Dataset Information

Proteomic identification of cyclophilin A as a potential biomarker and therapeutic target in oral submucous fibrosis.

ABSTRACT: Oral submucous fibrosis (OSF) is a pre-cancerous lesion, which is characterized by fibrosis of the oral submucosa. Despite large body of studies focusing on this disease, the molecular mechanisms underlying the progression of OSF remained unclear. In this study, 2-DE-based proteomic approaches were employed to identify the differently expressed proteins between OSF and normal tissues. In total, 88 proteins were identified with altered expression levels, including CypA. Upregulation of CypA was further validated through immunohistochemistry staining combined with Q-PCR and western blot by using clinical samples. Statistical analyses reveal that CypA expression level is correlated to the progression of OSF. Finally, functional study reveals a pro-proliferative property of CypA in fibroblast cells by using multiple in vitro models. The present data suggest that CypA might be a potential biomarker and therapeutic target for OSF, and will lead to a better understanding of OSF pathogenesis.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC5312388 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Proteomic identification of cyclophilin A as a potential biomarker and therapeutic target in oral submucous fibrosis.

Yuan Yao Y Hou Xiaohui X Feng Hui H Liu Rui R Xu Hao H Gong Wang W Deng Jing J Sun Chongkui C Gao Yijun Y Peng Jieying J Wu Yingfang Y Li Jiang J Fang Changyun C Chen Qianming Q

Oncotarget 20160901 37

Oral submucous fibrosis (OSF) is a pre-cancerous lesion, which is characterized by fibrosis of the oral submucosa. Despite large body of studies focusing on this disease, the molecular mechanisms underlying the progression of OSF remained unclear. In this study, 2-DE-based proteomic approaches were employed to identify the differently expressed proteins between OSF and normal tissues. In total, 88 proteins were identified with altered expression levels, including CypA. Upregulation of CypA was f ...[more]

PMID: 27533088

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Project description:BackgroundWe have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.MethodsRNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes.ResultsWe show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 × 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45α, and Ki67.ConclusionTogether, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.

Dataset Information

Proteomic identification of cyclophilin A as a potential biomarker and therapeutic target in oral submucous fibrosis.

Publications

Proteomic identification of cyclophilin A as a potential biomarker and therapeutic target in oral submucous fibrosis.

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