Increased mRNA expression of ADAMTS metalloproteinases in metastatic foci of head and neck cancer

Demircan, Kadir; Gündüz, Esra; Gündüz, Mehmet; Beder, Levent Bekir; Hirohata, Satoshi; Nagatsuka, Hitoshi; Cengiz, Beyhan; Cilek, Mehmet Zeynel; Yamanaka, Noboru; Shimizu, Kenji; Ninomiya, Yoshifumi

doi:10.1002/hed.21045

Cited by 50 publications

(45 citation statements)

References 23 publications

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“…Downregulation of ADAMTS8 has been found in some tumors, such as brain tumors (14), breast carcinoma (9), non-small cell lung carcinoma (15), head and neck squamous cell carcinoma (16), and pancreatic cancer (17), whereas its expression in other common solid tumors including nasopharyngeal (NPC), esophageal squamous cell (ESCC), gastric, colorectal (CRC), renal (RCC), and cervical carcinomas remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors.

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Section: Introductionmentioning

confidence: 99%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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“…We hypothesize that CA repeat contraction in the microsatellites located in the ADAMTS9 promoter may block RNA polymerase binding to the ADAMTS9 promoter. If this scenario is correct, cancer-related gene expression, such as that of ADAMTS9, in tumors would decrease (15,16), and lower matrix metalloproteinase activity would translate into a reduced ability to invade lymphatic vessels and metastasize. Porter et al reported that the expression of ADAMTS9 in breast cancer tissues was down-regulated with respect to noncancerous breast tissues and uncovered a potential association between ADAMTS9 and breast cancer (17).…”

Section: Discussionmentioning

confidence: 99%

“…Several matrix metalloproteinases are known to contribute to the invasion and traversal of the extracellular matrix in metastatic spreading. Together with ADAMS, the ADAMTS proteinases have been shown to play a role in cancer development and progression (16). Because ADAMTS9 is a matrix metalloproteinase, ADAMTS9 gene expression may be related to tumor progression and metastatic spreading.…”

Section: Discussionmentioning

confidence: 99%

A potential association between the number of CA repeats in the promoter region of the ADAMTS9 gene with lymphatic metastasis of breast cancer

et al. 2013

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Th is paper concentrates on the Early Oligocene palaeoclimate of the southern part of Eastern and Central Europe and gives a detailed climatological analysis, combined with leaf-morphological studies and modelling of the palaeoatmospheric CO 2 level using stomatal and δ 13 C data. Climate data are calculated using the Coexistence Approach for Kiscellian fl oras of the Palaeogene Basin (Hungary and Slovenia) and coeval assemblages from Central and Southeastern Europe. Potential microclimatic or habitat variations are considered using morphometric analysis of fossil leaves from Hungarian, Slovenian and Italian fl oras. Reconstruction of CO 2 is performed by applying a recently introduced mechanistic model. Results of climate analysis indicate distinct latitudinal and longitudinal climate patterns for various variables which agree well with reconstructed palaeogeography and vegetation. Calculated climate variables in general suggest a warm and frost-free climate with low seasonal variation of temperature. A diff erence in temperature parameters is recorded between localities from Central and Southeastern Europe, manifested mainly in the mean temperature of the coldest month. Results of morphometric analysis suggest microclimatic or habitat diff erence among studied fl oras. Extending the scarce information available on atmospheric CO 2 levels during the Oligocene, we provide data for a well-defi ned time-interval. Reconstructed atmospheric CO 2 levels agree well with threshold values for Antarctic ice sheet growth suggested by recent modelling studies. Th e successful application of the mechanistic model for the reconstruction of atmospheric CO 2 levels raises new possibitities for future climate inference from macro-fl ora studies.

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“…[23][24][25] Briefly, mRNA coding for CTGF, TGF-b1 and 18s rRNA was quantified using the LightCycler rapid thermal cycler system (Roche Diagnostics, Lewes, UK) according to the manufacturer's instructions. A typical protocol took approximately 45 min and included a 10-min denaturation step, followed by 40 cycles of denaturation at 95 1C for 10 s, annealing at 65 1C for 10 s and extension at 72 1C for 20 s.…”

Section: Quantitative Real-time Reverse Transcription Pcr (Rt-pcr) Anmentioning

confidence: 99%

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

et al. 2010

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Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF-and transforming growth factor-beta 1 (TGF-b1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77 ± 0.48 for olmesartan and 6.05 ± 1.45 for saline, Po0.01), fibrosis area (32.0 ± 15.5% compared with the saline group, Po0.05) and serum TGF-b1 level (62.6±10.6 ng ml À1 for olmesartan and 84.4±7.2 ng ml À1 for hydralazine, Po0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF-and TGF-b1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.

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Increased mRNA expression of ADAMTS metalloproteinases in metastatic foci of head and neck cancer

Abstract: Our findings suggest a metastasis model proposing accumulation of a subtype of cancer cells with high metastatic capacity within heterogenous primary tumor cell population.

Cited by 50 publications

References 23 publications

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

A potential association between the number of CA repeats in the promoter region of the ADAMTS9 gene with lymphatic metastasis of breast cancer

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

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