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Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

ABSTRACT: Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients.

SUBMITTER: Liu RZ

PROVIDER: S-EPMC5595534 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

Liu Rong-Zong RZ Li Shuai S Garcia Elizabeth E Glubrecht Darryl D DD Poon Ho Yin HY Easaw Jacob C JC Godbout Roseline R

Glia 20160219 6

Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly ...[more]

PMID: 26893190

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Project description:BACKGROUND:Nephroblastoma or Wilms tumor is the most frequent kidney cancer in children and accounts for 98% of kidney tumors in this age group. Despite favorable prognosis, a subgroup of these patients progresses to recurrence and death. The retinoic acid (RA) pathway plays a role in the chemoprevention and treatment of tumors due to its effects on cell differentiation and its antiproliferative, anti-oxidant, and pro-apoptotic activities. Reports describe abnormal cellular retinoic acid-binding protein 2 (CRABP2) expression in neoplasms and its correlation with prognostic factors and clinical and pathological characteristics. The aim of this study was to evaluate the immunohistochemical expression of retinoic acid receptor alpha (RARA) and CRABP2 in paraffin-embedded samples of nephroblastomas via semiquantitative and quantitative analyses and to correlate this expression with prognostic factors. METHODS:Seventy-seven cases of nephroblastomas were selected from pediatric oncology services. The respective medical records and surgical specimens were reviewed. Three representative tumor samples and one non-tumor renal tissue sample were selected for the preparation of tissue microarrays (TMA). The Allred scoring system was used for semiquantitative immunohistochemical analyses, whereas a morphometric analysis of the stained area was employed for quantitative evaluation. The nonparametric Mann-Whitney test was used for comparisons between two groups, while the nonparametric Kruskal-Wallis test was used to compare three or more groups. RESULTS:Immunopositivity for RARA and CRABP2 was observed in both the nucleus and cytoplasm. All histological components of the nephroblastoma (blastema, epithelium, and stroma) were positive for both markers. RARA, based on semiquantitative analyses, and CRABP2, bases on quantitative analyses, exhibited increased immunohistochemical expression in patients with metastasis, with p values of 0.0247 and 0.0128, respectively. These findings were similar to the results of the quantitative analysis of RARA expression, showing greater immunopositivity in tumor samples of patients subjected to pre-surgical chemotherapy. No significant correlation was found with the other variables studied, such as disease stage, anaplasia, risk group, histological type, nodal involvement, and clinical evolution. CONCLUSIONS:Semiquantitative and quantitative analyses of the markers RARA and CRABP2 indicate their potential as biomarkers for tumor progression and their participation in nephroblastoma tumorigenesis.

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Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

Publications

Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

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