Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.
Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.
复制标题
MacroH2A1 亚型在结肠癌中的差异调节和预测潜力。
DOI：
10.1016/j.ajpath.2012.02.027
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Jung,Barbara
中科院分区：
文献类型：
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作者：
Sporn,JudithC;Jung,Barbara
组蛋白变体 MacroH2A1 有两种剪接异构体：macroH2A1.1 和 MacroH2A1.2，具有组织和细胞特异性表达模式。虽然macroH2A1.1主要存在于分化的非增殖组织中，但macroH2A1.2的表达更为普遍，包括在正在进行细胞增殖的组织中。对乳腺癌和肺癌的研究一致表明，macroH2A1.1 水平与增殖之间存在很强的相关性，而 MacroH2A1.2 的情况并非如此。这是第一项评估 MacroH2A1 亚型在结肠癌中的差异调节和预测潜力的研究。我们发现，与匹配的正常结肠组织相比，原发性结直肠癌样本中的 MacroH2A1.1 mRNA 下调，而 MacroH2A1.2 mRNA 上调。在蛋白质水平上，macroH2A1.1 的下调与患者预后显着相关（P = 0.0012），而 MacroH2A1.1 的缺失与较差的预后相关。在Caco-2细胞分化过程中，macroH2A1.1在RNA和蛋白质水平上均上调，而macroH2A1.2在RNA水平上轻微下调并在蛋白质水平上稳定。这些变化伴随着表现出细胞衰老特征的抗增殖表型。 MacroH2A1.1 体外缺失的特征是与细胞生长和转移相关的表型。这些数据表明，macroH2A1亚型在结肠癌中受到差异性调节，反映了细胞分化的程度。值得注意的是，macroH2A1.1 表达可预测结肠癌的存活率，因此将 MacroH2A1.1 确定为一种新型结肠癌生物标志物。
Histone variant macroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, with tissue- and cell-specific expression patterns. Although macroH2A1.1 is mainly found in differentiated, nonproliferative tissues, macroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation. Consistently, studies in breast and lung cancer have demonstrated a strong correlation between macroH2A1.1 levels and proliferation, which is not the case for macroH2A1.2. This is the first study to assess the differential regulation and predictive potential of macroH2A1 isoforms in colon cancer. We found that macroH2A1.1 mRNA was down-regulated in primary colorectal cancer samples compared to matched normal colon tissue, whereas macroH2A1.2 was up-regulated. At the protein level, down-regulation of macroH2A1.1 correlated significantly with patient outcome (P= 0.0012), and loss of macroH2A1.1 was associated with a worse outcome. Over the course of Caco-2 cell differentiation, macroH2A1.1 was up-regulated at both the RNA and protein levels, whereas macroH2A1.2 was slightly down-regulated at the RNA level and stable at the protein level. These changes were accompanied by an antiproliferative phenotype exhibiting features of cellular senescence. Loss of macroH2A1.1in vitrowas characterized by a phenotype associated with cell growth and metastasis. These data demonstrate that macroH2A1 isoforms are differentially regulated in colon cancer, reflecting the degree of cellular differentiation. Notably, macroH2A1.1 expression predicts survival in colon cancer, thus identifying macroH2A1.1 as a novel colon cancer biomarker.