Translating Proteomic Into Functional Data: An High Mobility Group A1 (HMGA1) Proteomic Signature Has Prognostic Value in Breast Cancer.
Translating Proteomic Into Functional Data: An High Mobility Group A1 (HMGA1) Proteomic Signature Has Prognostic Value in Breast Cancer.
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DOI：
10.1074/mcp.m115.050401
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Sgarra R
中科院分区：
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作者：
Maurizio E;Wiśniewski JR;Ciani Y;Amato A;Arnoldo L;Penzo C;Pegoraro S;Giancotti V;Zambelli A;Piazza S;Manfioletti G;Sgarra R
癌症是一种异质性很强的疾病，生物多样性进一步增加了复杂性，从而限制了识别与癌症发展有关的新基因的能力。表达水平控制细胞侵袭性的癌基因对于开发细胞模型非常有用，该模型允许在等基因背景下进行差异表达筛选。HMGA1蛋白具有这种独特的特性，因为它是乳腺癌细胞的主要调节剂，控制从非致瘤性上皮样表型向高度侵袭性间质样表型的转变。从hmga1沉默和对照的MDA-MB-231细胞中提取的蛋白质采用无标记霰弹枪质谱法进行分析。差异表达蛋白与使用相同细胞模型获得的DNA微阵列数据交叉参考，并在乳腺癌基因表达元数据集中过滤重叠基因以筛选与预后不良相关的因素，得到由21个成员组成的HMGA1蛋白特征（HRS， HMGA1减少特征）。这一特征在乳腺癌中具有预后价值（总生存期、无复发生存期和远端无转移生存期）。qRT-PCR、Western blot和免疫组织化学分析验证了该特征的三个成员（KIFC1、LRRC59和TRIP13）在体外和体内与HMGA1表达水平的联系，伤口愈合实验表明这三个蛋白参与调节肿瘤细胞的运动。结合蛋白质组学和基因组学数据以及生物信息学工具的帮助，我们的研究结果强调了在癌症中尚未探索的有限因素列表中肿瘤转化的潜在参与。这些因素是可药物靶点，可用于开发针对三阴性乳腺癌的新的靶向治疗方法。
Cancer is a very heterogeneous disease, and biological variability adds a further level of complexity, thus limiting the ability to identify new genes involved in cancer development. Oncogenes whose expression levels control cell aggressiveness are very useful for developing cellular models that permit differential expression screenings in isogenic contexts. HMGA1 protein has this unique property because it is a master regulator in breast cancer cells that control the transition from a nontumorigenic epithelial-like phenotype toward a highly aggressive mesenchymal-like one. The proteins extracted from HMGA1-silenced and control MDA-MB-231 cells were analyzed using label-free shotgun mass spectrometry. The differentially expressed proteins were cross-referenced with DNA microarray data obtained using the same cellular model and the overlapping genes were filtered for factors linked to poor prognosis in breast cancer gene expression meta-data sets, resulting in an HMGA1 protein signature composed of 21 members (HRS, HMGA1 reduced signature). This signature had a prognostic value (overall survival, relapse-free survival, and distant metastasis-free survival) in breast cancer. qRT-PCR, Western blot, and immunohistochemistry analyses validated the link of three members of this signature (KIFC1, LRRC59, and TRIP13) with HMGA1 expression levels both in vitro and in vivo and wound healing assays demonstrated that these three proteins are involved in modulating tumor cell motility. Combining proteomic and genomic data with the aid of bioinformatic tools, our results highlight the potential involvement in neoplastic transformation of a restricted list of factors with an as-yet-unexplored role in cancer. These factors are druggable targets that could be exploited for the development of new, targeted therapeutic approaches in triple-negative breast cancer.