RESUMO
Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10-3 in all samples; p = 4.2 × 10-3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10-2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10-2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Genoma Mitocondrial , Síndrome do Hamartoma Múltiplo , Neoplasias da Glândula Tireoide , Humanos , Síndrome do Hamartoma Múltiplo/genética , Transtorno Autístico/genética , Transtorno do Espectro Autista/genética , Genoma Mitocondrial/genética , Variações do Número de Cópias de DNA/genética , Fenótipo , Neoplasias da Glândula Tireoide/genética , DNA Mitocondrial/genética , PTEN Fosfo-Hidrolase/genéticaRESUMO
Oxidized low density lipoprotein (ox-LDL) can induce the proliferation and differentiation of endothelial cells, which is one of the important mechanisms of ox-LDL atherosclerosis. Adiponectin is an endogenous bioactive polypeptide secreted by adipocytes, it participates in the metabolism of fat and glucose. It has the effect of reducing blood triglyceride and LDL content. Adiponectin also inhibits the abnormal proliferation and migration of endothelial cells, but its molecular mechanism is unclear. In this study, we used cell model of Ox-LDL-induced human aortic endothelial cells (HAECs) proliferation to analyze the molecular mechanism of APN inhibiting HAECs abnormal proliferation. The results showed that APN could inhibit the cell viability and DNA synthesis of HAECs after Ox-LDL treatment, up-regulate the apoptosis level and reduce the proportion of Sâ¯+â¯G2 phase cells. Further analysis showed that adiponectin could promote the dephosphorylation of Caveolin-1, which could dissociate eNOS and Caveolin-1, promote the phosphorylation of eNOS and enhance the synthesis of NO. NO increased expression levels of cleaved caspase 3 and p21 in the cells and inhibited the abnormal proliferation of HAECs. The regulation of phosphorylation and dephosphorylation of Caveolae-1 plays a key role in this process. Further study of the molecular mechanism of Caveolae-1 in the inhibition of HAECs abnormal proliferation by APN may reveal the potential of APN in the treatment of cardiovascular diseases.