MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease.
MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease.
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DOI：
10.1158/1078-0432.ccr-17-3673
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发表时间：
2018-08-01
期刊：
影响因子：
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通讯作者：
Vander Griend DJ
中科院分区：
文献类型：
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作者：
Bhanvadia RR;VanOpstall C;Brechka H;Barashi NS;Gillard M;McAuley EM;Vasquez JM;Paner G;Chan WC;Andrade J;De Marzo AM;Han M;Szmulewitz RZ;Vander Griend DJ
HOXB13 MEIS 相互作用域内的种系突变表明 MEIS-HOX 相互作用在前列腺癌病因和进展中发挥着关键作用。然而，MEIS 表达变化在前列腺肿瘤进展中的功能和预测作用在很大程度上仍未得到探索。在这里，我们利用 RNA 表达数据集、带注释的组织微阵列和基于细胞的功能测定来研究 MEIS1 和 MEIS2 在前列腺癌和转移进展中的作用。这些分析表明，从良性上皮到原发性肿瘤，再到转移组织，MEIS1 和 MEIS2 的表达逐步降低。然而，多变量分析后，原发肿瘤中 MEIS 蛋白的阳性表达与较低的临床转移风险相关（HR = 0.28）。通路和基因集富集分析确定了参与 cMYC 信号传导、细胞增殖、运动和局部肿瘤环境的 MEIS 相关网络。随着时间的推移，MEIS1和MEIS2的缺失会导致体内肿瘤生长增加，并且患者来源的肿瘤和MEIS缺失的细胞系中MEIS表达的减少与促肿瘤基因cMYC和CD142的表达增加以及AXIN2、FN1、ROCK1、SERPINE2、SNAI2和TGFβ2的表达减少相关。这些数据暗示 MEIS 蛋白在调节癌症进展中的功能作用，并支持这样的假设：MEIS1 和 MEIS2 表达的肿瘤表达赋予更惰性的前列腺癌表型，并降低转移进展的倾向。
Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored. Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression. These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the pro-tumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFβ2. These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression.