RESUMO
OBJECTIVES: The aim of the current study was to examine expression and the role, if any, of aldehyde dehydrogenase (ALDH)1B1 in pancreatic adenocarcinoma. METHODS: A tissue microarray of 61 pancreatic cancer patients were evaluated for protein expression of ALDH1B1 by immunohistochemistry. The ALDH1B1 small interfering (RNA) was used to assess the contribution of ALDH1B1 on proliferation of pancreatic cancer cells. RESULTS: In normal human pancreas, ALDH1B1 is abundantly expressed in glandular cells, but sparsely in the ducts (ALDH1B1 immunopositivity = 16.7 ± 1.7). In pancreatic ductal carcinoma, we found high ALDH1B1 expression in ductal cancerous tissues (ALDH1B1 immunopositivity = 197.2 ± 29.4). Analysis of ALDH1B1 expression in a human pancreatic adenocarcinoma tissue microarray showed the greatest expression in tumors that were more invasive. A variation in ALDH1B1 expression was also observed in 16 human pancreatic cancer cell lines. Knockdown of ALDH1B1 caused a 35% reduction in cell growth in the high ALDH1B1-expressing cell lines. CONCLUSIONS: Our data show for the first time that ALDH1B1 is expressed at very high levels in human pancreatic cancer, and it contributes to proliferation in these tumor cells. These data suggest a potential modulatory role for ALDH1B1 in pancreatic cancer.
Assuntos
Aldeído Desidrogenase/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Neoplasias Pancreáticas/enzimologia , Aldeído Desidrogenase/genética , Família Aldeído Desidrogenase 1 , Aldeído-Desidrogenase Mitocondrial , Animais , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos Nus , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Interferência de RNA , Transdução de Sinais , Análise Serial de Tecidos , Transfecção , Carga Tumoral , Regulação para CimaRESUMO
Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.