Contextual tumor suppressor function of T cell death-associated gene 8 (TDAG8) in hematological malignancies
Contextual tumor suppressor function of T cell death-associated gene 8 (TDAG8) in hematological malignancies
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DOI：
10.1186/s12967-017-1305-6
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发表时间：
2017-10-10
影响因子：
7.4
通讯作者：
Yang, Li V.
中科院分区：
文献类型：
--
作者：
Justus, Calvin R.;Sanderlin, Edward J.;Yang, Li V.
背景资料：细胞外酸中毒是由于血液灌注不足、缺氧和肿瘤细胞代谢改变而在肿瘤微环境中发现的病症。酸中毒对恶性进展具有多效性作用，因此了解酸中毒如何发挥其多种作用至关重要。TDAG 8是一种质子敏感的G蛋白偶联受体，可被细胞外酸中毒激活。方法：应用生物信息学分析和定量RT-PCR技术分析TDAG 8基因在恶性血液病中的表达。逆转录病毒转导用于恢复U937、拉莫斯和其它血液癌细胞中的TDAG 8表达。采用多种体外和体内肿瘤发生和转移测定来评估TDAG 8表达对血癌进展的影响。Western blotting，免疫组化和生物化学方法被应用于阐明与TDAG 8受体pathway.Results相关的潜在机制：TDAG 8的表达显着降低，在人类血液肿瘤相比，正常血细胞。重度酸中毒（pH 6.4）抑制U937癌细胞增殖，而轻度酸中毒（pH 6.9）刺激其增殖。然而，恢复TDAG 8基因的表达调节U937细胞的反应，轻度细胞外酸中毒和生理pH值，减少细胞增殖。肿瘤异种移植实验进一步揭示，恢复U937和拉莫斯癌细胞中的TDAG 8表达降低了肿瘤生长。还显示具有恢复的TDAG 8表达的U937细胞较少附着于基质胶，向化学引诱物迁移较慢，并且在严重联合免疫缺陷小鼠中转移较少。这些作用与c-myc癌基因表达的减少相关。机制的调查表明，Ga 13/Rho信号仲裁TDAG 8介导的c-myc癌基因的抑制反应acidosis.Conclusions：这项研究提供的数据支持的概念，TDAG 8作为一个上下文肿瘤抑制基因下调血液恶性肿瘤和增强TDAG 8受体途径可能会探讨作为一个潜在的抗肿瘤的方法在血液癌症。
Background: Extracellular 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.Methods: TDAG8 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.Results: TDAG8 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 Ga13/Rho signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis.Conclusions: This 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.