B7-H1 Overexpression Regulates Epithelial–Mesenchymal Transition and Accelerates Carcinogenesis in Skin

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 4; pp. 1235 - 1243
• Main Authors: Cao, Yujia, Zhang, Lu, Kamimura, Yosuke, Ritprajak, Patcharee, Hashiguchi, Masaaki, Hirose, Sachiko, Azuma, Miyuki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2011
• Subjects: Animal models; Animals; Antineoplastic agents; B7-1 Antigen - genetics; B7-H1 Antigen; Biological and medical sciences; Carcinogenesis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell culture; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Disease Models, Animal; Disease Progression; E-Cadherin; Epithelial cells; Epithelial-Mesenchymal Transition - genetics; Female; Humans; Inflammation; Keratinocytes; Lymphocytes T; Male; Medical sciences; Membrane Glycoproteins - genetics; Mice; Mice, Inbred BALB C; Mice, Transgenic; PD-1 protein; Peptides - genetics; Pharmacology. Drug treatments; Phorbol esters; Signal transduction; Skin; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Solid tumors; squamous cell carcinoma; Time Factors; TPA; Transcription factors; Transgenic mice; Transplantation, Heterologous; Tumor cells; Tumors; Up-Regulation - physiology; Gene overexpression; Mesenchymal cell; Carcinogenesis; Costimulatory molecule; B7-H1 molecule
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-2217

B7-H1 (CD274) is a T-cell coinhibitory molecule that is also often induced on human carcinoma cells, where its expression has been implicated in immune escape. Under inflammatory conditions, B7-H1 is also inducible in normal epithelial cells but little is known about its involvement in conversion of normal cells to tumor cells. Here, we show that skin-specific expression of B7-H1 accelerates inflammatory carcinogenesis in a methylcholantrene (MCA)-induced model of squamous cell carcinoma (SCC). Inflammatory responses induced by MCA or phorbol ester TPA were clearly inhibited in B7-H1 transgenic mice (B7-H1tg mice). Antibody-mediated blockade of either B7-H1 or the related molecule PD-1 revealed that their ability to limit inflammation relied on ligand interactions made by B7-H1 or PD-1. Skin keratinocytes derived from B7-H1tg mice exhibited constitutive reduction of E-cadherin, and SCC induced in B7-H1tg mice also showed loss of E-cadherin along with elevated expression of the transcription factors Slug and Twist that drive epithelial–mesenchymal transition (EMT). Our results indicate that upregulation of B7-H1 in skin epithelial cells promotes EMT and accelerates carcinogenesis, revealing insights into the significance of B7-H1 overexpression on solid tumor cells and hinting at a close relationship between EMT and immune escape signaling pathways in cancer. Cancer Res; 71(4); 1235–43. ©2010 AACR.