HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis.
HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis.
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DOI：
10.1186/1471-2164-12-549
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发表时间：
2011-11-04
期刊：
影响因子：
4.4
通讯作者：
Resar LM
中科院分区：
文献类型：
--
作者：
Schuldenfrei A;Belton A;Kowalski J;Talbot CC Jr;Di Cello F;Poh W;Tsai HL;Shah SN;Huso TH;Huso DL;Resar LM
尽管高迁移率组A1 （HMGA1）基因在多种癌症中广泛过表达，并且在一些肿瘤中预示着不良预后，但介导其转化作用的分子机制仍然是未知的。HMGA1在培养细胞中作为一种强致癌基因发挥作用，并在转基因小鼠中诱导侵袭性淋巴样肿瘤。由于HMGA1染色质重塑蛋白调节转录，HMGA1被认为通过调节特定基因的表达来驱动恶性转化。然而，在肿瘤发生过程中定义HMGA1转录网络的全基因组研究尚缺乏。为了确定HMGA1转录组，我们分析了HMGA1a转基因小鼠肿瘤发生不同阶段淋巴细胞的基因表达谱。通过微阵列分析（Affymetrix）使用参数和非参数方法筛选2个月（肿瘤发生前）和12个月（肿瘤建立后）淋巴样样本中的RNA，以确定bbbb20 000个独特基因的差异表达。通过定量RT-PCR证实了一部分基因的差异表达。使用Ingenuity Pathway Analysis分析差异表达基因的细胞通路和功能。在肿瘤发生早期，HMGA1诱导炎症通路，NFkappaB被确定为主要节点。在已建立的肿瘤中，HMGA1诱导通路参与细胞周期进程、细胞介导的免疫反应和癌症。在肿瘤发生的两个阶段，HMGA1诱导通路参与细胞发育、造血和血液学发育。基因集富集分析表明，干细胞和未成熟T细胞基因在已建立的肿瘤中富集。为了确定这些结果是否与人类肿瘤相关，我们在人类t细胞白血病细胞中敲低HMGA1，并在转基因和人类淋巴样肿瘤中发现了一个基因亚群失调。我们发现HMGA1在淋巴样肿瘤发生早期诱导炎症通路，并在已建立的肿瘤中诱导干细胞、细胞周期进展和癌症通路。HMGA1也在肿瘤发生的早期和晚期对参与干细胞、细胞发育和造血的基因和途径进行失调调节。这些结果提供了HMGA1在肿瘤发展过程中的功能，并指出了可以作为淋巴细胞和其他HMGA1异常表达的人类癌症的治疗靶点的细胞途径。
Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis. RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors. We found that HMGA1 induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. HMGA1 also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into HMGA1 function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant HMGA1 expression.
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影响因子：
8
作者：
Dhar, A;Hu, J;Colburn, NH
通讯作者：
Colburn, NH
影响因子：
11.2
作者：
Fedele, M;Fidanza, V;Fusco, A
通讯作者：
Fusco, A
影响因子：
11.2
作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
通讯作者：
Resar LM
DOI：
10.1158/1541-7786.mcr-08-0336
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Hillion J;Wood LJ;Mukherjee M;Bhattacharya R;Di Cello F;Kowalski J;Elbahloul O;Segal J;Poirier J;Rudin CM;Dhara S;Belton A;Joseph B;Zucker S;Resar LM
通讯作者：
Resar LM
影响因子：
2
作者：
Flohr, AM;Rogalla, P;Bullerdiek, J
通讯作者：
Bullerdiek, J