Mengying Xing1, Ying Yang1, Jiaxue Huang1, Yaqun Fang1, Yucui Jin1, Lingyun Li1, Xiang Chen2, Xiaoxia Zhu3, Changyan Ma4. 1. Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China. 2. Department of General Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, People's Republic of China. 3. Department of General Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, People's Republic of China. staff778@yxph.com. 4. Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China. cyma@njmu.edu.cn.
Abstract
BACKGROUND: Tissue factor pathway inhibitor-1 (TFPI) is a serine protease inhibitor, which is responsible for inactivating TF-induced coagulation. Recently, increasing studies revealed that TFPI was lowly expressed in tumor cells and exhibited the antitumor activity. OBJECTIVE: The aim of this study was to explore the role and underlying molecular mechanisms of TFPI in breast cancer. METHODS: The expression and prognostic value of TFPI were analyzed using UALCAN and Kaplan-Meier plotter website. The expression level of TFPI in breast cancer tissues and cells was examined by immunohistochemistry (IHC) and western blot analysis, respectively. Cellular proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were determined by transwell assay. The methylation level of TFPI promoter was determined by methylation-specific PCR. RESULTS: TFPI expression was significantly lower in breast cancer tissues and cells compared to normal breast tissues and normal breast cells. Patients with low TFPI levels showed worse overall survival (OS). Furthermore, overexpression of TFPI significantly inhibited the proliferation, migration and invasion of breast cancer cells. Conversely, knockdown of TFPI promoted the proliferation, migration and invasion of breast cancer cells. Mechanistically, TFPI inhibited the ERK/p38 MAPK signaling pathway in breast cancer. Moreover, DNA hypermethylation of TFPI promoter was responsible for the downregulation of TFPI in breast cancer cells. CONCLUSION: TFPI inhibited breast cancer cell proliferation, migration and invasion through inhibition of the ERK/p38 MAPK signaling pathway, suggesting that TFPI may serve as a novel prognostic biomarker and therapeutic target for breast cancer.
BACKGROUND: Tissue factor pathway inhibitor-1 (TFPI) is a serine protease inhibitor, which is responsible for inactivating TF-induced coagulation. Recently, increasing studies revealed that TFPI was lowly expressed in tumor cells and exhibited the antitumor activity. OBJECTIVE: The aim of this study was to explore the role and underlying molecular mechanisms of TFPI in breast cancer. METHODS: The expression and prognostic value of TFPI were analyzed using UALCAN and Kaplan-Meier plotter website. The expression level of TFPI in breast cancer tissues and cells was examined by immunohistochemistry (IHC) and western blot analysis, respectively. Cellular proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were determined by transwell assay. The methylation level of TFPI promoter was determined by methylation-specific PCR. RESULTS: TFPI expression was significantly lower in breast cancer tissues and cells compared to normal breast tissues and normal breast cells. Patients with low TFPI levels showed worse overall survival (OS). Furthermore, overexpression of TFPI significantly inhibited the proliferation, migration and invasion of breast cancer cells. Conversely, knockdown of TFPI promoted the proliferation, migration and invasion of breast cancer cells. Mechanistically, TFPI inhibited the ERK/p38 MAPK signaling pathway in breast cancer. Moreover, DNA hypermethylation of TFPI promoter was responsible for the downregulation of TFPI in breast cancer cells. CONCLUSION: TFPI inhibited breast cancer cell proliferation, migration and invasion through inhibition of the ERK/p38 MAPK signaling pathway, suggesting that TFPI may serve as a novel prognostic biomarker and therapeutic target for breast cancer.
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