Cheon Dong-Joo, Li Andrew J, Beach Jessica A, Walts Ann E, Tran Hang, Lester Jenny, Karlan Beth Y, Orsulic Sandra
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA and.
Carcinogenesis. 2015 Jul;36(7):739-47. doi: 10.1093/carcin/bgv059. Epub 2015 Apr 29.
ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)β signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective.
ADAM金属蛋白酶结构域12（ADAM12）是一种很有前景的生物标志物，因为它在正常组织中低表达，而在多种人类癌症中高表达。然而，卵巢癌中ADAM12的水平尚未得到充分表征。我们之前将ADAM12鉴定为与高级别浆液性卵巢癌（HGSOC）预后不良相关的标志性基因之一。在此，我们试图确定ADAM12蛋白和/或信使核糖核酸（mRNA）的高水平是否与HGSOC的临床变量相关。我们发现，储存的术前血清中ADAM12蛋白水平高与无进展生存期和总生存期缩短相关。ADAM12 mRNA的肿瘤水平也与无进展生存期和总生存期缩短以及淋巴和血管浸润以及减瘤手术后的残留肿瘤体积相关。在HGSOC中与ADAM12共表达的大多数基因是转化生长因子（TGF）β信号转导靶点，其在胶原蛋白重塑和细胞 - 基质黏附中起作用。在肿瘤切片中，ADAM12蛋白和mRNA在上皮癌细胞和周围基质细胞中表达。体外数据表明，TGFβ信号转导以及上皮细胞和基质细胞之间的直接接触可增加ADAM12 mRNA水平。ADAM12 mRNA的高肿瘤水平是HGSOC间充质/促结缔组织增生分子亚型的特征，已知该亚型预后最差。因此，ADAM12可能是侵袭性卵巢癌的一种有用生物标志物，而针对这种癌症的标准治疗无效。
