Tissue expression of retinoic acid receptor alpha and CRABP2 in metastatic nephroblastomas

Abstract

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.

Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling

“…CRABP2 has been found to be overexpressed in multiple cancers including bladder cancer 48 , Wilms tumor 49 , neuroblastoma 50 , pancreatic ductal adenocarcinoma 51 , serous sarcoma 52 , and non-small cell lung cancer (NSCLC) 5–7 . Increased CRABP2 levels were found in patients with metastatic nephroblastomas 53 . In glioblastoma tumors, CRABP2 were found to correlate with poor patient survival 26 .…”

Maintenance chemotherapy to reduce the risk of a metachronous Wilms tumor in children with bilateral nephroblastomatosis

“…Emerging evidence suggests that the retinoic acid pathway may play a role in nephroblastomagenesis. 10,11 One infant with bilateral diffuse nephroblastomatosis, who progressed on vincristine and dactinomycin, responded when 13-cis retinoic acid was added to her regimen. 12 Future studies are warranted to determine the optimal duration and interventions needed to prevent development of Wilms tumors in patients with predisposing lesions.…”

“…An alternative or potentially complementary approach to our maintenance chemotherapy could be treatment with a retinoic‐acid‐based differentiating agent. Emerging evidence suggests that the retinoic acid pathway may play a role in nephroblastomagenesis . One infant with bilateral diffuse nephroblastomatosis, who progressed on vincristine and dactinomycin, responded when 13‐cis retinoic acid was added to her regimen .…”

Hub Genes and Key Pathway Identification in Wilms Tumor Based on Bioinformatics Analysis

“…Similarly, GO enrichment analysis for down regulated genes was carried out. Enriched genes such as MEOX2 [217], SIX1 [218] and RARA (retinoic acid receptor, alpha) [219] were identi ed with development of WT. Methylation inactivation of enriched tumor suppressor genes such as HOXA5 [220], SALL2 [221], TCF21 [222], PAX1 [223], ZNF516 [224], EBF3 [225] and ZNF677 [226] were liable for advancement of various cancer types, but loss of these genes may be important for pathogenesis of WT.…”