Loss of endothelial cell-specific molecule 1 promotes the tumorigenicity and metastasis of prostate cancer cells through regulation of the TIMP-1/MMP-9 expression.

Chien-Min Chen,Chia-Hung Hung,Chu-Liang Lin,Hui-Ling Chiou,Yi-Hsien Hsieh,Jen-Pi Tsai,Chun-Wen Cheng,Shu-Ching Hsieh,Chia-Liang Lin

doi:10.18632/oncotarget.14684

Abstract

The Endothelial cell specific molecule-1 (ESM1) protein has been involved in proliferation and metastatic progression in multiple tumors. However, there are no studies regarding the mechanism of ESM1 in prostate cancer. We found that ESM1 knockdown in prostate cancer cells resulted in increased cell proliferation and colony formation ability response evidenced by decreased expression of p21 and increased expression of cyclin D1 in prostate cancer cells. Moreover, we revealed that knockdown ESM1 also induced the epithelial-mesenchymal transition (EMT), motility and invasiveness in accordance with the upregulated the MMP-9 expression, while downregulated the TIMP-1 expression. Recombinant human (Rh) TIMP-1 significantly attenuated ESM1-mediated cell migration and invasion. Additionally, ESM1 knockdown increased in vivo tumorigenicity and metastasis of prostate cancer cells. These findings provide the first evidence that the imbalance of MMP-9/TIMP-1, is one of the regulation mechanisms by which ESM1 promotes tumorigenicity and metastasis of prostate cancer cells.

Highlights

Prostate cancer is the common type of cancer and is a second leading cause of cancer-related death in men worldwide [1]
To study biological consequences of Endothelial cell specific molecule-1 (ESM1) upregulation in prostate cancer cells, our data revealed that stably expressing ESM1 short hairpin RNA (shRNA) in PC3 and DU145 cells, ESM1 protein and mRNA expression were significantly reduced compared to the shLuc cells by western blotting and qRT-PCR analysis (Figure 1C and 1D)
We found that ESM1 knockdown were significantly decreased expression of p21, whereas the expression of cyclin D1 was significantly increased in shESM1-PC3 and shESM1-DU145 cells compared to shLuc cells (Figure 2C)

Summary

Introduction

Prostate cancer is the common type of cancer and is a second leading cause of cancer-related death in men worldwide [1]. In addition to the well-known modalities of treatment including operation, radiotherapy or hormone therapy, patients who develop androgenindependent prostate cancer after radiation therapy or hormone ablation therapy and those who had metastatic disease at the time of diagnosis are much less to be cured and with dismal survival [5, 6]. The mechanisms of biological capacities developed during the development of prostate cancer, including proliferative signaling, evading growth factors, resisting cell death, enhancing www.impactjournals.com/oncotarget replicative immortality, inducing angiogenesis, invasion and metastasis, were still remained to be elucidated [2]. The malignant cells must develop a complex of molecular changes that regulated cell morphology and function, the so-called epithelial-mesenchymal transition (EMT), to destroy intercellular relationship and cell-matrix adhesive characteristics, break down the extracellular matrix (ECM), and breach the basement membrane by the modulation of matrix metalloproteinases (MMP) to be motile and invasive, [7,8,9]. Lichtinghagen et al had reported that expression of MMP-9 and the ratio of MMP-2 and MMP-9 to the tissue inhibitor of metalloproteinase 1 to be higher in cancerous prostate tissues than in normal prostate tissues [13]

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Results

Conclusion