Expression and prognostic significance of microsomal triglyceride transfer protein in brain tumors: a retrospective cohort study

Introduction

Glioblastoma (GBM), which originates from astrocytes, is the most common central nervous system (CNS) tumors, explaining 55% of all gliomas and 45.2% of malignant brain tumors (1,2). GBM is associated with significant mortality (3) and the 5-year survival rate of GBM is only 3–4% despite therapeutic advances (4). The fact indicates that understanding the pathogenesis of GBM is important for effective treatment. The significance of molecular markers in diagnosis has been emphasized by the World Health Organization (WHO) CNS5 classification of 2021 (5). The most significant alterations are related to diffuse gliomas, in which isocitrate dehydrogenase (IDH) status have gained importance (6,7). IDH wild type (WT) is referred to grade 4 in 2021 WHO CNS5 classification. Even though it has low-grade features histologically, IDH-WT glioma is considered grade 4 GBM. IDH-WT GBM has a lower survival rate compared to IDH-mutant type (15 vs. 31 months) (8). Therefore, new approaches to GBM are needed to better understand its molecular properties and improve survival.

Cholesterol has received increasing attention because of its function in cancer. Studies have shown that the altered cholesterol metabolism is associated with cancer development and progression (9). High serum cholesterol levels have been reported to increase the incidence of developing cancers, and cholesterol-lowering agents have beneficial effects by reducing the risk of mortality from colorectal, breast, and prostate cancers (10,11). It has been found that the cholesterol pathway is upregulated in patients with GBM and that cholesterol biosynthesis-related genes are downregulated in densely plated normal astrocytes (12). David et al. showed that the hazard ratios for death due to GBM were significantly reduced by using high-intensity statins, the most common lipid-lowering drugs (13). Therefore, targeting the regulation of cholesterol metabolism may be a potential strategy for GBM treatment.

Microsomal triglyceride transfer protein (MTTP), a target of lomitapide which was approved by Food and Drug Administration [2012], is a principal cellular protein that transfers neutral lipids between membrane vesicles and is a target molecule to treat diseases that produce high apolipoprotein B (apoB) lipoproteins such as familial combined hyperlipidemia, hypertriglyceridemia, and atherosclerosis (14,15). The main site of MTTP expression is the small intestine and the liver and MTTP is expressed in neurons as well (15). A study reported that Mttp intestinal knock-out mice showed increased tumor formation (16). However, it is unidentified if the change of MTTP expression associates with the occurrence of CNS tumors and prognosis of patients with CNS tumors.

In this study, the comparison of MTTP expression between normal and brain tumors was evaluated, and the correlation between the MTTP expression and clinical information in CNS tumors was also examined. In addition, the effects of MTTP on the survival rate of patients with brain tumors were assessed, and the impact of MTTP as a prognostic marker of brain tumors was determined when compared with other prognostic factors. We present this article in accordance with the REMARK reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2286/rc).

Methods

Patients and data collection

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Cancer Genome Atlas (TCGA) database includes clinical information of a large number of patients and also contains information on RNA expression, DNA methylation, and miRNAs in several types of cancers. TCGA data of 1,099 patients with brain tumors were downloaded, as previously described (17). Among them, 434 patients were excluded owing to a lack of information on MTTP expression in 432 patients and clinical data of two patients. Finally, clinical data corresponding to 665 patients with brain tumors was included for prognosis analysis in this study.

Age, sex, race, histological type, overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), and MTTP expression were selected as the clinical attributes. Histological types were divided into low-grade glioma (LGG) and GBM based on the tumor stage. OS refers to the period from the initial day of diagnosis of brain tumors to death from any cause or the last follow-up. PFS refers to the time from the initiation of the treatment to the initial stage of cancer acceleration or relapse for any reason. DSS refers to the period from the day of diagnosis to death due to brain tumors compared to other causes.

MTTP expression datasets of normal tissues corresponding to brain tumor tissues were extracted from the database of the Genome Data Analysis Center. The Gene Expression Omnibus (GEO) is a public genomics database that includes array- and sequence-based data. The GSE50161 dataset was retrieved from GEO to investigate whether the expression of MTTP is higher in brain tumors than in normal tissues and the GSE4271 dataset was used to confirm the prognostic significance of MTTP in brain tumors.

Definition of brain tumors in TCGA

Brain tumor samples included in TCGA were collected between 1989 and 2013. All cases were diagnosed according to WHO guidelines and were classified into only two groups based solely on histopathological characteristics in this study. Low-grade glioma (LGG) was defined as grades II and III and GBM was defined as grade IV according to the histopathological classification of primary brain tumors.

Statistical analyses

The comparison of the MTTP expression values between normal and brain tumors (LGG and GBM) was examined as the Mann-Whitney U-test or the Student’s t-test after applying the Shapiro-Wilk normality test. A Chi-squared formula was used to assess the relation between MTTP expression and patient’s characteristics. For Kaplan-Meier (KM) survival plots, subjects with brain tumors were classified into two groups (low MTTP and high MTTP expression) depending on the median of MTTP expression. To calculate P values, a log-rank test was performed. Univariable and multivariable Cox proportional hazard regression analyses were conducted to investigate whether MTTP was a significant marker of OS, PFS, and DSS.

Box and whisker plots were generated using Microsoft Excel. IBM SPSS Statistics for Windows version 21 (IBM Corp., Armonk, NY, USA) was used for KM plots and statistical analyses. MedCalc (version 22.016) was conducted for obtaining number at risk. P value less than 0.05 is considered significant. To determine the association between immune cell infiltration and MTTP expression, TIMER 2.0 was used (http://timer.cistrome.org/).

Results

Clinical characteristics

The clinical information of patients with brain tumors was represented (Table 1). Of the 665 participants, 505 (75.9%) were ≤60 years old, 110 (16.5%) were >60 years old, and the age of 50 (7.5%) patients was unknown. The sex proportion was 52.0% for males and 40.5% for females, and the sex of 7.5% of the patients was unknown. The proportion of white people was higher (n=567, 85.3%) than non-white people (5.6%). A higher number of patients had LGG (77.1%) than GBM (22.9%). The mean OS of patients with brain tumors was 27.62±29.34 months.

Expression level of MTTP in normal brain tissue, LGG, and GBM

MTTP expression was higher in brain cancers than in normal samples (normal tissues: 4.45±0.406, brain tumors: 5.92±1.670, P=0.01) (Figure 1A). The GEO dataset (GSE50161) was analyzed to determine if MTTP expression levels corresponding to normal tissues and brain tumors were consistent with the results obtained using TCGA database (Figure 1B). As a result, MTTP expression in brain tumors was significantly elevated than that in normal samples. Importantly, the expression of MTTP in GBM was significantly higher than that in LGG (LGG: 5.67±1.477, GBM: 6.75±1.995, P<0.001) (Figure 1C). However, MTTP expression levels did not differ between males and females (males: 5.81±1.628, females: 5.94±1.665, P=0.35) (Figure 1D).

Figure 1 MTTP expression in normal and brain tumor tissues. (A) The mean ± SD of MTTP expression in normal (n=5) and brain tumor (n=665) was 4.45±0.406 and 5.92±1.670, respectively (P=0.01). (B) MTTP expression in normal (n=13) and brain tumor (n=117) tissues (GSE50161). The mean ± SD of MTTP expression in normal and brain tumor tissues was 2.54±0.114 and 4.06±2.127, respectively (P<0.001). (C) MTTP expression level in LGG (n=513) and GBM (n=152). The mean ± SD of MTTP expression in LGG and GBM was 5.67±1.477 and 6.75±1.995, respectively. (D) MTTP expression in males and females. The number of males and females was 346 and 269, respectively. The mean ± SD of MTTP expression in males and females was 5.81±1.628 and 5.94±1.665, respectively (P=0.35). MTTP, microsomal triglyceride transfer protein; LGG, low-grade glioma; GBM, glioblastoma; SD, standard deviation.

Correlation between MTTP expression and clinical information

To assess the relation between MTTP expression and patient information, patients with brain tumors were classified into the low- and the high-expression groups based on the level of MTTP expression. High expression of MTTP was significantly associated with older age and higher tumor stage but not with sex or race (Table 2).

OS, PFS, and DSS for MTTP expression groups

To investigate the value of MTTP expression as a prognostic factor for GBM, KM survival analysis was conducted for the MTTP-high and MTTP-low expression groups against OS (Figure 2, Table 3). The median OS of the high MTTP expression was lower than that of the low MTTP expression in the total cohort (MTTP-high: 36.82±6.612 months, MTTP-low: 75.02±8.096 months, P<0.001) (Figure 2A). In LGG, the OS was 98.24±21.862 months for low MTTP expression group and was 73.48±17.560 months for high MTTP expression group (P=0.03) (Figure 2B). Similarly, the median OS of the high MTTP expression group was lower than that of the low MTTP expression group in GBM (MTTP-high: 11.28±1.113 months, MTTP-low: 14.93±0.847 months, P=0.008) (Figure 2C). To determine whether MTTP expression had a more significant effect on the prognosis of LGG and GBM, KM plots were plotted for the high and low MTTP expression group against PFS and DSS. The PFS of high MTTP expression group was less than that of low MTTP expression group (MTTP-high: 18.15±2.335 months, MTTP-low: 39.62±4.909 months, P<0.001) (Figure 2D). There was no difference between the high and low MTTP expression group in LGG (P=0.08) (Figure 2E). The PFS of high MTTP expression group was significantly decreased, as compared to that of low MTTP expression group in GBM (MTTP-high: 5.16±0.663 months, MTTP-low: 7.59±0.739 months, P=0.02) (Figure 2F). The median DSS of the high MTTP expression group was lower than that of the low MTTP expression group (MTTP-high: 40.54±7.345 months, MTTP-low: 78.21±10.468 months, P=0.02) (Figure 2G). In LGG, the DSS of the high and low MTTP expression groups was estimated to be 87.45±14.980 months and 98.24±21.099 months, respectively (P=0.02) (Figure 2H). Similarly, the median DSS of high MTTP expression group was less than that of low MTTP expression group in GBM (MTTP-high: 11.28±1.113 months, MTTP-low: 15.78±0.795 months, P=0.02) (Figure 2I). Next, GSE4271 was analyzed to confirm whether patients with high MTTP expression in brain tumors had poorer survival (Figure 3). The result revealed that the median OS of the high MTTP expression group was lower than that of the low MTTP expression group (MTTP-high: 62.00±4.151 months, MTTP-low: 150.00±60.325 months, P=0.001).

Figure 2 OS, PFS, and DSS based on MTTP expression. Kaplan-Meier analysis was performed for MTTP low- and high-expression groups for OS, PFS, and DSS. Blue line: low MTTP expression; red line: high MTTP expression. (A) The median OS of MTTP high and low. (B) In LGG, the median OS of MTTP high and low. (C) In GBM, the median OS of MTTP high and low. (D) The median PFS of MTTP high and low. (E) In LGG, the median PFS of MTTP high and low. (F) In GBM, the median PFS of MTTP high and low. (G) The median DSS of MTTP high and low. (H) In LGG, the median DSS of MTTP high and low. (I) In GBM, the median DSS of MTTP high and low. MTTP, microsomal triglyceride transfer protein; OS, overall survival; PFS, prognostic free survival; DSS, disease-specific survival; LGG, low-grade glioma; GBM, glioblastoma.

Figure 3 OS based on MTTP expression (GSE4271 dataset). Kaplan-Meier analysis of the MTTP low- and high-expression groups for OS. The median OS of MTTP high- (red, n=39) and low- (blue, n=38) groups was 62.00±4.151 and 150.00±60.325 weeks (P=0.001), respectively. OS, overall survival; MTTP, microsomal triglyceride transfer protein.

Relationship between MTTP expression and prognosis

To identify the prognostic importance of MTTP, the Cox proportional hazard regression were conducted. With the MTTP expression, factors known to affect prognosis, such as matrix metallopeptidase 2 (MMP2), insulin-like growth factor binding protein 2 (IGFBP2), phosphatase and tensin homolog (PTEN), and marker of proliferation Ki-67 (MKI67) were evaluated. Univariable analysis showed that age, tumor stage, expression levels of IGFBP2, MKI67, PTEN, and MTTP were significantly related with OS (Table 4). Similarly, the multivariable analyses showed that age, tumor stage, expression levels of IGFBP2, MKI67, PTEN, and MTTP were significantly related with OS (Table 4). The hazard ratios for age, stage, IGFBP2, MKI67, PTEN, and MTTP were 2.875, 2.773, 2.947, 1.536, 0.556, and 1.369, respectively.

Survival analysis of the combined prognostic factors

KM analysis was performed using a combination of age and MTTP expression in the total cohort and the LGG and GBM patient sub-groups (Figure 4, Table 5). For the total cohort, the OS was decreased significantly with older age (median OS of aged patients >60/≤60 years: 15.95±1.996/78.21±10.865 months, P<0.001) (Figure 4A). Survival curves produced by a combination of MTTP expression and age, showed that the median of older age with high MTTP expression was 12.56±0.876 months, and these patients showed the worst prognosis (P<0.001) (Figure 4B). In addition, the mixed group, i.e., younger patients with high MTTP expression or older patients with low MTTP expression showed moderate prognosis (median OS: 50.14±5.349 months, P<0.001). In the LGG group, the median OS was 94.52±10.984 months in younger patients, and 23.90±6.085 months in older patients (P<0.001) (Figure 4C). Survival curves produced by a combination of age and MTTP expression showed that the median OS of older age with high MTTP expression was 18.44±5.585 months, and these patients showed the worst prognosis in LGG (P<0.001) (Figure 4D). Similarly, in patients with GBM, median OS was decreased with increasing age, as in LGG (median OS of older/younger patients: 11.01±2.080/16.64±1.392 months, P=0.006) (Figure 4E). After combination with the level of MTTP expression, the median OS of older age with high MTTP expression was 8.84±3.190 months, which was the worst prognosis among all groups, similar to the pattern above (P=0.02) (Figure 4F).

Figure 4 Kaplan-Meier analysis after a combination of age and MTTP expression level in LGG and GBM. Survival analyses were performed after age (low: ≤60 years vs. high: >60 years) and MTTP (low vs. high expression) groups were divided into three subgroups, blue line: low age + low MTTP; green line (mixed): low age + high MTTP or high age + low MTTP; red line: high age + high MTTP. (A) The median OS of the low- and high-aged groups. (B) The median OS of the low-age + low MTTP, high-age + high MTTP, and mixed groups. (C) In LGG, the median OS of the low- and high-aged groups. (D) In LGG, the median OS of the low-age + low MTTP, high-age + high MTTP, and mixed groups. (E) In GBM, the median OS of the low- and high-aged groups. (F) In GBM, the median OS of the low age + low MTTP, high age + high MTTP, and mixed groups. MTTP, microsomal triglyceride transfer protein; LGG, low-grade glioma; GBM, glioblastoma; OS, overall survival.

MTTP expression in IDH-WT and mutant

MTTP expression was significantly higher in IDH-WT than that in IDH-mutant (262.20±334.932 vs. 56.47±52.671, P=0.01) (Figure 5).

Figure 5 MTTP expression in IDH-WT and IDH-mutant brain tumors. MTTP expressions in IDH-WT vs. IDH-mutant brain tumors are shown as a box and whisker plot. The mean ± standard deviation of MTTP expression in WT (n=197) and IDH mutant (n=419) was 262.20±334.932 and 56.47±52.671, respectively (P=0.01). IDH, isocitrate dehydrogenase; IDH-WT, IDH-wild type; MTTP, microsomal triglyceride transfer protein.

Discussion

MTTP was first discovered as a major molecule that transfers neutral lipids from ER membranes to apoB-lipoproteins and is a target of lomitapide, a medicine used to treat patients with abetalipoproteinemia. However, the expression of MTTP and its prognostic significance in brain tumors have been poorly characterized.

Intestine-specific Mttp deletion in mice increased the tumor burden of colorectal cancer, which was associated with increased colorectal inflammation as well as changes in cytokine expression (16). Moreover, low MTTP expression has been correlated with poor recurrence-free survival in breast cancer (18). In contrast, in this study, MTTP expression was increased in the order of normal, LGG, and GBM and also was associated with the stage and age of patients with brain tumors (Figure 1, Table 2), suggesting that the function of MTTP was altered depending on kinds of cancer. For instance, high Notch signaling is associated with tumor grade and metastasis, but it has an inhibitory effect on GBM (19,20). Therefore, the role of MTTP in the occurrence and progression of cancers may be dependent on the cancer type.

Abnormal lipid metabolism plays important roles in the proliferation, migration, invasion, and angiogenesis of cancers (21,22). The brain, the most cholesterol-rich organ, consists of 23% total body cholesterol, and GBM also requires lipids for cell survival (23,24). GBM accumulates more fatty acids than the surrounding normal brain tissue and uses lipids as energy reservoirs (25,26). These lipid stores promote GBM proliferation and are maintained to avoid oxidative damage and lipotoxicity (27). Thus, it is worthwhile to investigate the association between the molecular targets involved in lipid metabolism and the prognosis of GBM. In this study, patients with high MTTP expression showed a significantly shorter OS, PFS, and DSS than those with low MTTP expression, except for median PFS in LGG (Figure 2, Table 3). Those results suggest that MTTP expression has a prognostic importance in brain tumors, especially GBM.

IGFBP2, which acts as the antagonist of the insulin-like growth factor (IGF) signal involved in tumor suppression, increases the proliferation and invasiveness of gliomas (28,29). In a study, the median survival of patients with low IGFBP2 mRNA expression was 16.9 months while that of patients with high IGFBP2 mRNA expression was only 11.6 months (30). KM analysis revealed a shorter survival time with a higher level of MMP2, which was also associated with brain tumors and metastasis (31). MKI67 is a non-histone nuclear protein that enters the mitotic cycle and is positively related to histological tumor grade in gliomas (32,33). Chen et al. reported that high levels of MKI67 expression are associated with poor OS in gliomas (34). PTEN is a tumor suppressor whose expression in glioma cells suppresses growth and inhibits migration and dissemination (35,36). Phillips et al. showed that low PTEN mRNA expression is associated with poor survival (37). Consistent with the reported studies, the present study reported IGFBP2, MMP2, MKI67, and PTEN as significant indicators of OS (Table 4). Importantly, MTTP expression level was also significantly associated with OS (Table 4). Thus, these findings suggest that MTTP is a prognostic factor in brain tumors.

Age and tumor stage are known as prognostic factors correlated with survival in LGG and GBM (38). According to the literature, the median survival of patients with LGG ranged from 5.6 to 13.3 years depending on specific histological and molecular characteristics, and the median survival of GBM was reported to be only 6 to 10 months (39,40). Since the survival period of patients with GBM is short, it is important to identify and manage patients with poor prognoses. Moreover, genes related to lipid metabolism have recently been identified as potential targets for the treatment of GBM and brain metastasis (25). For example, the activation of the liver X receptor (LXR) by LXR-623 (LXR agonist) decreased intracellular cholesterol levels and selectively killed GBM cells with improved survival in a mouse model (41). The survival period of mice treated with both temozolomide (TMZ) and lomitapide, which is supposed to pass through the blood-brain barrier, was increased by 1.34 times compared to the control group and by 1.14 times compared to mice treated with only TMZ (42). In this study, high MTTP expression is correlated with a higher brain tumor stage and higher MTTP expression with older patients showed the worst prognosis in all the groups (the total cohort, LGG, and GBM) (Tables 2,3,5, Figures 2,4). Those results suggest that MTTP can serve as a screening marker for GBM patients with poorer prognosis and may be a possible target for improving the prognosis of GBM patients.

The WHO classification of CNS tumors published in 2021, relied more heavily on molecular tests for diagnosis and grading than in 2016 with certain molecular markers providing strong prognostic information (8). Since the data used in the analysis were prepared before the 2021 WHO classification of brain tumors was announced, there may be differences from the current staging results. Nevertheless, IDH type is still an important factor in brain tumor prognosis. Previous studies showed that IDH-WT had a significantly poorer prognosis than IDH-mutant in CNS tumors (median survival of IDH-WT: 15 months, IDH-mutant: 31 months) (43). IDH plays several roles in cellular function such as lipogenesis, glucose sensing, and regulation of cellular redox status (44). Contrary to IDH-mutant, IDH1 and IDH2 (IDH-WT) increase NADPH/NADP⁺ which facilitates lipid biosynthesis and promotes cellular defense against reactive oxidative stress, and reduces the effect of chemotherapy and radiotherapy in GBM (45). In the present research, MTTP expression in brain tumors was significantly higher in the IDH-WT than in the IDH-mutant (Figure 5). In general, more than 90% of GBM is IDH-WT although there are several GBM with poor prognosis despite being IDH-mutant (46). Taken together, these results suggest that the role of MTTP in the lipid metabolism for cell proliferation of brain tumors may be associated with IDH status.

Strengths and limitations

The present study has some strengths. First, this is the first research to identify MTTP as an independent prognostic marker of patients with brain tumors. Thus, clinicians may use MTTP expression as a marker of poor prognosis for clinical management. Second, this is a large-scale study including MTTP expression and clinical data of patients with CNS tumors. Third, the research provides a basis for future investigation to improve the survival rate of patients with GBM using lomitapide.

Despite its strength, the present study has a few limitations. First, there was no patient information on risk factors including obesity, diabetes, history of smoking, and alcohol consumption. Second, this dataset does not contain information about spatial distribution, characteristics of MTTP expressing cells and the origin of brain tumor cells. Tumor purity is defined as the percent of cancer cells in the admixture. TCGA claims that 60% purity is sufficient to distinguish cancer signals from other cells and the purities of LGG and GBM in the TCGA database were more than 80% according to a systematic pan-cancer analysis of tumor purity (47). Thus, in this study, MTTP expression in LGG and GBM may be distinct from other cells. In addition, interestingly, it was found that the association between mRNA and protein expression was high in cancer cell lines (GBM, osteosarcoma, and epidermoid carcinoma) from 0.58 to 0.63 (48). If there is a high relation between mRNA and protein expression in cancers, MTTP protein expression in brain tumors may be high relative to the transcript of MTTP. Finally, there was no experimental evidence that high MTTP expression affects brain tumor development and progression. Therefore, further experimental investigation is needed to prove the findings of this study.

Conclusions

In conclusion, the present study showed that high MTTP expression in brain tumors including GBM is correlated with poor survival. Thus, MTTP is an independent prognostic indicator in brain tumor patients which may serve as a predictor for managing patients with brain tumors, thereby improving their OS. In addition, the study showed that MTTP is upregulated in brain tumors and is correlated with the tumor stage and IDH status. These findings provide a framework for experimental studies on the function of MTTP in the occurrence and progression of brain tumors and for studying the possibility of using lomitapide as adjuvant treatment for GBM through drug repositioning.

Acknowledgments

The authors wish to acknowledge the ‘The Cancer Genome Atlas’ (TCGA) database and the tools provided by the TCGA database.

Funding: This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2022R1F1A1074769; R.J.K.) and the Research Institute for Convergence of Biomedical Science and Technology (No. 20-2023-002), Pusan National University Yangsan Hospital. This study was supported by 2024 research grant from Pusan National University Yangsan Hospital. The funding bodies did not have a role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2286/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2286/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

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