title: B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells.
abstract: B7-H4 is expressed in a variety of tumor cells and functions as a negative regulator of T cells. However, clarification is needed as to whether B7-H4 mediates tumorigenesis through mechanisms, such as apoptosis, in addition to mediating tumor immune escape. We investigate the mechanisms involved in enhanced oncogenicity and the inhibition of apoptosis by B7-H4 in pancreatic cancer cells. Short interfering RNAs (siRNAs) specific for B7-H4 were evaluated for their ability to knockdown B7-H4 mRNA and protein expression in pancreatic cancer cells and the most effective siRNA was selected for investigating the effect of B7-H4 gene silencing in a number of functional assays. The inhibition of B7-H4 increased cell-cell adhesion and decreased the formation of pseudopodia. It also increased the expression of E-cadherin and decreased the expression of vimentin and CD44. B7-H4 siRNA inhibited cell proliferation, colony formation and migration of pancreatic cancer cells. Moreover, increased apoptosis in pancreatic cancer cells following B7-H4 silencing was demonstrated in vitro by using flow cytometry and in a xenograft tumor model and was associated with increased caspase activity and decreased Erk1/2 phosphorylation both in vitro and in vivo. Loss of B7-H4 function thus prevents tumor growth through many processes, including the induction of apoptosis and inhibition of the Erk1/2 signaling pathway indicating that B7-H4 is a cancer promoter and a potentially important therapeutic target. B7-H4 inhibition might offer an exciting opportunity to inhibit the progression of human pancreatic cancers.
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, 310003, Hangzhou, China. qianyunm@hotmail.com
authors: Yun
authors: Y
authors: Qian
authors: Bo
authors: B
authors: Hong
authors: Ling
authors: L
authors: Shen
authors: Zhigang
authors: Z
authors: Wu
authors: Hangping
authors: H
authors: Yao
authors: Lihuang
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis; D063646:Carcinogenesis / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011554:Pseudopodia / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D015820:Cadherins; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D014746:Vimentin; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases