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

Journal of Translational Medicine

Research

Kvin Lertpiriyapong¹  Jen-Tsan Chi²  Tianai Sun²  Calvin R. Justus³  Edward J. Sanderlin³  Lixue Dong³  Li V. Yang⁴ 

[1] Department of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA;Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA;Center for Genomic and Computational Biology, Duke University, Durham, NC, USA;Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA;Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, USA;Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, 27834, Greenville, NC, USA;

关键词: TDAG8;    GPR65;    Acidosis;    Tumor microenvironment;    Hematological malignancies;   

DOI  :  10.1186/s12967-017-1305-6

 received in 2017-08-04, accepted in 2017-09-30,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundExtracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. TDAG8 is a proton-sensing G-protein-coupled receptor that can be activated by extracellular acidosis.MethodsTDAG8 gene expression was analyzed by bioinformatic analyses and quantitative RT-PCR in human hematological malignancies. Retroviral transduction was used to restore TDAG8 expression in U937, Ramos and other blood cancer cells. Multiple in vitro and in vivo tumorigenesis and metastasis assays were employed to evaluate the effects of TDAG8 expression on blood cancer progression. Western blotting, immunohistochemistry and biochemical approaches were applied to elucidate the underlying mechanisms associated with the TDAG8 receptor pathway.ResultsTDAG8 expression is significantly reduced in human blood cancers in comparison to normal blood cells. Severe acidosis, pH 6.4, inhibited U937 cancer cell proliferation while mild acidosis, pH 6.9, stimulated its proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that Gα13/Rho signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis.ConclusionsThis study provides data to support the concept that TDAG8 functions as a contextual tumor suppressor down-regulated in hematological malignancies and potentiation of the TDAG8 receptor pathway may be explored as a potential anti-tumorigenic approach in blood cancers.

【 授权许可】

CC BY   
© The Author(s) 2017