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A disintegrin and metallopeptidase with thrombospondin motifs (ADAMTSs), which is frequently dysregulated in cancers and is involved in carcinogenesis and cancer progression. The present study identified that ADAMTS8 expression is downregulated in esophageal squamous cell carcinoma (ESCC) tissues when compared with nontumor tissue. The expression of ADAMTS8 is closely associated with clinical stage and lymph node metastasis in patients with ESCC. Furthermore, functional studies have shown that ADAMTS8 overexpression could reduce abilities of proliferation, migration, and invasion and promote apoptosis of ESCC cells. Meanwhile, monocyte chemotactic protein-1 and interleukin-6 are markedly deregulated by ADAMTS8 overexpression. Consistently, in vivo data showed that ADAMTS8 overexpression led to a reduction in tumor growth. These results indicate that altering ADAMTS8 expression could modify the outcomes of ESCC by inhibiting cell proliferation and invasion, while promoting the apoptosis of ECSS cells. Thus, ADAMTS8 represents a potential therapeutic target for ESCC therapy.

Introduction A disintegrin and metallopeptidase with thrombospondin motifs (ADAMTSs), whose expression is dysregulated in various cancers, is implicated in cancer development. Herein, we aimed to investigate the functional role of ADAMTS8 in breast cancer (BC) and explore the underlying mechanisms. Methods The protein expression of ADAMTS8 in BC cell lines and tumor tissues from BC patients was quantified by Western blot. ADAMTS8 overexpression was induced by transfection with pEZ-M90-ADAMTS8 plasmid using lipofectamine 2000. To generate ADAMTS8 stable knockdown cells, MDA-MB-231 cells were transfected with psi-H1-ADAMTS8siRNA plasmids. Cell counting kit-8 (CCK-8) assay, wound-healing assay, transwell assay and flow cytometry assay were employed to analyze the effects of ADAMTS8 on the proliferation, migration, invasion and apoptosis of BC cells. Chemosensitivity also was assessed using CCK-8 assay. The expressions of β-catenin, MMP-7 and c-Myc were measured by Western blot. Results Our results showed that ADAMTS8 expression was significantly lower in BC tissues than that in adjacent non-tumor tissues. Overexpression of ADAMTS8 in MDA-MB-453 cells could inhibit the cell proliferation, migration and invasion and promote apoptosis. ADAMTS8 knockdown displayed the reverse effect in MDA-MB-231 cells. Consistently, in vivo data showed that ADAMTS8 overexpression led to a reduction in tumor growth. In addition, chemosensitivity testing in MDA-MB-453 cells transfected with pEZ-M90-ADAMTS8 plasmid indicated that cisplatin inhibited cell growth dramatically. Furthermore, attenuated β-catenin, MMP-7 and c-Myc level was detected after ADAMTS8 overexpression. Conclusion These results indicate that increased ADAMTS8 expression could modify the progression of BC by inhibiting cell proliferation and invasion while promoting the apoptosis of BC cells. Thus, ADAMTS8 represents a potential therapeutic target for BC therapy.

Rheumatoid arthritis (RA), chronic, autoimmune causing joint stiffness, pain, fatigue and functional disorders is a disease. The aim of this study is to investigate the presence of ADAMTS-8 expression in cells in synovial fluid in rheumatoid arthritis patients. Patients with active RA were aspirated with arthro synthesis from the knee joint. Blood samples were taken from the patients at the same time, plasma samples were separated. Patients with sinovial fluid treated between 2019-2020 year in the Gazi Yasargil Hospital Physical Therapy and Rehabilitation Clinic were involved in the study that was consulted with knee pain and difficulty in performing their daily activities. Informed consent form was obtained from all of the patients (10 RA and 10 patients). CRP, RF and ESH results were statistically evaluated in patients with Control and Rheumatoid arthritis. CRP, RF and ESH results were statistically evaluated in patients with Control and Rheumatoid arthritis. In patient samples with Rheumatoid arthritis, degeneration in synovial cells was observed in some nuclei in the form of pycnosis and apoptotic. ADAMTS-8 expression in the form of aggregates in synovial cells was found to be positive. It was observed that rheumatoid arthritis increased apoptotic change in synovial cells. ADAMTS8 in synovial cells in rheumatoid arthritis cases may cause a significant increase in apoptosis levels by suppressing some signal pathways, and predicts that apoptosis induction may play a role in the inhibition of ADAMTS8-mediated synovial cell proliferation.

Introduction A disintegrin and metallopeptidase with thrombospondin motifs (ADAMTSs), whose expression is dysregulated in various cancers, is implicated in cancer development. Herein, we aimed to investigate the functional role of ADAMTS8 in breast cancer (BC) and explore the underlying mechanisms. Methods The protein expression of ADAMTS8 in BC cell lines and tumor tissues from BC patients was quantified by Western blot. ADAMTS8 overexpression was induced by transfection with pEZ-M90-ADAMTS8 plasmid using lipofectamine 2000. To generate ADAMTS8 stable knockdown cells, MDA-MB-231 cells were transfected with psi-H1-ADAMTS8siRNA plasmids. Cell counting kit-8 (CCK-8) assay, wound-healing assay, transwell assay and flow cytometry assay were employed to analyze the effects of ADAMTS8 on the proliferation, migration, invasion and apoptosis of BC cells. Chemosensitivity also was assessed using CCK-8 assay. The expressions of β-catenin, MMP-7 and c-Myc were measured by Western blot. Results Our results showed that ADAMTS8 expression was significantly lower in BC tissues than that in adjacent non-tumor tissues. Overexpression of ADAMTS8 in MDA-MB-453 cells could inhibit the cell proliferation, migration and invasion and promote apoptosis. ADAMTS8 knockdown displayed the reverse effect in MDA-MB-231 cells. Consistently, in vivo data showed that ADAMTS8 overexpression led to a reduction in tumor growth. In addition, chemosensitivity testing in MDA-MB-453 cells transfected with pEZ-M90-ADAMTS8 plasmid indicated that cisplatin inhibited cell growth dramatically. Furthermore, attenuated β-catenin, MMP-7 and c-Myc level was detected after ADAMTS8 overexpression. Conclusion These results indicate that increased ADAMTS8 expression could modify the progression of BC by inhibiting cell proliferation and invasion while promoting the apoptosis of BC cells. Thus, ADAMTS8 represents a potential therapeutic target for BC therapy.

Xuetao Zhao,1 Congrong Yang,2 Jianhua Wu,3 Yuemin Nan4 1Department of Blood Transfusion, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system. A disintegrin and metallopeptidase with thrombospondin motif (ADAMTS) has been identified as a secreted metalloproteinase that participates in the inhibition of tumor cell growth and invasion. The aims of the present study were to investigate the clinical significance of ADAMTS8 in patients with HCC and to determine the effect of ADAMTS8 on HCC cell biological activity in vitro and in vivo.Methods: The tumor tissues and matched adjacent non-tumor tissues were collected from 61 patients with HCC, and ADAMTS8 expression was detected with immunohistochemistry. Flow cytometry and MTT assays were used to assess cell apoptosis and cell viability, respectively, and ERK, p-ERK, Stat3, p-Stat3, Akt, and p-Akt protein expressions were measured by Western blot.Results: The results showed that ADAMTS8 expression was significantly lower in HCC tissues than that in adjacent non-tumor tissues. Moreover, ADAMTS8 expression was inversely associated with clinical stages and metastasis in patients with HCC. Furthermore, we found that transfection with exogenous ADAMTS8 inhibited proliferation and migration and induced apoptosis in HepG2 cells. In the in vivo study, tumor growth of upregulated HepG2 cells in nude mice was significantly slower. Moreover, decreased ERK activity was detected after transfection with ADAMTS8.Conclusion: These results indicate that low ADAMTS8 expression is a predictor of a poor prognosis in patients with HCC and that ADAMTS8 plays an important role in regulating HCC growth, invasion, and apoptosis by modulating the ERK signaling pathway. ADAMTS8 maybe a new target in HCC treatment. Keywords: hepatocellular carcinoma, ADAMT8, apoptosis, invasion and metastasis, signaling pathway

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. Implications: This study uncovers the tumor suppressive function of ADAMTS8, one of the ADAMTS family members, and its frequent methylation in certain tumors could be developed as a potential biomarker. Mol Cancer Res; 12(2); 228–38. ©2013 AACR.