RESUMO
Neuregulins (NRGs) are a family of signaling proteins that bind to receptor tyrosine kinases of the ErbB family (ErbB2 to ErbB4), which can homo- or heterodimerize depending on their structural features and cell type. Many studies have proposed that decreased NRG levels are a common characteristic of obesity. In liver and adipose tissue, the increase in NRG expression has protective effects against obesity. However, it is still unknown whether ErbBs expression is altered in this pathology. We hypothesized that high fat diet-induced obesity downregulates ErbB receptors expression in obese mice compared to normal weight mice. Males C57BL/6 mice (n=6-7 for each group) were fed for 12 weeks and divided into: (i) control diet (CD; 10%-kcal fat, 20%-kcal protein, 70%-kcal carbohydrates), and (ii) high fat diet (HFD; 60%-kcal fat, 20%-kcal protein, 20%-kcal carbohydrates). General parameters and ErbBs expression (qPCR, immunohistochemistry and Western blot) were evaluated. We observed a significant increase in final body weight (47%), adipose tissue to body weight ratio (244%) and HOMA-IR (69%), among other parameters, in obese mice. In HFD group significantly decreased ErbB2 (48%) and ErbB3 (66%) mRNA levels in liver (no change in ErbB4), and ErbB2 (43%), ErbB3 (76%) and ErbB4 (35%) in adipose tissue, compared to CD. Furthermore, ErbB2 and ErbB3 protein levels decreased significantly in HFD group compared to the CD in liver. Therefore, our results suggest that HFD-induced obesity significantly decreases ErbBs expression in liver and adipose tissue in this murine model, that may be associated with alterations in the NRG pathway in obese mice.
Las neuregulinas (NRGs) son una familia de proteínas de señalización que se unen a receptores tirosina quinasas de la familia ErbB (ErbB2 a ErbB4), que pueden homo- o heterodimerizar dependiendo de sus características estructurales y del tipo celular. Estudios han propuesto que la disminución de los niveles de NRG es una característica común de la obesidad. En el hígado y el tejido adiposo (TA), el aumento de la expresión de NRG tiene efectos protectores contra la obesidad. Sin embargo, aún se desconoce si la expresión de ErbBs está alterada en esta patología. Nuestra hipótesis es que la obesidad inducida por una dieta alta en grasas (DAG) disminuye la expresión de los ErbB en ratones obesos. Ratones machos C57BL/6 (n=6-7 para c/grupo) fueron alimentados durante 12 semanas y divididos en: (i) dieta control (DC; 10%-kcal grasa, 20%-kcal proteína, 70%-kcal carbohidratos), y (ii) DAG (60%-kcal grasa, 20%-kcal proteína, 20%-kcal carbohidratos). Se evaluaron los parámetros generales y la expresión de ErbBs (qPCR, inmunohistoquímica y Western blot). Observamos un aumento significativo del peso corporal final (47%), de la relación tejido adiposo/peso corporal (244%) y del HOMA-IR (69%), entre otros parámetros, en ratones obesos. En este grupo disminuyó significativamente los niveles de ARNm de ErbB2 (48%) y ErbB3 (66%) en el hígado (sin cambios en ErbB4), y de ErbB2 (43%), ErbB3 (76%) y ErbB4 (35%) en el TA. Además, los niveles de proteína ErbB2 y ErbB3 disminuyeron significativamente, en comparación con el grupo DC en el hígado. Nuestros resultados sugieren que la obesidad inducida por DAG disminuye significativamente la expresión de ErbBs en el hígado y el TA, que puede estar asociado con alteraciones en la vía NRG en ratones obesos.
RESUMO
ABSTRACT Objective: To investigate the histological subtypes and mutational profiles of non-small cell lung cancer in Brazil, looking for correlations among histological subtypes, expression of anaplastic lymphoma kinase (ALK), EGFR mutation status, and programmed death-ligand 1 (PD-L1) expression. Methods: We evaluated 173 specimens obtained from patients with lung adenocarcinoma in northeastern Brazil. Expression of PD-L1 and ALK was evaluated by immunohistochemistry; EGFR mutation status was evaluated by sequencing. We categorized the histological subtypes in accordance with the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Results: The most common histological subtypes of lung adenocarcinoma were solid predominant (in 46.8%), acinar predominant (in 37.0%), and lepidic predominant (in 9.8%). ALK expression was detected in 10.4% of the samples, and 22.0% of the tumors harbored EGFR mutations. The most common EGFR mutation was an exon 21 L858R point mutation (in 45.5%), followed by an exon 19 deletion (in 36.3%). The tumor proportion score for PD-L1 expression was ≥ 50% in 18.2% of the samples, 1-49% in 32.7%, and 0% in 49.5%. The solid predominant subtype was significantly associated with wild-type EGFR status (p = 0.047). Positivity for PD-L1 expression was not found to be significantly associated with ALK expression or EGFR mutation status. Conclusions: Our results suggest that the molecular profile of non-small cell lung cancer in northeastern Brazil differs from those of populations in other regions of the country, with ALK positivity being higher than the other biomarkers. Further studies including clinical and genetic information are required to confirm these differences, as well as studies focusing on populations living in different areas of the country.
RESUMO Objetivo: Investigar os subtipos histológicos e perfis de mutação do carcinoma pulmonar de células não pequenas no Brasil, bem como as correlações entre os subtipos histológicos, a expressão do gene anaplastic lymphoma kinase (ALK, quinase do linfoma anaplásico), o estado de mutação do gene EGFR e a expressão de programmed death-ligand 1 (PD-L1, ligante de morte celular programada 1). Métodos: Avaliamos 173 espécimes provenientes de pacientes com adenocarcinoma pulmonar no Nordeste brasileiro. A expressão de PD-L1 e ALK foi avaliada por meio de imuno-histoquímica, ao passo que o estado de mutação do EGFR foi avaliado por meio de sequenciamento. Os subtipos histológicos foram classificados de acordo com a International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. Resultados: Os subtipos histológicos mais comuns de adenocarcinoma pulmonar foram o predominantemente sólido (em 46,8%), o predominantemente acinar (em 37,0%) e o predominantemente lepídico (em 9,8%). A expressão de ALK foi detectada em 10,4% das amostras, e 22,0% dos tumores apresentavam mutações do gene EGFR. As mutações mais comuns do EGFR foram a mutação pontual L858R no éxon 21 (em 45,5%) e a deleção do éxon 19 (em 36,3%). O tumor proportion score relativo à expressão de PD-L1 foi ≥ 50% em 18,2% das amostras, = 1-49% em 32,7% e = 0% em 49,5%. O subtipo predominantemente sólido relacionou-se significativamente com EGFR selvagem (p = 0,047). A expressão positiva de PD-L1 não se relacionou significativamente com a expressão de ALK ou o estado de mutação do EGFR. Conclusões: Nossos resultados sugerem que o perfil molecular do carcinoma pulmonar de células não pequenas no Nordeste brasileiro difere do de populações em outras regiões do país: a expressão positiva de ALK é maior que os demais biomarcadores. Mais estudos com informações clínicas e genéticas são necessários para confirmar essas diferenças, além de estudos que se concentrem em populações em diferentes áreas do país.