Ferritin heavy chain in triple negative breast cancer: a favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8+) effector T-cell response.
Ferritin heavy chain in triple negative breast cancer: a favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8+) effector T-cell response.
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DOI：
10.1074/mcp.m113.037176
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Umar A
中科院分区：
文献类型：
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作者：
Liu NQ;De Marchi T;Timmermans AM;Beekhof R;Trapman-Jansen AM;Foekens R;Look MP;van Deurzen CH;Span PN;Sweep FC;Brask JB;Timmermans-Wielenga V;Debets R;Martens JW;Foekens JA;Umar A
铁蛋白重链 (FTH1) 是铁蛋白复合物的一个 21 kDa 亚基，以其在铁代谢中的作用而闻名，最近被确定为三阴性乳腺癌 (TNBC) 患者的有利预后蛋白。目前，FTH1 如何促进抗肿瘤反应尚不清楚。在这里，我们探讨了 FTH1 的表达和细胞区室化是否与 TNBC 患者的有效免疫反应相关。对肿瘤组织转录组的分析以及计算机通路分析表明，FTH1 是细胞因子信号传导、适应性免疫和细胞死亡的免疫调节网络的组成部分。这些发现通过质谱 (MS) 衍生的蛋白质组数据和组织微阵列的免疫组织化学染色得到证实。我们观察到 FTH1 位于癌细胞的细胞质和/或细胞核中。然而，高细胞质 (c) FTH1 与良好的预后相关 (Log-rank p = 0.001)，而核 (n) FTH1 染色与不良预后相关 (Log-rank p = 0.019)。通过 MS 分析测量，cFTH1 染色与 TNBC 组织样本中的总 FTH1 表达显着相关（Rs = 0.473，p = 0.0007），但 nFTH1 染色则不然（Rs = 0.197，p = 0.1801）。值得注意的是，产生 IFN γ 的 CD8+ 效应 T 细胞，而不是 CD4+ T 细胞，优先富集于 cFTH1 高表达的肿瘤中 (p = 0.02)。总的来说，我们的数据为 TNBC 中 FTH1 新的免疫调节特性提供了证据，这可能有助于新治疗靶点的开发。
Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells. However, high cytoplasmic (c) FTH1 was associated with favorable prognosis (Log-rank p = 0.001), whereas nuclear (n) FTH1 staining was associated with adverse prognosis (Log-rank p = 0.019). cFTH1 staining significantly correlated with total FTH1 expression in TNBC tissue samples, as measured by MS analysis (Rs = 0.473, p = 0.0007), but nFTH1 staining did not (Rs = 0.197, p = 0.1801). Notably, IFN γ-producing CD8+ effector T cells, but not CD4+ T cells, were preferentially enriched in tumors with high expression of cFTH1 (p = 0.02). Collectively, our data provide evidence toward new immune regulatory properties of FTH1 in TNBC, which may facilitate development of novel therapeutic targets.