Chaperone protein P4HB predicts temozolomide response and prognosis in malignant glioma
- Authors:
- Published online on: June 16, 2022 https://doi.org/10.3892/ol.2022.13385
- Article Number: 264
Abstract
Introduction
Malignant glioma is the most common subtype of primary brain tumour in adults, with an overall survival (OS) time of ~18 months (1). Temozolomide (TMZ), an oral DNA alkylating agent, has been the current standard of care. In the standard regimen after maximal surgical resection, patients receive concomitant chemoradiotherapy with TMZ (75 mg/m2), followed by adjuvant TMZ (150 to 200 mg/m2) for five days every 28 days for six cycles after radiotherapy (2). Despite promising results in terms of improving patient survival, drug resistance and tumour relapse are almost inevitable. The expression of DNA damage repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells may also protect cells from alkylating drugs including TMZ (3), whereas a methylated MGMT gene promoter may inactivate MGMT expression, leading to a greater therapeutic response to TMZ. The MGMT methylation status has thus been adopted as a useful prognostic and predictive biomarker for better patient management.
The endoplasmic reticulum (ER) stress response and the associated unfolded protein response (UPR) are one major mechanism in the development of TMZ resistance in glioblastoma (4). In cancer cells, adaptive ER stress response due to prolonged ER stress (e.g. caused by hypoxia and glucose deprivation) is a common feature and chronic ER stress imposed by long-term chemotherapeutic treatments may protect against further insults by tipping the balance in favour of a pro-survival UPR (5). Cancer cells with constitutive activation of ER stress response and upregulation of ER chaperone have been indicated to be associated with therapeutic resistance (4,6). One of the ER chaperone proteins, prolyl 4-hydroxylase, beta polypeptide (P4HB), has been reported to have critical roles in TMZ resistance and contribute to glioma recurrence driven by ER stress response. Significant upregulation of P4HB expression was observed in patients with recurrent glioma, as well as in TMZ-resistant xenografts (7,8). P4HB gene silencing also enhanced cellular apoptosis in TMZ-resistant glioma cells (4). Furthermore, Xipell et al (9) demonstrated the adjuvant effect for TMZ treatment through targeting ER stress, where MGMT expression was reduced following a combinatorial treatment regimen, suggesting a dual effect in sensitizing tumours to TMZ by mediating ER stress-induced apoptosis, as well as limiting the DNA damage repair by MGMT.
ER chaperones have emerged as predictive markers for treatment response. Given that P4HB is associated with glioma malignancy and TMZ resistance, the present study evaluated whether assessment of P4HB expression may provide valuable clinical information for predicting response to TMZ and patient survival, irrespective of the MGMT promoter methylation status. The potential application of P4HB as a novel biomarker to further stratify glioma into more clinically relevant entities was also discussed and highlighted.
Materials and methods
Study population
The present study was a retrospective analysis of 73 patients (age range, 6–75 years; mean age, 47.3±14.9 years; 61.6% males and 38.4% females) with gliomas [World Health Organization (WHO) grade I, 4.1%; WHO grade II, 17.8%; WHO grade III, 19.2% and WHO grade IV, 58.9%]. All patients recruited in the study received the standard of care, i.e. maximal surgical resection followed by adjuvant radiation with concurrent and adjuvant TMZ, except those labelled as ‘patients without TMZ treatment’, who had undergone maximal surgical resection and were treated with radiotherapy without TMZ from the same cohort. Clinical specimens were collected from Queen Mary Hospital, Hong Kong, between February 2001 and February 2012. Clinical data were retrieved for statistical analysis, including patients' demographic data, tumour characteristics (i.e. lesion sites, pathological classification, WHO grade), treatment approaches after surgical resection (radiotherapy and/or chemotherapy), number of TMZ cycles received (≤6 or >6) and MGMT promoter methylation status, as well as OS and progression-free survival (PFS) duration. OS is defined as the time from initial pathological diagnosis to death or to the last contact if the patient was alive or the last day of the study period. PFS is defined as the time from initiation of treatment to the occurrence of disease progression or death. All patients had their diagnosis confirmed by a pathology specialist. The study was approved by the Institutional Review Board of The University of Hong Kong, Hong Kong west cluster and all tissues were collected with written informed consent from the patients.
P4HB immunohistochemical analysis
Immunohisto-chemical staining procedures were performed according to the protocol described in a previous study by our group (8). Paraffin sections were deparaffinized in xylene and rehydrated in a descending ethanol series. Heat-induced antigen retrieval was performed with citrate buffer (pH 6.0; MilliporeSigma) for 10 min in a microwave at high power and endogenous tissue peroxidase in the sections was quenched with 3% hydrogen peroxide for 20 min at room temperature. After blocking with 5% normal goat serum (Dako; Agilent Technologies, Inc.) for 30 min at room temperature, sections were immunostained with rabbit monoclonal anti-P4HB (cat. no. 3501; 1:1,000 dilution; Cell Signaling Technology Inc.) at 4°C overnight. After incubation with HRP-conjugated antibody (Zymed; Thermo Fisher Scientific, Inc.) for 1 h at room temperature, signals were detected using an EnVision™+ Kit (Dako; Agilent Technologies, Inc.). P4HB expression was assessed semi-quantitatively by two experienced pathologists. A total of 10 random high-power fields were examined under a light microscope (Olympus Corporation). The staining intensity was scored as follows: 0 (negative), 1 (weak), 2 (moderate) and 3 (strong). The proportional of stained tumour cells was scored as 0 (0%), 1 (1–25%), 2 (26–50%), 3 (51–75%) and 4 (>75%). Multiplication of these two variables was performed to calculate the final score. Samples were considered positive if the score exceeded the median value.
Statistical analysis
SPSS 18.0 (SPSS, Inc.) was used for statistical analysis. The difference between two sets of data was analyzed by the χ2 test, Mann-Whitney U-test (non-parametric test) or Fisher's exact test. The Kruskal-Wallis test was used to compare differences among more than two groups of data. In the Kaplan-Meier survival analysis, patients were dichotomized into two groups and survival differences between groups were assessed by the log-rank test. Risk factors for mortality after treatment were identified by univariate and multivariate analysis using the Cox proportional hazards regression model. All statistical tests were two-sided and P<0.05 was considered to indicate statistical significance.
Results
P4HB levels in glioma
P4HB has previously been identified by our group to be dysregulated in high-grade glioma (8). In the present study, its association with other clinicopathological parameters was further analyzed in 73 patients with glioma with complete clinical follow-up data using immunohistochemical staining. Consistent with the previous findings by our group, P4HB expression was significantly associated with the WHO grade (P=0.002; Table I). WHO grade IV glioma had the highest expression of P4HB among all WHO grades of glioma (Fig. 1A). The χ2 test revealed that high P4HB expression levels were significantly associated with a patient age of >55 years (P=0.035). Fisher's exact test further indicated that in patients who received radiotherapy (P=0.015) and chemotherapy (P=0.050), significant differences between P4HBLow and P4HBHigh groups were present (Table I).
 | Table I.Association of P4HB expression with the clinical and molecular characteristics in high-grade glioma (n=57). |
Prognostic value of P4HB in glioma
To explore the prognostic value of P4HB in glioma, patients were stratified into two groups by transforming the continuous variable of P4HB immunohistochemical scoring into a categorical variable [P4HBLow (score values ranging from 0 to <1) and P4HBHigh groups (score values ranging from ≥1-12)], based on the median value of the study samples. According to Kaplan-Meier analysis, patients of the two groups differed significantly in terms of OS duration; the median survival of patients with a high level of P4HB was ~16 months, significantly shorter than that of patients with a lower level of P4HB (131 months; log-rank P=0.015; Fig. 1B). To avoid potential bias due to relatively low P4HB expression in less malignant gliomas and to identify a meaningful subgroup for the clinical predictive value of P4HB, only WHO grades III and IV were included in the subsequent analysis (n=57). Similar results were obtained, suggesting that high P4HB predicted unfavorable survival and vice versa (P4HBLow, 20 months; P4HBHigh, 13 months; log-rank P=0.014; Fig. 1C).
To further investigate the prognostic value of P4HB in the prediction of PFS, Kaplan-Meier survival analysis was performed in the same dataset of WHO III and IV gliomas. The results demonstrated that the subgroup with low P4HB expression had a longer time to progression, whereas that with high P4HB had a shorter time to progression (P4HBLow, 12 months; P4HBHigh, 6 months; log-rank P=0.026; Fig. 1D).
P4HB predicts survival in TMZ-treated population
Whilst several chemotherapeutic agents are available for the treatment of glioma (10), TMZ is the most widely used and is a Food and Drug Administration-approved first-line chemotherapeutic (11,12). In the present dataset, patients who received TMZ exhibited longer OS (20 months) than those who did not (11 months; P=0.001; Fig. 2A). Patients who were on TMZ treatment expressed a significant level of P4HB compared to those who did not receive TMZ (P=0.045; Fig. 2B). The patients were then stratified into those who had received TMZ treatment and those who had not in order to determine the prognostic value of P4HB with regard to TMZ treatment. Among the patients who had received TMZ, a high level of P4HB expression was observed to be significantly associated with shorter OS as compared with a lower level of P4HB expression (P=0.014; Fig. 2C), whereas no such association was found in patients who received no TMZ therapy, suggesting a potential relationship between TMZ chemotherapy response and P4HB expression (Fig. 2D). The same was observed with regard to PFS: High P4HB expression was associated with shorter PFS (8 months) compared to low P4HB expression in patients treated with TMZ (39 months; P=0.027), but not in those who did not receive TMZ therapy (Fig. 2E and F). These results are suggestive of a prominent predictive impact of P4HB in a subset of patients with high-grade glioma who received TMZ therapy.
P4HB predicts survival in patients with methylated MGMT
MGMT is a DNA repair enzyme that is able to effectively reverse DNA damage induced by TMZ, and the MGMT promoter methylation status has a significant impact on survival of patients with glioma. A high level of MGMT activity may render tumours resistant to alkylating agents and may therefore serve as both a predictive and prognostic molecular marker in high-grade glioma (3). A significant difference in OS was determined between patients with tumours exhibiting MGMT methylation and those without, regardless of treatment received in this subset of patients with high-grade glioma (MGMTMeth, 47 months; MGMTUnmeth, 16 months; log-rank P=0.002; Fig. 3A). The association between the MGMT methylation status and P4HB expression was then investigated. A significant difference in OS was observed between the P4HBLow (254 months) and P4HBHigh groups (8 months) of patients with methylated MGMT tumours (P=0.002; Fig. 3B), whereas patients with unmethylated MGMT tumours exhibited no significant difference in OS between P4HB subgroups (data not shown). Univariate analysis using the Cox proportional hazards model indicated that P4HB expression had a significant impact on OS of patients with methylated MGMT tumours [hazard ratio (HR)=4.261, 95% CI=1.312-13.846, P=0.016] but not in those with unmethylated MGMT lesions (HR=1.038, 95% CI=0.372-2.892, P=0.944; Table SI).
MGMT is a well-established biomarker for the prediction of TMZ treatment response (3) and high P4HB expression has previously been identified by our group to be associated with TMZ resistance both in vitro and in vivo (4). In the present study, the interrelationship between MGMT promoter methylation and P4HB expression was further investigated by Kaplan-Meier analysis of PFS. Patients were divided into four groups according to the expression of the two markers. Among the 42 TMZ-treated patients with high-grade glioma, MGMTMethP4HBLow was associated with the longest PFS (n=11; 48 months), followed by MGMTMethP4HBHigh (n=15; 7 months), MGMTUnmethP4HBLow (n=2; 6 months) and MGMTUnmethP4HBHigh (n=14; 4 months; Fig. 3C). Results were statistically significant (P=0.001), suggesting that P4HB may be used to assist in the survival prediction of patients with methylated MGMT and by identifying certain patients who may respond poorly to TMZ.
P4HB in the prediction of response to TMZ in high-grade glioma
Since it has been observed that P4HB expression was significantly associated with both OS and PFS exclusively in patients treated with TMZ and that P4HB may have important roles in affecting glioma malignancy and TMZ resistance both in vitro and in vivo (8), the clinical significance of P4HB in predicting TMZ treatment response was further investigated.
Among the 57 patients with high-grade glioma, 37 patients had been treated with adjuvant TMZ, and 19 patients with high P4HB expression were indicated to have relapse during TMZ treatment. The latter group exhibited a mean P4HB expression score of 6.74, which was almost double that in those who exhibited favourable responses to TMZ (P4HB mean expression score, 3.25). High expression of P4HB was significantly associated with relapse during TMZ treatment (P=0.015; Fig. 3D).
P4HB is an independent prognostic factor for high-grade glioma
Clinicopathological factors affecting OS and PFS in patients with high-grade glioma were examined (Table II). Univariate analysis indicated that age at diagnosis (P=0.005), WHO grade (P=0.000), chemotherapy (i.e., TMZ) (P=0.001), MGMT methylation status (P=0.004) and P4HB expression level (P=0.018) were significantly associated with OS. Multivariate analysis using the Cox regression model demonstrated that not only WHO grade (P=0.002) and chemotherapy (TMZ) (P=0.001), but also P4HB expression levels were independent prognostic markers for OS (P=0.048). Patients with high P4HB expression also had less favorable PFS outcomes compared with those with low P4HB expression. On univariate analysis, WHO grade (P=0.007), MGMT (P=0.010), the number of TMZ cycles (P=0.020) and P4HB expression (P=0.035) were significant prognostic factors by PFS. Multivariate analysis indicated that among all prognostic factors, whilst P4HB expression did not reach statistical significance, it was the only factor with a marginal association with PFS, suggestive of its potential as an independent prognostic factor in terms of PFS (Table II).
| Table II.Univariate and multivariate Cox regression analyses of OS and PFS in patients with high-grade glioma (n=57). |
Discussion
TMZ has been widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is frequently limited by the development of chemoresistance. Intertumoral heterogeneity among patients with glioma, such as epigenetic silencing of MGMT, is the most studied mechanism and is a promising predictive marker for TMZ response (13). Whilst the prognosis of patients with high-grade malignant glioma is generally poor (with median OS <16 months in the present cohort), it was observed that it is possible to further identify subgroups of patients with differing prognoses according to P4HB expression, on top of MGMT promoter methylation status. As a key member of the protein disulfide isomerases (PDI) family, P4HB acts as a chaperone mediator in the UPR and modulates ER stress response similar to glucose-regulated protein 78, which is a master regulator of UPR (14). Activation of UPR via inhibition of chaperone proteins has previously been identified to be associated with a reduction in DNA repair capacity (15) and may create vulnerabilities that sensitize aggressive tumours to cytotoxic drugs and prevent cancer progression and/or recurrence (16,17).
P4HB was previously identified by our group to possess oncogenic (pro-survival) properties in malignant glioma (7). PDI has recently been reported to be a promising target for survival prediction and tumour progression in glioma (18). However, the reported findings were limited to bioinformatics modeling of gene expression using datasets from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases; no clinical specimens were directly used in that study. In the present study, a glioma cohort comprising 73 patients was included to evaluate the prognostic significance of P4HB. The results were consistent with the literature that reported upregulation of P4HB in high-grade gliomas when compared to low-grade lesions. Furthermore, overexpression of P4HB was significantly associated with several clinical parameters, including older age and prolonged use of TMZ, which may be indicative of a more aggressive tumour that required extended treatment.
The present study indicated that P4HB expression may be used to predict OS and PFS in patients with malignant glioma treated with TMZ. The predictive value of P4HB was particularly prominent in subgroups of TMZ-treated malignant glioma populations as compared with those who did not receive TMZ. This may be explained by the poor pre-existing neurological or general condition of the patients who were not fit for chemotherapy, as the median OS in both P4HBLow and P4HBHigh patients in the non-TMZ-treated group were only 10 and 12 months, respectively. It is important to note that the median OS in P4HBLow patients was significantly longer (254 months) than in P4HBHigh patients (14 months), suggesting that tumours with low P4HB may be more responsive to TMZ treatment compared to tumours with P4HB upregulation. In other words, overexpression of P4HB may confer resistance to chemotherapies secondary to increased ER stress and UPR, which is in line with previous findings by our group. Under treatment with TMZ, the UPR signaling cascade is initiated upon activation of protein kinase RNA-like ER kinase, an ER stress sensor. Such perturbation on ER activates upregulation of different target genes, including ER chaperones and folding enzymes, in order to restore ER homeostasis (4). Indeed, aberrant expression of P4HB was previously reported to be associated with TMZ-resistant D54 and U87 glioma cell lines (7).
Furthermore, inhibition of P4HB was reported to be able to attenuate TMZ resistance (4), whereas overexpression promoted malignancy via MAPK signaling (8). Chronic TMZ treatment may also exacerbate drug resistance by further upregulating P4HB expression (4).
Of note, P4HB expression levels enabled the stratification of patients with methylated MGMT to guide the treatment by predicting the response to TMZ. Whilst the MGMT promoter methylation status retained significance in predicting treatment response, P4HB expression was observed to have additional value, when used alone or in combination with the MGMT methylation status, for identifying patients at risk of adverse health outcomes (19). P4HBLow in conjunction with MGMTMeth was associated with the most favorable prognosis regarding PFS in TMZ-treated patients with malignant glioma, whereas P4HBHigh MGMTUnmeth tumours were more likely to have suboptimal responses to TMZ. It is noteworthy that the MGMT promoter methylation status may be altered upon tumour recurrence. Kohsaka et al (20) demonstrated upregulation of MGMT protein expression during the acquisition of TMZ resistance in U87 glioma cells. Whilst it remains elusive whether this was the result of MGMT promoter unmethylation, the increase in MGMT expression during the course of TMZ treatment appeared to further reduce TMZ responsiveness.
It is a common observation that initially, TMZ-sensitive malignant glioma may eventually become resistant, partly due to the restoration of MGMT activity (21). The present findings suggest that P4HB expression may be used to identify tumours likely to benefit from prolonged TMZ treatment even before recurrence. For recurrent diseases, rechallenge with TMZ is a commonly adopted strategy but no reliable predictive factors have been identified so far (22). It may be surmised that P4HB expression may be used to identify recurrent tumours that may still respond favourably to TMZ rechallenge. The present findings also have the potential for informing future treatment paradigms. While the stratification of patient subgroups by P4HB was primarily based on the MGMT methylation status, the clinical significance of P4HB may be limited by the small cohort size and missing clinical parameters, such as extent of resection and other prognostic markers, including isocitrate dehydrogenase mutation status. Future studies may also include molecular investigations to determine drug response upon P4HB inhibition in glioma.
In conclusion, P4HB is a component of UPR that has important roles in mediating glioma survival, therapeutic resistance and tumour progression. In this context, P4HB expression has been indicated to be significantly associated with PFS and OS in patients with malignant glioma and may be used as an independent prognostic marker. P4HB may be used on its own or in combination with MGMT to stratify patients who are good responders to glioma therapeutics. Furthermore, P4HB expression may also inform a more nuanced approach to the use of an extended TMZ regimen as well as TMZ rechallenge. Future research may be conducted in a larger and standardized cohort, and evaluate the association between P4HB expression and other important biomarkers, which eventually give rise to fruitful clinical translations.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SS collected the data, performed statistical analysis and wrote the manuscript. KK participated in the study design and wrote the manuscript. GL conceived the study and contributed to the critical revision. SS, KK and GL confirm the authenticity of the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study protocol was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Human tissue specimens were obtained with informed consent from the patients.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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