Department of Pathology, Stanford University, Stanford, California, United States of America.
PLoS One. 2013 Sep 9;8(9):e74562. doi: 10.1371/journal.pone.0074562. eCollection 2013.
Clear cell carcinoma (CCC) is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B) was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001), as was hypomethylation of the HNF1B promoter (P<0.001). From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites) (P<0.03), as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01), and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015). Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043), and with a 2.3-fold increased risk (P = 0.011) in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC) derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality), based on the direct production of clotting factors by cancer cells.
透明细胞癌（CCC）是一种组织学上明显的癌亚型，发生在几个器官系统中，其特征是细胞质透明，归因于丰富的细胞内糖原。以前，转录因子肝细胞核因子 1-β（HNF1B）被鉴定为卵巢 CCC 的生物标志物。在这里，我们广泛探索了 HNF1B 与具有透明细胞组织学的癌之间的关系。通过免疫组织化学评估，HNF1B 的表达与不同的妇科和肾细胞癌的透明细胞组织学显著相关（P<0.001），HNF1B 启动子的低甲基化也显著相关（P<0.001）。通过微阵列分析，经验衍生的 HNF1B 特征显著富集了计算预测的靶标（具有 HNF1 结合位点）（P<0.03），以及与糖原代谢相关的基因，包括葡萄糖-6-磷酸酶，以及令人瞩目的是凝血级联，包括纤维蛋白原、凝血酶原和因子 XIII。凝血级联的富集在卵巢 CCC 与其他组织类型的微阵列数据中也很明显（P<0.01），并且 HNF1B 相关的凝血酶原表达通过免疫组织化学验证（P = 0.015）。最后，在具有细胞质透明的妇科癌中，HNF1B 免疫染色与临床上显著静脉血栓形成的风险增加 3.0 倍相关（P = 0.043），在妇科和肾细胞癌的联合队列中与风险增加 2.3 倍相关（P = 0.011）。我们的研究结果将 HNF1B 定义为透明细胞表型的广泛标志物，并支持与糖原积累和血栓形成的机制联系，这可能反映了（对于妇科 CCC）来源于分泌性子宫内膜。我们的发现还表明，基于癌细胞直接产生凝血因子，肿瘤相关血栓形成（癌症死亡率的主要原因）存在一种新的机制。
