Clinicopathological Significance of Human Macrophage Metalloelastase Expression in Esophageal Squamous Cell Carcinoma

Ding, Yongzeng; Shimada, Yutaka; Gorrin-Rivas, Manuel J.; Itami, Atsushi; Li, Zhigang; Hong, Tao; Maeda, Masato; Komoto, Izumi; Kawabe, Akira; Kaganoi, Junichi; Imamura, Masayuki

doi:10.1159/000066231

Cited by 34 publications

(16 citation statements)

References 13 publications

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“…In addition to its proapoptotic effect, we also found that DIRAS1 could mediate ESCC cell motility and invasiveness via deregulating MMP2 and MMP9, which are reported to be involved in tumor cell migration, spreading, invasion and metastasis (40)(41)(42)(43)(44). Luciferase reporter assay further confirmed that DIRAS1 could modulate MMP2 and MMP9 expression at the transcriptional level, suggesting that MMP2 and MMP9 are indeed downstream targets of DIRAS1-mediated signaling.…”

Section: Discussionsupporting

confidence: 58%

Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

Zhu

Chen

et al. 2013

Cancer Research

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Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras-like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal-regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies. Cancer Res; 73(7); 2298-309. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 58%

Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

Zhu

Chen

et al. 2013

Cancer Research

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“…32 Moreover, this MMP has been found in different cancers, though its role is still controversial. For example, MMP-12 expression has been associated with dedifferentiation and histological aggressiveness in skin cancer, 33 with increased invasiveness in squamous cell carcinomas of the vulva and esophagus, 34,35 and with metastatic disease in nonsmall cell lung cancer patients. 36 On the contrary, overexpression of MMP-12 has been correlated with better prognosis in patients with colorectal and hepatocellular carcinomas, 37,38 and with diminished growth of lung metastases.…”

Section: Intraosseous Pc3 Tumors Express Mmp-12mentioning

confidence: 99%

Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP‐12 dependent manner

Nabha

Santos

Yamamoto

et al. 2008

Intl Journal of Cancer

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At the cellular level, the process of bone metastasis involves many steps. Circulating cancer cells enter the marrow, proliferate, induce neovascularization, and ultimately expand into a clinically detectable, often symptomatic, metastatic deposit. Although the initial establishment and later expansion of the metastatic deposit in bone require tumor cells to possess invasive capability, the exact proteases responsible for this phenotype are not well known. The objective of our study was to take an unbiased approach to determine which proteases were expressed and functional during the initial interactions between prostate cancer cells and bone marrow stromal (BMS) cells. We found that the combination of human prostate cancer PC3 and BMS cells stimulates the invasive ability of cancer cells through type I collagen. The use of inhibitors for each of the major protease families indicated that 1 or more MMPs was/were responsible for the BMS-induced invasion. Gene profiling and semiquantitative RT-PCR analysis revealed an increased expression of several MMP genes because of PC3/BMS cell interaction. However, only MMP-12 showed an increase in protein expression. Downregulation of MMP-12 expression in PC3 cells by siRNA inhibited the enhanced invasion induced by PC3/BMS cell interaction. In vivo, MMP-12 was found to be primarily expressed by prostate cancer cells growing in bone. Our data suggest that BMS cells induce MMP-12 expression in prostate cancer cells, which results in invasive cells capable of degradation of type I collagen. ' 2008 Wiley-Liss, Inc.Key words: bone metastasis; matrix metalloproteinases (MMPs); protease inhibitors Prostate cancer is the second leading cause of cancer-related death and the most common cancer in males, resulting in~27,000 deaths of men per year in the United States.1 Almost all patients with advanced disease have bone metastasis, and most patients experience painful complications from skeletal involvement. 2Although the biology of tumor growth in bone is beginning to be unraveled, the initial steps of tumor-bone interaction that promote the establishment and expansion of the metastatic deposit are still undefined.Matrix metalloproteinases (MMPs) are endopeptidases that can cleave virtually any compound of the extracellular matrix (ECM). MMPs are produced by both tumor cells and host cells and have been shown to play a role in regulating cancer cell growth, apoptosis, invasion, metastasis and angiogenesis.3 Although ECM remodeling and invasion are thought to occur by virtue of MMPs' capacity to destroy underlying cellular foundations, it is now known that MMPs can alter signaling pathways triggered by molecules concealed in the ECM, thereby profoundly influencing the local microenvironment.4 Proliferation, survival and invasiveness of prostate cancer cells depend on their interaction with stromal cells. 5,6 This interaction affects cellular behavior through direct cell-cell contact or through diffusible factors using existent intracellular signaling pathways. 7 In any case, in orde...

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“…Despite the use of modern surgical techniques in conjunction with multitreatment modalities such as radio-and chemotherapy, the overall 5-year survival rate remains 40 -60% (1)(2)(3)(4). In an effort to better understand this disease and predict its clinical outcome, numerous molecular markers for tumor progression and prognosis, e.g., STMY3 (5), interleukin 6 (6), C1orf10 (7), and EC45 (8), and for lymph node metastasis, e.g., caveolin-1 (9), EphA2 (10), FAK (11), cystain B (12), and MMP-12 (13), have been identified. This limited information, however, is not enough to clarify the carcinogenesis, tumor progression, and invasiveness of esophageal cancer; just as in the allegory about the five blind men and the elephant, the complete picture of the pathophysiology of the disease remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Gene-Expression Profile Changes Correlated with Tumor Progression and Lymph Node Metastasis in Esophageal Cancer

Tamoto¹,

Tada

Murakawa³

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers.Experimental Design: We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC. Conclusion: We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.

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Clinicopathological Significance of Human Macrophage Metalloelastase Expression in Esophageal Squamous Cell Carcinoma

Cited by 34 publications

References 13 publications

Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP‐12 dependent manner

Gene-Expression Profile Changes Correlated with Tumor Progression and Lymph Node Metastasis in Esophageal Cancer

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