blocking for 30 min at 37°C. Then, incubation of the slides was done overnight at 4°C using rabbit polyclonal anti-C-myc antibody (1:200 dilution, ab39688, Abcam) and rabbit polyclonal anti-β-catenin antibody (1:1200 dilution, ab16051, Abcam). First, the primary antibody was washed off, serving as a negative control. Then, we used goat anti-rabbit/mouse secondary antibody with biotinylated anti-immunoglobulin vector for incubation at 37°C for 30 min followed by three times of phosphate buffered saline (PBS) washing. Finally, we examined the slides and took pictures using a light microscope with a digital camera (DM2000; Leica Microsystems, Wetzlar, Germany). Five fields (original magnification ×400) were randomly selected, and cells with positive staining were counted. For the control, a similar procedure was performed without replacing the primary antibody with PBS.

We scanned ×400 power objectives for each core with five fields and focused on the immunoreactive areas for field selections. The final area ratio was equal to the average of five fields. β-catenin and C-myc staining intensity were 0+, 1+, 2+, and 3+, whereas the percentage of β-catenin and C-myc–positive cells were 1 (1%–25%), 2 (26%–50%), 3 (51%–75%), and 4 (76%–100%). For the immunoreactive score (IRS), we multiplied the intensity by the percentage. Based on IRS, a score of ≥8 was classified as positive expression and ≤8 as negative expression.

Statistical analyses

Independent t-test was used to analyze continuous variables. Chi-square test was used for analyzing qualitative data. Spearman correlation methods were used for correlation analysis. Kaplan–Meier survival functions were used to plot survival time, and a log-rank test was used for analyzing statistical significance. Cox multivariate regression analysis was used to determine independent prognostic parameters. A two-tailed P value <0.05 was considered statistically significant. All data were analyzed using Statistical Package for the Social Sciences (SPSS, v. 25.0, IBM) and PRISM (v. 7.0; GraphPad Software Inc., San Diego, CA, USA).


 > Results Top


Patient distribution, survival, and relapsed status

Anonymized and de-identified glioma patient samples from 100 patients were collected for this study. Patient information, such as patient demographics (age, gender, prior radiotherapy, and prognosis) and tumor characteristics (location and histopathologic grade), for all tissues used in this study was collected. Only two patients were exempted until the last day of follow-up. Disease-free interval (DFI) is defined in this study as the period between the first surgery and disease relapse. The initial overall survival (iOS) was calculated from the date of the operation at primary diagnosis to the date of death or last follow-up. The relapsed overall survival (rOS) was calculated from the date of the operation at relapse to the date of death or last follow-up. The average age of patients at primary diagnosis was 40.89 years (range 6–77), and the age at relapse was 43.68 years (range 9–79). The mean values of DFI, iOS, and rOS for all patients were 33.04 months (range 2.10–127.40), 63.40 months (range 6.00–165.80), and 30.37 months (range 0.50–127.20), respectively. Part of the data was previously published by our group.[21]

Expression levels of β-catenin and C-myc, as well as tumor grade, increased in human relapsed malignant glioma specimens

The histopathologic analyses of glioma specimens by immunohistochemistry (IHC) demonstrated that β-catenin expression levels and its downstream target C-myc increased in relapsed glioma than in primary tumor. Positive staining of both proteins was predominantly distributed in the cytoplasm and nuclei of tumor cells. By individually scoring the IHC results, we confirmed the statistical significance of the increase in β-catenin and C-myc in relapsed tumors than in primary ones [Table 1]. Chi-square test revealed that the percentage of positive expressions of β-catenin and C-myc staining was significantly higher in relapsed gliomas than in primary tumors (P = 2.500 × 10−5, P = 6.124 × 10−13). Statistics also showed that tumor grade significantly increased in relapsed gliomas than in primary tumors (P = 4.629 × 10−7).
Table 1: Significance of changes in grade and protein expression between primary diagnosis and relapse

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The discordance rate was evaluated to indicate the change in individual protein expression. β-catenin discordance rate between primary and relapsed glioma was evaluated to be 47% (47 patients). Among 64 cases of primary tissue with negative expression of β-catenin, 38 (59.38%) cases showed positive expression in their corresponding relapsed tissues. C-myc discordance rate between primary and relapsed disease was 52% (52 patients), with 66.67% patients showing positive expressions in the relapsed phase.

The expression levels of β-catenin and C-myc were positively correlated with tumor grade, and the levels of C-myc and β-catenin were positively correlated

The results from Spearman correlation showed a significant and positive correlation between β-catenin expression and tumor grade in both primary and relapsed tumors (r = 0.609, P = 1.728 × 10−11 and r = 0.538, P = 8.068 × 10−9, respectively). Meanwhile, a significant positive correlation between C-myc and tumor grade in primary and relapsed tumors (r = 0.362, P = 2.190 × 10−4 and r = 0.472, P = 7.201 × 10−7, respectively) was found. The distribution of both proteins was localized mainly in the cytoplasm or cell membrane in the lower glioma grade. While in the higher glioma grade, positive nuclear staining of tumor cells was more commonly detected [Figure 1]. The simultaneous positive expressions of β-catenin and C-myc were more commonly shown by tumors with a higher tumor malignancy grade. In primary tumor, there were 18 samples with simultaneous positive expressions of β-catenin and C-myc in grade III/IV glioma and one sample in grade I/II glioma. In the relapsed tumor, there were 57 samples with simultaneous positive expressions of β-catenin and C-myc in grade III/IV glioma and one sample in grade I/II glioma. Spearman correlation analysis also revealed a significant and positive correlation between the two proteins C-myc and β-catenin in primary and relapsed tumors (r = 0.481, P = 4.042 × 10−7 and r = 0.498, P = 1.330 × 10–7, respectively).
Figure 1: IHC staining of β-catenin and C-myc in different primary glioma grades. (a) β-Catenin increased in higher primary glioma grade. (b) C-myc increased in higher primary glioma grade. Distribution of the proteins was localized mainly in the cytoplasm or cell membrane in lower glioma grade, while in higher glioma grade, positive nuclear staining of tumor cells was more commonly detected. IHC = immunohistochemistry. SD = standard deviation

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Radiotherapy did not change tumor grade and the protein levels of β-catenin and C-myc in relapsed glioma

Of the 100 patients, 66 received radiotherapy after primary tumor resection and 34 did not. For primary tumors, the analysis of age, gender, location, histological grade, and protein level of β-catenin and C-myc showed no significant differences between radiotherapy and nonradiotherapy [Table 2]. Additionally, relapsed gliomas were divided into radiotherapy and nonradiotherapy groups, according to whether they received radiotherapy after initial surgery, and further, the pathology and expression levels of β-catenin and C-myc were compared. No statistical differences were found in these parameters (P > 0.05) [Table 3].
Table 2: Comparison of primary tumors (as baseline of relapsed tumors) with and without radiotherapy

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Table 3: Comparison of relapsed tumors with and without radiotherapy

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Survival analyses

Here, the prognostic values of the clinicopathological parameters, including gender, age, radiotherapy, tumor location, histological grade, and the expressions of β-catenin and C-myc in primary glioma were analyzed. Additionally, we analyzed the relationship of all parameters with three survival parameters: DFI, iOS (overall survival from initial glioma diagnosis), and rOS (overall survival from the time of glioma relapse).

β-catenin and C-myc were the affecting factors, but not independent factors for DFI. Our previous data revealed that age and tumor grade are independent factors affecting DFI.[21] Here, Kaplan–Meier estimation revealed significantly different DFI at β-catenin and C-myc expressions (P = 0.017 and P = 0.047, respectively). Also, we performed correlation analysis and found that DFI was unrelated to β-catenin (P = 0.155) or C-myc (P = 0.090). Additionally, multivariate Cox analysis showed that β-catenin or C-myc was not an independent factor affecting DFI (P = 0.370 and P = 0.275, respectively).

Age and tumor grade were independent factors affecting iOS. However, the level of β-catenin was only an affecting factor, but not an independent factor for iOS. Kaplan–Meier estimation revealed significant differences in iOS with regard to age, grade, location, and β-catenin expression (P = 1.400 × 10−5, P = 0.003, P = 0.016 and P = 0.029, respectively) [Table 4]. Higher age or grade was associated with lower iOS; also, high expression of β-catenin was significantly associated with decreased iOS. However, other clinicopathological parameters, such as radiotherapy, C-myc, and gender, showed no significant differences in patients first diagnosed with glioma. Correlation analysis for them showed that iOS was negatively related to age (r = –0.379, P = 1.000 × 10−4), grade (r = –0.414, P = 1.900 × 10–5), and β-catenin (r = –0.223, P = 0.026) in tumor samples. Furthermore, by a multivariate Cox analysis, age (hazard ratio [HR] = 2.680, 95% confidence interval [CI] 1.569–4.576, P = 3.050 × 10–4) and grade (HR = 1.989, 95% CI 1.224–3.234, P = 0.006) were shown to be independent factors for iOS. However, β-catenin level was the only affecting factor, but not an independent factor for iOS (HR = 0.833, 95% CI 0.505–1.376, P = 0.476).
Table 4: Prognostic values of the clinicopathological parameters and markers in iOS

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β-Catenin and C-myc were independent affecting factors for rOS, but the grade was the only factor affecting rOS. Significant differences in rOS between age, grade, β-catenin, and C-myc (P = 0.021, P = 0.005, P = 4.134 × 10−7, and P = 4.662 × 10−9, respectively) were revealed by Kaplan–Meier estimation [Table 5]. In other words, we demonstrated that with increasing age, grade, and β-catenin and C-myc expression, the rOS of relapsed glioma was poorer. However, other clinicopathological parameters, such as gender and location, showed no significant differences in patients with secondly diagnosed glioma. Their correlation analysis showed that rOS was negatively related to grade (r = –0.218, P = 0.029), β-catenin (r =–0.512, P = 5.300 × 10−8), and C-myc (r = –0.583, P = 1.978 × 10−10) in tumor samples, while age showed no relation. Furthermore, by multivariate Cox analysis, the levels of β-catenin (HR = 2.898, 95% CI 1.665–5.044, P = 1.680 × 10–4) and C-myc (HR = 4.310, 95% CI 2.266–8.198, P = 8.000 × 10−6) were independent factors for rOS. However, tumor grade was the only affecting factor for rOS, but not an independent factor for iOS (HR = 0.542, 95% CI 0.236–1.246, P = 0.149).
Table 5: Prognostic values of the clinicopathological parameters and markers in rOS

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 > Discussion Top


Growing evidence shows that β-catenin and C-myc influence the development of glioma, where β-catenin and C-myc have been shown to regulate cellular proliferation, apoptosis, and invasion.[17],[18],[19],[22] However, the studies of β-catenin and C-myc in relapsed glioma patients are rare and incomplete.

β-Catenin was initially described as a membrane adhesion protein of the calmodulin-mediated cell–cell adhesion system. Aberrant degradation of β-catenin leads to increased cytoplasmic β-catenin and its nuclear translocation. In relapsed gliomas, the expression of nuclear β-catenin increases with increasing grade. Recently, it has been reported that Wnt signaling can further promote C-myc accumulation through posttranscriptional mechanisms, increasing MYC transcripts in the cytoplasm.[23] As shown in the “Results” section, with Spearman correlation analysis, we found that C-myc was positively correlated with β-catenin and grade.

Our previous study revealed that relapsed gliomas with elevated pathological grade and increased malignancy predicted increased cell proliferation and invasiveness,[21] and numerous studies have confirmed that β-catenin and C-myc participate in various biological processes and are closely correlated with various human tumorigenesis.[6],[24] Furthermore, overexpression of active β-catenin causes high-grade intraepithelial neoplasia and promotes invasive carcinoma.[25],[26] Similar to the above results, here, we recorded elevated levels of β-catenin and C-myc expressions in relapsed glioma specimens with secondary postoperative and a positive correlation with pathology. Meanwhile, another study reported that[21] relapsed astrocytomas showed significantly higher tumor grades than their corresponding primary tumors. Therefore, the expression of β-catenin increases after surgery.

As mentioned above,[3] there is a potential relationship between radiotherapy and tumor relapse. Studies have revealed that with radiotherapy, a significant increase in β-catenin mRNA transcript levels and WNT molecule expression while blocking the Wnt/β-catenin pathway could increase radiotherapy sensitivity and decrease Wnt/β-catenin radioresistance.[27] Paradoxically, our results showed that radiotherapy did not change tumor grade and the protein levels of β-catenin and C-myc in relapsed glioma. In another study, the number of necrotic lesions at different stages of radiotherapy showed significant differences.[28] Altogether, the possible explanation is that the effect of radiotherapy on these proteins is transient. After a period of radiation, the stimulation of β-catenin and C-myc by radiation gradually decreased and disappeared by the second surgery. To test this hypothesis, periodic detection of the tumor after radiation could be performed, which is followed by pathway activity analysis. Another possible reason for the discrepancy in results is that other studies were in vitro studies, while our study was in vivo. Notably, although higher activities of β-catenin and C-myc were detected in relapsed glioma, they might be attributed to the inherent characteristic of glioma and not to the effect of X-ray radiation.

Lastly, we used survival analysis to investigate the possible prognostic values of β-catenin and C-myc with multiple clinicopathological parameters. Patients with β-catenin overexpression had a poor prognosis.[29] By univariate analysis, we found that β-catenin impacted the rOS and iOS of patients. The higher the expression level of β-catenin or C-myc, the poorer the DFI. By univariate analysis, it was found that the higher the expression of β-catenin, the poorer the prognosis of primary or relapsed glioma. Furthermore, we found that C-myc impacted the rOS of patients, but not iOS. By multivariate analysis, they were found to independently affect rOS, but not iOS. In a study, patients with β-catenin overexpression had poorer prognoses.[29] Combined with the results of our study, we believe that β-catenin and C-myc can be used as specific biomarkers for screening high-risk population and in the diagnosis and prognosis of relapsed glioma. Considerable efforts have been made to develop drugs specifically inhibiting this signaling pathway at different levels. The agents currently being investigated mainly target Wnt ligands and receptors (LGK974 I, OMP-54F28, etc.), the β-catenin destruction complex (celecoxib, DIF1/3, etc.), β-catenin cytoplasmic–nuclear translocation wheat germ agglutinin (WGA), and β-catenin transcriptional complexes (PRI 724, vitamin D, etc.).[30] Although the drugs are still in research due to difficulties such as in penetrating the blood–brain barrier, we believe that a rational, effective, and potentially universal strategy against β-catenin and C-myc is on its way.


 > Conclusions Top


Conclusively, our results indicated that β-catenin and C-myc were activated in glioma, their activity increased in relapsed glioma than in primary tumor, and the proteins contributed to the malignancy of glioma. Increased β-catenin and C-myc activities were related to poor glioma prognosis. Radiotherapy was not found to affect them at the time of relapse. Therefore, our findings disclosed that β-catenin and C-myc may be new therapeutic targets for patients with relapsed glioma.

Acknowledgements

We are grateful to Mr. Jian Wang, Mr. Bin Huang, and Mrs. Anjing Chen from Brain Science Research Institute, Key Laboratory of Brain Functional Remodeling, Shandong University, China, for their technical contribution.

Ethics approval and participation consent

All procedures in our study involving human subjects complied with the Declaration of Helsinki and the regulations made by the ethical committee of Qilu Hospital affiliated to Shandong University (KYLL-2015(KS)-068).

Financial support and sponsorship

The study was funded by the Natural Science Foundation of Shandong Province (ZR2019PH 098) and the Medical and Health Foundation of Shandong Province (2018WS476).

Conflicts of interest

No conflict of interest was declared. However, all listed authors are responsible for the reliability and freedom from bias of the data in the manuscript and related interpretation.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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