CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis.
CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis.
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CD44 剪接变体 v8-10 作为浆液性卵巢癌预后的标志。
DOI：
10.1371/journal.pone.0156595
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pépin D
中科院分区：
文献类型：
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作者：
Sosulski A;Horn H;Zhang L;Coletti C;Vathipadiekal V;Castro CM;Birrer MJ;Nagano O;Saya H;Lage K;Donahoe PK;Pépin D
CD44是一种跨膜透明质酸受体基因，编码100多种不同的组织特异性蛋白亚型。最普遍的CD44标准已经被用作卵巢癌和其他癌症的癌症干细胞标记物。含有外显子V8-10的上皮性CD44变异体(CD44v8-10)的表达与胃肠道和乳腺癌中更多的化疗耐药和转移肿瘤有关，但其在卵巢癌中的作用尚不清楚；因此，我们研究了它在这种疾病中作为预后标志物的作用。对来自癌症基因组图谱RNAseqV2的254个肿瘤样本的基因表达谱进行了分析，以确定CD44亚型的存在。在包括外显子V8-10的CD44亚型高表达的患者中，观察到生存时间更长的趋势。应用肿瘤组织芯片对210例高级别浆液性卵巢癌患者的肿瘤进行了CD44v8-10的免疫组织化学分析。基于染色软件分析的患者分层显示，跨膜蛋白表达水平最高的患者(前10%或20%)与表达最低的患者(后10%和20%)相比，存活率显著增加(p=0.0181，p=0.0262)。原代卵巢癌细胞株CD44v8-10的表达与以上皮型为主的表型有关，qPCR、Western印迹和IHC结果显示，CD44v8-10上皮型标志高表达，间叶型标志低表达。反之，在患者腹水标本中检测到CD44v8-10的蛋白降解和可溶胞外区与显著的不良预后相关(p<；0.05)。因此，原代肿瘤细胞表面跨膜CD44v8-10的存在可能是高上皮性肿瘤预后较好的标志，而腹水中存在可溶性胞外结构域检测到的CD44v8-10的酶裂解可能预示着疾病的转移性更强，预后更差。
CD44 is a transmembrane hyaluronic acid receptor gene that encodes over 100 different tissue-specific protein isoforms. The most ubiquitous, CD44 standard, has been used as a cancer stem cell marker in ovarian and other cancers. Expression of the epithelial CD44 variant containing exons v8-10 (CD44v8-10) has been associated with more chemoresistant and metastatic tumors in gastrointestinal and breast cancers, but its role in ovarian cancer is unknown; we therefore investigated its use as a prognostic marker in this disease. The gene expression profiles of 254 tumor samples from The Cancer Genome Atlas RNAseqV2 were analyzed for the presence of CD44 isoforms. A trend for longer survival was observed in patients with high expression of CD44 isoforms that include exons v8-10. Immunohistochemical (IHC) analysis of tumors for presence of CD44v8-10 was performed on an independent cohort of 210 patients with high-grade serous ovarian cancer using a tumor tissue microarray. Patient stratification based on software analysis of staining revealed a statistically significant increase in survival in patients with the highest levels of transmembrane protein expression (top 10 or 20%) compared to those with the lowest expression (bottom 10 and 20%) (p = 0.0181, p = 0.0262 respectively). Expression of CD44v8-10 in primary ovarian cancer cell lines was correlated with a predominantly epithelial phenotype characterized by high expression of epithelial markers and low expression of mesenchymal markers by qPCR, Western blot, and IHC. Conversely, detection of proteolytically cleaved and soluble extracellular domain of CD44v8-10 in patient ascites samples was correlated with significantly worse prognosis (p<0.05). Therefore, presence of transmembrane CD44v8-10 on the surface of primary tumor cells may be a marker of a highly epithelial tumor with better prognosis while enzymatic cleavage of CD44v8-10, as detected by presence of the soluble extracellular domain in ascites fluid, may be indicative of a more metastatic disease and worse prognosis.