Contextual tumor suppressor function of T cell death-associated gene 8 (TDAG8) in hematological malignancies.

摘要: Extracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it essential understand how exerts its diverse effects. TDAG8 proton-sensing G-protein-coupled receptor that can be activated by extracellular acidosis. gene expression was analyzed bioinformatic analyses quantitative RT-PCR in human hematological malignancies. Retroviral transduction used restore U937, Ramos other cancer cells. Multiple vitro vivo tumorigenesis metastasis assays were employed evaluate of progression. Western blotting, immunohistochemistry biochemical approaches applied elucidate underlying mechanisms associated with pathway. significantly reduced cancers comparison normal Severe acidosis, pH 6.4, inhibited U937 proliferation while mild 6.9, stimulated proliferation. However, restoring modulated response physiological reducing Tumor xenograft experiments further revealed cells growth. It also shown restored attached less Matrigel, migrated slower toward chemoattractant, metastasized severe combined immunodeficient mice. These correlated reduction c-myc oncogene expression. The mechanistic investigation indicated Gα13/Rho signaling arbitrated TDAG8-mediated repression This study provides data support concept functions as contextual suppressor down-regulated malignancies potentiation pathway may explored potential anti-tumorigenic approach cancers.