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Regulation of the amino acid transporter SNAT4 expression in human liver cancer cells.

机译：人肝癌细胞中氨基酸转运蛋白SNAT4表达的调节。

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摘要

SNAT4 (s&barbelow;odium-dependent n&barbelow;eutral a&barbelow;mino acid t&barbelow;ransporter 4), isolated in 2001, is a member of the System A and System N family of amino acid transporters. Among the SNAT family members, SNAT4 is unique in mediating cationic (essential amino acids arginine and lysine) as well as neutral amino acid uptake. SNAT4 is upregulated at the mRNA level by over an order of magnitude in response to the three-dimensional growth of HepG2 multicellular tumor spheroids in vitro, after the aggregates show signs of central necrosis (due to lack of angiogenic oxygen and nutrient supply). This observation suggested that it could play an essential role in the initial avascu1ar growth or survival of tumors. The hypothesis that SNAT4 upregulation was due cell stress caused by the microenvironments such as hypoxia or nutrient limitation known to develop during spheroid growth was tested by introduction of chemical cell-stressors (cobalt chloride and buthionine sulfoximine), oxygen deprivation, glucose limitation and amino acid starvation, alone or in combination, in cell culture media: none of these factors resulted in significant induction of SNAT4 mRNA expression. Fluorescent in situ hybridization studies suggested that SNAT4 mRNA localization patterns differed between HepG2 and Huh7 large spheroids, two hepatoma cell lines that exhibit different levels of liver-specific gene expression. Hypothesizing that SNAT4 expression could be linked to levels of differentiation, RT-PCR studies were conducted to determine the expression levels of liver-enriched transcription factors; however, no differential expression was observed between the cell lines tested, or between HepG2 cells in monolayer culture or large spheroids. However, evidence of a correlation between SNAT4 expression and the expression of the urea cycle enzyme arginase I was elucidated. These results demonstrate that SNAT4 expression: (1) is not stress-related, (2) may be linked to a differentiation program tied to urea cycle enzyme expression, and (3) may function to deliver arginine to liver cells that express arginase I.
机译：SNAT4（s依赖于钠，n依赖于中性，a依赖于氨基酸t运输子4），是氨基酸转运蛋白系统A和系统N家族的成员。在SNAT家族成员中，SNAT4在介导阳离子（必需氨基酸精氨酸和赖氨酸）以及中性氨基酸摄取方面是独特的。在聚集体显示中央坏死的迹象（由于缺乏血管生成的氧气和营养供应）后，SNAT4在mRNA水平上调了一个数量级，以响应体外HepG2多细胞肿瘤球的三维生长。该观察结果表明它可能在肿瘤的初始血管生长或存活中起重要作用。 SNAT4上调是由微环境引起的细胞应激引起的假说，例如在球体生长过程中发生的缺氧或营养限制，通过引入化学细胞应激因子（氯化钴和丁硫氨酸亚砜亚胺），缺氧，葡萄糖限制和氨基酸来检验细胞培养基中单独或联合饥饿时：这些因素均未导致SNAT4 mRNA表达的明显诱导。荧光原位杂交研究表明，SNAT4 mRNA的定位模式在HepG2和Huh7大球体之间是不同的，这两个肝癌细胞系表现出不同水平的肝特异性基因表达。推测SNAT4表达可能与分化水平有关，因此进行了RT-PCR研究，以确定富含肝脏的转录因子的表达水平。但是，在测试的细胞系之间，单层培养的HepG2细胞或大球体之间未观察到差异表达。但是，阐明了SNAT4表达与尿素循环酶精氨酸酶I表达之间相关性的证据。这些结果表明SNAT4的表达：（1）与应激无关，（2）可能与与尿素循环酶表达相关的分化程序相关，并且（3）可能起到将精氨酸传递至表达精氨酸酶I的肝细胞的作用。

著录项

  • 作者

    Perry, Douglas K.;

  • 作者单位

    Saint Louis University.;

  • 授予单位 Saint Louis University.;
  • 学科 Biology Molecular.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 47 p.
  • 总页数 47
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;肿瘤学;
  • 关键词

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