Identification of LEFTY as a molecular marker for ovarian clear cell carcinoma.
Identification of LEFTY as a molecular marker for ovarian clear cell carcinoma.
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DOI：
10.18632/oncotarget.18882
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发表时间：
2017-09-08
期刊：
影响因子：
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通讯作者：
Saegusa M
中科院分区：
文献类型：
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作者：
Akiya M;Yamazaki M;Matsumoto T;Kawashima Y;Oguri Y;Kajita S;Kijima D;Chiba R;Yokoi A;Takahashi H;Kodera Y;Saegusa M
为了鉴定与卵巢透明细胞癌（OCCCa）相关的蛋白，我们对卵巢癌的福尔马林固定和石蜡包埋样品进行了鸟枪蛋白组学分析。对1521个蛋白的分析显示，在4个OCCCa样品和12个非OCCCa样品中，有52个蛋白存在差异表达。在OCCCa的高表达蛋白中，我们重点关注了左右决定因子（LEFTY），这是转化生长因子-β超家族的一个新成员。在143例卵巢上皮癌（包括99例OCCCas和44例非OCCCas）中，OCCCas中LEFTY mRNA和蛋白水平的表达均显著高于非OCCCas，且LEFTY1 mRNA的表达高于LEFTY2。稳定过表达LEFTY1的OCCCa细胞显示细胞增殖减少，pSmad2表达减少，并且直接或间接地显示p53/p21waf1通路激活或p27kip1表达增加。此外，用顺铂处理稳定细胞系导致凋亡细胞增加，同时抑制psmad2介导的x -连锁凋亡抑制剂的蛋白表达，降低bcl2/bax比率。用特异性短发夹RNA阻断LEFTY1表达抑制顺铂诱导的细胞凋亡，可能是通过增加XIAP和bcl2的表达，而不是bax。在临床样本中，LEFTY评分高的OCCCas中凋亡细胞数量明显高于LEFTY评分低的OCCCas， Ki-67标记指数明显低于LEFTY评分低的OCCCas。这些发现提示LEFTY可能是一种优秀的occca特异性分子标记物，它在改变细胞增殖和细胞凋亡易感性方面具有抗肿瘤作用。
To identify proteins involved in ovarian clear cell carcinoma (OCCCa), shotgun proteomics analysis was applied using formalin-fixed and paraffin-embedded samples of ovarian carcinoma. Analysis of 1521 proteins revealed that 52 were differentially expressed between four OCCCa and 12 non-OCCCa samples. Of the highly expressed proteins in OCCCa, we focused on left-right determination factor (LEFTY), a novel member of the transforming growth factor-β superfamily. In 143 cases of ovarian epithelial carcinoma including 99 OCCCas and 44 non-OCCCas, LEFTY expression at both mRNA and protein levels was significantly higher in OCCCas compared with non-OCCCas, with the mRNA expression of LEFTY1 being predominant compared to that of LEFTY2. OCCCa cells stably overexpressing LEFTY1 showed reduced cell proliferation, along with decreased pSmad2 expression, and also either displayed an activated p53/p21waf1 pathway or increased p27kip1 expression, directly or indirectly. Moreover, the treatment of stable cell lines with cisplatin led to increased apoptotic cells, together with the inhibition of protein expression of a pSmad2-mediated X-linked inhibitor of apoptosis and a decreased bcl2/bax ratio. Blocking LEFTY1 expression with a specific short hairpin RNA inhibited cisplatin-induced apoptosis, probably through the increased expression of both XIAP and bcl2, but not bax. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in OCCCas with a high LEFTY score relative to those with a low score. These findings suggest that LEFTY may be an excellent OCCCa-specific molecular marker, which has anti-tumor effects in altering cell proliferation and cellular susceptibility to apoptosis.