Aberrant Calreticulin Expression Is Involved in the Dedifferentiation of Dedifferentiated Liposarcoma
Aberrant Calreticulin Expression Is Involved in the Dedifferentiation of Dedifferentiated Liposarcoma
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DOI：
10.1016/j.ajpath.2012.01.042
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发表时间：
2012-05-01
影响因子：
6
通讯作者：
Nakamoto, Mitsuhiro
中科院分区：
文献类型：
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作者：
Hisaoka, Masanori;Matsuyama, Atsuji;Nakamoto, Mitsuhiro
脂肪肉瘤是软组织肉瘤的代表性群体，其脂肪生成受到不同程度的阻碍，最典型的是其去分化亚型。然而，抑制脂肪细胞分化的因素仍然未知。最近的一项基因表达谱研究发现了几个在去分化脂肪肉瘤中高表达的独特基因，并且发现编码钙网蛋白（CALR）的基因过度表达，CALR是一种可抑制脂肪细胞分化的主要Ca2+缓冲蛋白。因此，我们在 45 例脂肪肉瘤（包括 15 例去分化肿瘤）中研究了钙网蛋白在蛋白质和 mRNA 水平上的表达。免疫组织化学显示，钙网蛋白在去分化脂肪肉瘤的去分化区域一致表达，并且在分化良好区域的非典型基质细胞和/或脂肪母细胞中常见（87%），而肿瘤或正常脂肪中的大空泡脂肪细胞基本呈阴性。这些结果得到了蛋白质印迹和定量 RT-PCR 分析结果的进一步支持。尽管通过荧光原位杂交检测的去分化脂肪肉瘤中 CALR 定位的 19p13.1-13.2 异常并不常见，但 miR-1257（一种靶向钙网蛋白的假定 microRNA）的表达在去分化亚型中受到抑制。小干扰RNA下调钙网蛋白可以诱导去分化脂肪肉瘤细胞的脂肪形成并减少细胞增殖。因此，我们的结果表明，去分化脂肪肉瘤中异常表达的钙网蛋白参与其去分化和/或肿瘤进展。 （《美国病理学杂志》2012 年，180：2076-2083；DOI：10.1016/j.ajpath.2012.01.042）
Liposarcomas are a representative group of soft tissue sarcomas with variably hampered adipogenesis, which is most exemplified by its dedifferentiated subtype. However, the factor(s) responsible for inhibiting adipocyte differentiation remains unknown. A recent gene expression profiling study identified several unique genes that were highly expressed in dedifferentiated liposarcoma, and the gene encoding calreticulin (CALR), a major Ca2+-buffering protein that can inhibit adipocyte differentiation, was found to be overexpressed. Thus, we investigated the expression of calreticulin in 45 cases of liposarcomas, including 15 dedifferentiated tumors, at both the protein and mRNA levels. Immunohistochemically, calreticulin was consistently expressed in the dedifferentiated areas of dedifferentiated liposarcomas and commonly observed in atypical stromal cells and/or lipoblasts in the well-differentiated areas (87%), whereas large vacuolated adipocytic cells in either the tumors or normal fat were essentially negative. These results were further supported by the findings of Western blot and quantitative RT-PCR analyses. Although abnormalities in 19p13.1-13.2 where CALR is localized were uncommon in the dedifferentiated liposarcomas examined by fluorescence in situ hybridbation, expression of miR-1257, a putative microRNA that targets calreticulin, was suppressed in the dedifferentiated subtype. The down-regulation of calreticulin by small-interfering RNA could induce adipogenesis in dedifferentiated liposarcoma cells and reduce cell proliferation. Our results therefore suggest that aberrantly expressed calreticulin in dedifferentiated liposarcoma is involved in its dedifferenitation and/or tumor progression. (Am J Pathol 2012, 180: 2076-2083; DOI: 10.1016/j.ajpath.2012.01.042)