This work is based on using suppressor-tRNAs as a possible therapeutic tool for inherited cancer syndromes, where about 10-20% of the mutations described in are nonsense mutations. A suppressor-tRNA is a tRNA that can be altered to recognize premature stop codons (nonsense mutations), promoting their readthrough to produce full-length proteins. As a model, we used hereditary diffuse gastric cancer (HDGC), which is associated with mutations in CDH1 gene, encoding the adhesion molecule E-cadherin.
Gastric cancer is one of the most prevalent and fatal in the world, especially due to its invasive nature, and the capacity to metastasize at distance, frequently without symptoms. E-cadherin is one of the most important structural molecules in the stomach, and its expression in the gastric epithelia suppresses cancer development. Carriers of mutations in the gene encoding E-cadherin have high probability of developing hereditary diffuse gastric cancer. Strategies aiming to prevent the loss of E-cadherin expression enclose high therapeutic potential for gastric cancer.
A proteína Caderina-P é um marcador tumoral associado a um mau prognóstico em cancro da mama. Em estudos prévios, demonstrámos que a expressão desta proteína promove a capacidade invasiva de células de cancro da mama, em modelos onde a expressão membranar de Caderina-E é mantida; no entanto, em modelos de melanoma (negativos para a Caderina-E), a Caderina-P tem um papel exactamente oposto, funcionando como um factor supressor de invasão.
