Lee Dhong Hyun, Forscher Charles, Di Vizio Dolores, Koeffler H Phillip
Division of Hematology and Oncology, Departments of Surgery,Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center, Los Angeles, CA, USA.
1] Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] The Urological Diseases Research Center; Boston Children's Hospital, Boston, MA, Department of Surgery, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2015 Jul 29;5:12580. doi: 10.1038/srep12580.
Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells.
去分化脂肪肉瘤（DDLPS）是人类脂肪肉瘤（LPS）的一种高度恶性亚型，其基因组特征是12q13 - q22处的染色体扩增。miR - 26a - 2是该区域最常扩增的基因之一，抑制其下游靶基因可能有助于LPS的肿瘤发生。我们之前对LPS的研究预测同源框蛋白A5（HOXA5）是miR - 26a - 2的一个靶标，在此我们进一步探究了HOXA5的功能及其在DDLPS细胞中与miR - 26a - 2的关系。与正常人脂肪细胞相比，所有LPS细胞系均显示HOXA5显著下调（p = 0.046），使用抗miR - 26a - 2抑制miR - 26a - 2可使这些LPS细胞中HOXA5的表达大幅上调。有趣的是，单独过表达HOXA5可诱导LPS细胞产生非常强烈的凋亡反应。HOXA5诱导的凋亡不依赖p53且依赖半胱天冬酶。令人惊讶的是，HOXA5的过表达诱导RELA（p65）的核转位，这与RELA的转录活性无关。相反，观察到RELA的核仁隔离。总体而言，我们的研究首次证明LPS细胞中HOXA5的下调，部分是由于DDLPS中miR - 26a - 2的过表达，赋予了LPS细胞对凋亡死亡的抗性。需要进一步研究以了解HOXA5与LPS细胞中NFκB途径的关系。
