RESUMO
Progression of breast cancers often depends on hormones among which human growth hormone is prominently involved in breast cancer progression. Earlier studies have reported constitutive activation of nuclear factor-κB, a key regulator of growth hormone receptor-mediated signaling pathway in breast carcinoma, but the precise molecular mechanisms are still elusive. In this study, we investigated the effect of human growth hormone on nuclear factor-κB activation and epithelial-mesenchymal transition in breast carcinoma. Our results explored that autocrine production of human growth hormone enhances cellular proliferation by the activation of nuclear factor-κB (65 kDa) and downregulation of E-cadherin expression. Furthermore, enhanced nuclear factor-κB expression significantly increases cell proliferation and diminishes apoptosis in MCF-7 cell line. Increased expression of nuclear factor-κB significantly enhances mammary carcinoma cell migration and invasion stimulated by autocrine human growth hormone, which results in epithelial-mesenchymal transition of MCF-7 cells. In conclusion, our study revealed the influence of human growth hormone on nuclear factor-κB activity and epithelial-mesenchymal transition in mammary carcinoma. Our findings will help to understand molecular role of "growth hormone-nuclear factor-κB axis" in mammary carcinogenesis which may facilitate the discovery of suitable pathway inhibitors for disease treatment.
Assuntos
Neoplasias da Mama/genética , Caderinas/biossíntese , Transição Epitelial-Mesenquimal/genética , Hormônio do Crescimento/genética , Animais , Apoptose/genética , Comunicação Autócrina/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Hormônio do Crescimento/biossíntese , Humanos , Células MCF-7 , NF-kappa B/genética , Transdução de SinaisRESUMO
Mitochondrial displacement loop (D-loop) is the hot spot for mitochondrial DNA (mtDNA) alterations which influence the generation of cellular reactive oxygen species. In the present study, we sequenced the entire mitochondrial D-loop region (1124 bp) of colorectal cancer (CRC) patients (n = 174) and controls (n = 170) of south Indian origin to identify significant mutations/polymorphisms. Our results showed 152 polymorphisms in the D-loop region of patients and/or controls. Polymorphisms were predominantly located in hypervariable region I (54.6%) than in II (45.4%) of D-loop region. The frequencies of 310'C' insertion (p = 0.0078), T16189C (p = 0.0097) variants and 310'C'ins/16189C haplotype (p = 0.0029) were significantly higher in cases than in controls. Furthermore, strong linkage disequilibrium was observed between nucleotide position 310 and 16189 in cases (D'=0.68) as compared with controls (D'=0.27). In conclusion, mitochondrial D-loop sequence alterations may constitute inherent risk factor for CRC.
Assuntos
Neoplasias Colorretais/genética , DNA Mitocondrial/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , População Branca/genética , DNA Mitocondrial/química , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia , Desequilíbrio de Ligação , Masculino , Mitocôndrias/genéticaRESUMO
Mitochondrial displacement loop (D-loop) is a hot spot for mitochondrial DNA (mtDNA) alterations that effects cellular reactive oxygen species (ROS) generation. Manganese-superoxide dismutase (Mn-SOD) is a major antioxidant enzyme that protects cells from ROS-mediated damage. In the present study, we investigated the relationship between sequence alterations of mitochondrial D-loop and Mn-SOD expression in colorectal cancer (CRC). Genotyping of entire mitochondrial D-loop (1124 bp) was carried out on mtDNA of analogous tumor and normal tissues from 35 CRC patients of south Indian origin by PCR-sequencing analysis. Tumor-specific large-scale mtDNA deletions and Mn-SOD expression was analyzed by PCR and Western blot analysis, respectively. We identified 87 polymorphisms in the D-loop region of tumor and/or control tissues. Polymorphisms were predominantly located in hypervariable region I (67.9 %) than in II (32.1 %) of D-loop. Significantly increased mtDNA microsatellite instability (mtMSI) [310'C' insertion (P = 0.00001) and T16189C (P = 0.0007)] and elevated Mn-SOD expression was observed in tumor tissues compared with controls. Interestingly, mtMSI was significantly high in tumors with Mn-SOD overexpression. Tumor-specific large-scale mtDNA deletions were not observed in CRC tissues. In conclusion, mtMSI and Mn-SOD overexpression are a common event in CRC. The analysis of mtMSI and/or Mn-SOD expression might help to identify patients at high risk for disease outcome, thereby helping to refine therapeutic decisions in CRC.