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Objectives: The prognostic significance and potential carcinogenic mechanism of ADAM metallopeptidase with thrombospondin type 1 motif 12 (ADAMTS12) in head and neck squamous cell carcinoma (HNSC) remain unclear. Materials and Methods: Immunohistochemistry was used to analyze the correlation between ADAMTS12 protein expression and clinicopathological factors in tumor samples from 195 patients with HNSC. Based on clinicopathological data of patients, Cox regression and Kaplan–Meier analysis were used to identify the prognostic significance of the ADAMTS12 expression. The carcinogenicity of the ADAMTS12 in HNSC cells was analyzed by CCK‐8 assay, the wound‐healing assay, and transwell assays after transfection of ADAMTS12 overexpression or knock‐down vector. Results: The expression of ADAMTS12 was up‐regulated in HNSC compared with normal tissue, related to pathology grade and lymph node metastasis of patients with HNSC, which was an independent prognostic factor. ADAMTS12 overexpression facilitated cell viability, invasion, and migration of HNSC cells, while ADAMTS12 knock‐down had inverse results. Moreover, enrichment analysis, ADAMTS12 overexpression assay, and ADAMTS12 knock‐down assay confirmed that ADAMTS12 mediated the activation of P13K/Akt pathway in HNSC. Conclusions: Our studies indicated that ADAMTS12 was a novel prognostic biomarker and potentially therapeutic target in HNSC. [ABSTRACT FROM AUTHOR]

Abstract Background Gastric cancer (GC) is a common malignancy with its morbidity increasing worldwide. Hence, it is imperative to develop effective treatments. Studies have shown that metformin has potential antitumor effects. The objective of this study was to probe the antitumor mechanism of metformin in GC. Methods The expression of ADAMTS12 in GC tissues and its enrichment pathways were analyzed by bioinformatics methods. ADAMTS12 expression in GC cells was assessed by qRT-PCR. Cell viability and proliferation were analyzed by CCK-8 and colony formation assays, respectively. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of GC cells in different treatment groups were analyzed by Seahorse XP 96, and glycolysis metabolites were detected by corresponding kits. Western blot was employed to analyze the level of glycolysis pathway related protein HK-2, and cell functional assays were conducted to verify the functions of metformin on GC cells. A xenograft model was constructed to validate the inhibitory role of metformin in GC. Results ADAMTS12 expression was elevated in GC tissues/cells and concentrated in glycolysis pathway. Cell functional assays found that ADAMTS12 promoted the proliferation and glycolysis of GC cells. Rescue experiments showed that metformin could reduce the promoting effect of ADAMTS12 overexpression on the proliferation and glycolysis of GC cells. In vivo studies confirmed that metformin suppressed the proliferation and glycolysis process via ADAMTS12 in GC cells. Conclusion Metformin can repress the proliferation and glycolysis of GC cells via ADAMTS12. The results suggest the potential of ADAMTS12 being a target for the metformin therapy of GC.

Abstract ADAMTS12 is a gene widely expressed in human tissues. We studied the expression level of ADAMTS12 in cervical cancer tissue and its relationship with clinicopathological features. We also explored the function of ADAMTS12 in cervical cancer cells and its underlying mechanisms. We found the higher expression level of ADAMTS12 in cancer tissues, which was associated with the worse overall survival rate. The immunofluorescence assay showed that the cytoplasm of cervical cancer cells is the main expression site of ADAMTS12. Overexpression of ADAMTS12 in HeLa and CaSki cells prominently promoted the cell proliferation, migration and invasion. We found that 2032 genes were correlated with ADAMTS12, which was mainly related to extracellular matrix, TGF-β signaling pathway. The phosphorylation levels of mTOR and 4E-BP1 were upregulated in ADAMTS12-overexpressing cells. Co-Immunoprecipitation combined with protein mass spectrometry showed that TGF-β signaling pathway-related proteins interacting with ADAMTS12 were screened from HeLa cells with ADAMTS12 overexpression. Therefore, we concluded that ADAMTS12 may affect the mTOR signaling pathway through the interacting with TGF-β1, and then affect the biological function of cervical cancer cells.

Abstract Background Osteoarthritis (OA) is a degenerative joint disease with lacking effective prevention targets. A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is a member of the ADAMTS family and is upregulated in OA pathologic tissues with no fully understood molecular mechanisms. Methods The anterior cruciate ligament transection (ACL-T) method was used to establish rat OA models, and interleukin-1 beta (IL-1β) was administered to induce rat chondrocyte inflammation. Cartilage damage was analyzed via hematoxylin-eosin, Periodic Acid-Schiff, safranin O-fast green, Osteoarthritis Research Society International score, and micro-computed tomography assays. Chondrocyte apoptosis was detected by flow cytometry and TdT dUTP nick-end labeling. Signal transducer and activator of transcription 1 (STAT1), ADAMTS12, and methyltransferase-like 3 (METTL3) levels were detected by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blot, or immunofluorescence assay. The binding ability was confirmed by chromatin immunoprecipitation-qPCR, electromobility shift assay, dual-luciferase reporter, or RNA immunoprecipitation (RIP) assay. The methylation level of STAT1 was analyzed by MeRIP-qPCR assay. STAT1 stability was investigated by actinomycin D assay. Results The STAT1 and ADAMTS12 expressions were significantly increased in the human and rat samples of cartilage injury, as well as in IL-1β-treated rat chondrocytes. STAT1 is bound to the promoter region of ADAMTS12 to activate its transcription. METTL3/ Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) mediated N6-methyladenosine modification of STAT1 promoted STAT1 mRNA stability, resulting in increased expression. ADAMTS12 expression was reduced and the IL-1β-induced inflammatory chondrocyte injury was attenuated by silencing METTL3. Additionally, knocking down METTL3 in ACL-T-produced OA rats reduced ADAMTS12 expression in their cartilage tissues, thereby alleviating cartilage damage. Conclusion METTL3/IGF2BP2 axis increases STAT1 stability and expression to promote OA progression by up-regulating ADAMTS12 expression.

Adamalysins, a family of metalloproteinases containing a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTSs), belong to the matrisome and play important roles in various biological and pathological processes, such as development, immunity and cancer. Using a liver cancer dataset from the International Cancer Genome Consortium, we developed an extensive in silico screening that identified a cluster of adamalysins co‐expressed in livers from patients with hepatocellular carcinoma (HCC). Within this cluster, ADAMTS12 expression was highly associated with recurrence risk and poorly differentiated HCC signatures. We showed that ADAMTS12 was expressed in the stromal cells of the tumor and adjacent fibrotic tissues of HCC patients, and more specifically in activated stellate cells. Using a mouse model of carbon tetrachloride‐induced liver injury, we showed that Adamts12 was strongly and transiently expressed after a 24 h acute treatment, and that fibrosis was exacerbated in Adamts12‐null mice submitted to carbon tetrachloride‐induced chronic liver injury. Using the HSC‐derived LX‐2 cell line, we showed that silencing of ADAMTS12 resulted in profound changes of the gene expression program. In particular, genes previously reported to be induced upon HSC activation, such as PAI‐1, were mostly down‐regulated following ADAMTS12 knock‐down. The phenotype of these cells was changed to a less differentiated state, showing an altered actin network and decreased nuclear spreading. These phenotypic changes, together with the down‐regulation of PAI‐1, were offset by TGF‐β treatment. The present study thus identifies ADAMTS12 as a modulator of HSC differentiation, and a new player in chronic liver disease. [ABSTRACT FROM AUTHOR]

ADAMTS12 is a gene widely expressed in human tissues. We studied the expression level of ADAMTS12 in cervical cancer tissue and its relationship with clinicopathological features. We also explored the function of ADAMTS12 in cervical cancer cells and its underlying mechanisms. We found the higher expression level of ADAMTS12 in cancer tissues, which was associated with the worse overall survival rate. The immunofluorescence assay showed that the cytoplasm of cervical cancer cells is the main expression site of ADAMTS12. Overexpression of ADAMTS12 in HeLa and CaSki cells prominently promoted the cell proliferation, migration and invasion. We found that 2032 genes were correlated with ADAMTS12, which was mainly related to extracellular matrix, TGF-β signaling pathway. The phosphorylation levels of mTOR and 4E-BP1 were upregulated in ADAMTS12-overexpressing cells. Co-Immunoprecipitation combined with protein mass spectrometry showed that TGF-β signaling pathway-related proteins interacting with ADAMTS12 were screened from HeLa cells with ADAMTS12 overexpression. Therefore, we concluded that ADAMTS12 may affect the mTOR signaling pathway through the interacting with TGF-β1, and then affect the biological function of cervical cancer cells. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative joint disease with lacking effective prevention targets. A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is a member of the ADAMTS family and is upregulated in OA pathologic tissues with no fully understood molecular mechanisms. Methods: The anterior cruciate ligament transection (ACL-T) method was used to establish rat OA models, and interleukin-1 beta (IL-1β) was administered to induce rat chondrocyte inflammation. Cartilage damage was analyzed via hematoxylin-eosin, Periodic Acid-Schiff, safranin O-fast green, Osteoarthritis Research Society International score, and micro-computed tomography assays. Chondrocyte apoptosis was detected by flow cytometry and TdT dUTP nick-end labeling. Signal transducer and activator of transcription 1 (STAT1), ADAMTS12, and methyltransferase-like 3 (METTL3) levels were detected by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blot, or immunofluorescence assay. The binding ability was confirmed by chromatin immunoprecipitation-qPCR, electromobility shift assay, dual-luciferase reporter, or RNA immunoprecipitation (RIP) assay. The methylation level of STAT1 was analyzed by MeRIP-qPCR assay. STAT1 stability was investigated by actinomycin D assay. Results: The STAT1 and ADAMTS12 expressions were significantly increased in the human and rat samples of cartilage injury, as well as in IL-1β-treated rat chondrocytes. STAT1 is bound to the promoter region of ADAMTS12 to activate its transcription. METTL3/ Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) mediated N6-methyladenosine modification of STAT1 promoted STAT1 mRNA stability, resulting in increased expression. ADAMTS12 expression was reduced and the IL-1β-induced inflammatory chondrocyte injury was attenuated by silencing METTL3. Additionally, knocking down METTL3 in ACL-T-produced OA rats reduced ADAMTS12 expression in their cartilage tissues, thereby alleviating cartilage damage. Conclusion: METTL3/IGF2BP2 axis increases STAT1 stability and expression to promote OA progression by up-regulating ADAMTS12 expression. [ABSTRACT FROM AUTHOR]

Considering its speedy development and extremely low 5-year overall survival rate worldwide, bladder cancer (BCa) is one of the most common and highly malignant tumors. Increasing evidence suggests that protein-coding mRNAs and non-coding RNAs, including long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), play an essential role in regulating the biological processes of cancer. To investigate the molecular regulation associated with poor prognosis during advanced BCa development, we constructed a competitive endogenous RNA (ceRNA) network. Using transcriptome profiles from The Cancer Genome Atlas and Gene Expression Omnibus databases, we performed differential expression (DE) analysis, weighted gene co-expression network analysis, functional enrichment analysis, survival analysis, prediction of miRNA targeting, and Pearson correlation analysis. Through layers of selection, 8 lncRNAs-28 mRNAs and 8 miRNAs-28 mRNAs pairs shared similar expression patterns, constituting a core ceRNA regulatory network related to the invasion, progression, and metastasis of advanced clinical stage (ACS) BCa. Subsequently, we conducted real time qPCR, western blotting, and immunohistochemistry to validate expression trend bioinformatics analysis on 3, 2, and 3 differentially expressed mRNAs, lncRNAs, and miRNAs, respectively. The most significantly differentially expressed LINC01929, miR-6875-5p and ADAMTS12 were selected for in vitro experiments to assess the functional role of the LINC01929/miR-6875-5p/ADAMTS12 axis. RNA pull-down, luciferase assays, and rescue assays were performed to examine the binding of LINC01929 and miR-6875-5p. Increasing trends in COL6A1, CDH11, ADAMTS12, LINC01705, and LINC01929 expression variation were verified as consistent with previous DE analysis results in ACS-BCa, compared with low clinical stage (LCS) BCa. Expression trends in parts of these RNAs, such as hsa-miR-6875-5p, hsa-miR-6784-5p, COL6A1, and CDH11, were measured in accordance with DE analysis in LCS-BCa, compared with normal bladder urothelium. Through experimental validation, the cancer-promoting molecule ADAMST12 was found to play a key role in the development of advanced BCa. Functionally, ADAMTS12 knockdown inhibited the progression of bladder cancer. Overexpression of LINC01929 promoted bladder cancer development, while overexpression of miR-6785-5p inhibited bladder cancer development. Mechanistically, LINC01929 acted as a sponge for miR-6785-5p and partially reversed the role of miR-6785-5p. Our findings provide an elucidation of the molecular mechanism by which advanced bladder cancer highly expressed LINC01929 upregulates ADAMTS12 expression through competitive adsorption of miR-6875-5p. It provides a new target for the prognosis and diagnosis of advanced bladder cancer. [ABSTRACT FROM AUTHOR]

Considering its speedy development and extremely low 5-year overall survival rate worldwide, bladder cancer (BCa) is one of the most common and highly malignant tumors. Increasing evidence suggests that protein-coding mRNAs and non-coding RNAs, including long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), play an essential role in regulating the biological processes of cancer. To investigate the molecular regulation associated with poor prognosis during advanced BCa development, we constructed a competitive endogenous RNA (ceRNA) network. Using transcriptome profiles from The Cancer Genome Atlas and Gene Expression Omnibus databases, we performed differential expression (DE) analysis, weighted gene co-expression network analysis, functional enrichment analysis, survival analysis, prediction of miRNA targeting, and Pearson correlation analysis. Through layers of selection, 8 lncRNAs-28 mRNAs and 8 miRNAs-28 mRNAs pairs shared similar expression patterns, constituting a core ceRNA regulatory network related to the invasion, progression, and metastasis of advanced clinical stage (ACS) BCa. Subsequently, we conducted real time qPCR, western blotting, and immunohistochemistry to validate expression trend bioinformatics analysis on 3, 2, and 3 differentially expressed mRNAs, lncRNAs, and miRNAs, respectively. The most significantly differentially expressed LINC01929, miR-6875-5p and ADAMTS12 were selected for in vitro experiments to assess the functional role of the LINC01929/miR-6875-5p/ADAMTS12 axis. RNA pull-down, luciferase assays, and rescue assays were performed to examine the binding of LINC01929 and miR-6875-5p. Increasing trends in COL6A1, CDH11, ADAMTS12, LINC01705, and LINC01929 expression variation were verified as consistent with previous DE analysis results in ACS-BCa, compared with low clinical stage (LCS) BCa. Expression trends in parts of these RNAs, such as hsa-miR-6875-5p, hsa-miR-6784-5p, COL6A1, and CDH11, were measured in accordance with DE analysis in LCS-BCa, compared with normal bladder urothelium. Through experimental validation, the cancer-promoting molecule ADAMST12 was found to play a key role in the development of advanced BCa. Functionally, ADAMTS12 knockdown inhibited the progression of bladder cancer. Overexpression of LINC01929 promoted bladder cancer development, while overexpression of miR-6785-5p inhibited bladder cancer development. Mechanistically, LINC01929 acted as a sponge for miR-6785-5p and partially reversed the role of miR-6785-5p. Our findings provide an elucidation of the molecular mechanism by which advanced bladder cancer highly expressed LINC01929 upregulates ADAMTS12 expression through competitive adsorption of miR-6875-5p. It provides a new target for the prognosis and diagnosis of advanced bladder cancer.

The new agents are needed in treatment of gastric ulcer that have less side effects, adequate efficacy, and no drug interactions. In this study, we aimed to investigate the potential protective effects of humic acid on experimental gastric ulcer. Wistar Albino male rats (n = 48) were randomly divided into 8 groups as follow; Control (without any applications), Humic acid (50 mg/kg), ethanol group (1 mL/rat), and indomethacin group (25 mg/kg). In the treatment groups, both gastric ulcer model and humic acid 50 mg/kg were applied. In addition, famotidine the antiulcer drug was used as positive control. All medications were administered by oral gavage. Levels of ADAM10 and ADAMTS12 in gastric mucosa were determined by ELISA method. Hematoxylin-Eosin (H&E) staining, iNOS, and PCNA immunohistochemical staining were performed for histopathological investigations. Apoptosis was demonstrated by using the TUNEL method. In addition, the levels of inflammatory cytokines (TNF-α, IL-6, IL-10) and caspase-3 gene were determined by qRT-PCR. ADAM10 and ADAMTS12 levels significantly increased in the treatment groups compared to the ulcer groups (p < 0.05). The experimental groups showed mucosal erosion, bleeding, leukocyte infiltration and edema. Treatment with humic acid and famotidine was found to suppress iNOS activity, thereby decreasing proinflammatory activity and preventing damage to the gastric mucosa, while reducing the number of apoptotic cells. IL-6, IL-10, TNF-α and caspase-3 levels were significantly decreased in the treatment groups compared to damaged gastric mucosa. As a result, humic acid may be defined as a potential protective agent with its anti-inflammatory effect in gastric ulcer. [ABSTRACT FROM AUTHOR]

While ADAMTS12 (A disintegrin and metalloproteinase with thrombospondin motifs 12) has been established as an important regulator of gastrointestinal tumor development and angiogenic activity, the precise mechanistic functions of ADAMTS12 have yet to be fully clarified in gastric cancer (GC). Accordingly, this study was developed to explore the molecular functions of ADAMTS12 in GC and to examine its utility as a biomarker associated with chemoresistance and prognostic outcomes in this cancer type. The ability of ADAMTS12 to modulate the proliferative, migratory, invasive, chemoresistant, and tube formation activity of tumor cells was assessed in vivo and in vitro through gain- and loss-of-function approaches. Correlations between ADAMTS12, CD31, and VEGF expression levels in GC patient tumor tissue samples from individuals that did and did not undergo neoadjuvant chemotherapy (NAC) treatment were analyzed via immunohistochemical staining. These analyses revealed the ability of ADAMTS12 to promote in vivo and in vitro cellular proliferative and angiogenic activity, promoting the activation of ERK and the consequent upregulation of VEGF, thereby inducing angiogenesis and decreasing GC cell oxaliplatin sensitivity. A positive correlation between ADAMTS12 levels and both the expression of VEGF as well as the density of microvessels was observed in GC patient tumor tissues. Moreover, those GC patients exhibiting higher intratumoral ADAMTS12 expression exhibited worse responses to NAC treatment and worse overall survival outcomes. These findings suggest that ADAMTS12 can modulate signaling via the MAPK/VEGF axis in GC cells to enhance tumor cell resistance to oxaliplatin treatment under hypoxic and normoxic conditions. Elevated ADAMTS12 levels can additionally predict vascular abnormalities, worse survival outcomes, and chemoresistance in patients with GC. • Inhibition of angiogenesis and promotion of chemosensitivity are the two main therapeutic strategies for the clinical treatment of advanced gastric cancer. • In this study, we found that ADAMTS12 can promote angiogenesis and abnormalization in gastric cancer and promote chemotherapy resistance. • For the first time, we described the correlation and potential regulatory mechanism of ADAMTS12 with angiogenesis and chemotherapy resistance in gastric cancer, providing a new target for the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC)., Methods: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting., Results: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT., Conclusions: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Pre-eclampsia is the result of impaired trophoblast invasion and spiral artery remodeling managed by inflammatory response in its etiology and physiopathology. The aim of this study was to compare serum molecules including IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels between pre-eclampsia and control groups and to investigate the role of these molecules in pre-eclampsia. Methods: Forty-one women diagnosed as pre-eclampsia between 30 and 40 weeks of gestation and 41 non-complicated pregnant women were enrolled in this cross-sectional, case-control prospective study. ELISA method was used to determine IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels within serums in two groups. Results: Serum ADAMTS12 and IL-33 levels were significantly lower in pre-eclampsia group (p < 0.001 and p: 0.028, respectively), however, in sub-group analysis, no significant difference was observed (p > 0.05). The cut-off value of ADAMTS12 levels to discriminate pre-eclampsia with %73.17 sensitivity and %92.68 specificity was 8.27 ng/ml while the cut-off value for IL-33 was 0.23 pg/ml with 82.93% sensitivity and 53.66% specificity. Conclusion: Pre-eclampsia is associated with lower serum IL-33 and ADAMTS12 levels. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we aim to investigate the association between articular damage in diabetes and a disintegrin-like and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) at gene expression and protein levels. Materials and methods: OUMS-27 human chondrosarcoma cells were used to investigate how ADAMTS12 levels changed in vitro condition in presence and absence of insulin. The study included three groups of cells treated with 10 µg/mL of insulin, and a control group. Cells were incubated with insulin in medium for one day, three days, and seven days. The effects of insulin on ADAMTS12 were investigated at both gene expression and protein levels. The relationships between the variables were tested by Mann-Whitney U test. Results: ADAMTS12 expression was significantly lower in the groups treated with insulin medium for one day and seven day periods (p=0.008 and p=0.008, respectively) compared to the control group. No significant difference was detected in the expression level between the groups kept in insulin medium for three days and the control group (p=0.55). In addition, protein amounts of the groups exposed to insulin medium for one, three, and seven day periods were lower. Conclusion: Insulin reduces the amount of ADAMTS12 which causes delayed recovery of cartilage tissue in the OUMS-27 cell lines utilized in our study for their chondrocytic properties. This reduction due to insulin treatment may contribute to recovery of cartilage tissue. [ABSTRACT FROM AUTHOR]

The identification of chromosomal breakpoints in association with human abnormal phenotypes can enable elucidation of gene function. We report on epiphyseal aseptic necrosis of the lesser head of the second metatarsal bone, known as Freiberg's infraction (FI), in two female carriers of the apparently balanced t(5;7)(p13.3;p22.2) ascertained by a 16-year-old girl with cri-du-chat syndrome and unusual skeletal features in association with an unbalanced translocation der(5) t(5;7)(p13.3;p22.2). Mapping of the chromosome breakpoints using fluorescent in situ hybridization (FISH) narrowed them to the coding sequence of ADAMTS12 on chromosome 5p13.3 and SDK1 on 7p22.2. In addition, several skeletal abnormalities classified as brachydactyly type A1B (BDA1B) were present in the proband and in both carriers of t(5;7)(p13.3;p22.2), suggesting a potential role of ADAMTS12 in the development of the BDA1B observed in this family. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: Bladder cancer (BCa) is a common malignancy in the urinary system. This study aims to explore the role of miR-186 in BCa tumorigenesis., Methods: The expression of miR-186 and ADAMTS12 in clinical BCa tissues and cell lines was detected. BCa cell lines T24, 5637 and EJ were used to transfect miR-186 mimics or inhibitors. Luciferase reporter gene detection confirmed the correlation between miR-186 and ADAMTS12. MTT method and flow cytometry were used to detect cell viability and apoptosis. Cell migration and invasion ability was detected by transwell assay. The protein level of ADAMTS12, β-catenin, GSK-3β and p-GSK-3β was determined using western blot analysis., Results: MiR-186 was negatively correlated with the expression of ADAMTS12 in BCa tissues. Further research confirmed that ADAMTS12 is the direct target of miR-186. In addition, overexpression of miR-186 down-regulated the expression of ADAMTS12, inhibiting cell viability and apoptosis, while knockout of miR-186 led to the opposite result. miR-186 also inhibits the phosphorylation of GSK-3 β and β-catenin without changing the total GSK-3β level. Our study shows that miR-186 has a negative regulatory effect on the expression of ADAMTS12 in clinical specimens and in vitro. miR-186 can inhibit the proliferation and invasion of BCa cells., Conclusions: miR-186 has the potential to be used as a biomarker in the early detection of BCa., Competing Interests: All authors have no conflicts of interest or financial ties to disclose., (© 2022 Liang JF et al.)

ADAMTS12 belongs to the family of metalloproteinases that mediate a communication between specific cell types and play a key role in the regulation of normal tissue development, remodeling, and degradation. Members of this family have been implicated in neurodegenerative and neuroinflammatory, as well as in muscular-skeletal, cardiovascular, respiratory and renal diseases, and cancer. Several metalloproteinases have been associated with schizophrenia. In our previous study of the pedigree from a genetic isolate of Spanish origin in Puerto Rico, we identified a schizophrenia susceptibility locus on chromosome 5p13 containing ADAMTS12. This gene, therefore, is not only a functional but also a positional candidate gene for susceptibility to the disorder. In order to examine possible involvement of ADAMTS12 in schizophrenia, we performed mutation analysis of the coding, 5′- and 3′-untranslated, and putative promoter regions of the gene in affected members of the pedigree and identified 18 sequence variants segregated with schizophrenia. We then tested these variants in 135 unrelated Puerto Rican schizophrenia patients of Spanish origin and 203 controls and identified the intronic variant rs256792 ( P = 0.0035; OR = 1.59; 95% CI = 1.16-2.17) and the two-SNP haplotype rs256603-rs256792 ( P = 0.0023; OR = 1.62; 95% CI = 1.19-2.21) associated with the disorder. The association remained significant after correction for multiple testing. Our data support the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the role of ADAMTS12 in colorectal cancer progression and to examine whether ADAMTS-12 can be considered as a prognostic indicator for colorectal cancer.Methods: This study was performed on formalin-fixed paraffin-embedded resected specimens obtained from 112 patients with colorectal cancer. The expression level of ADAMTS12 was investigated by immunohistochemical staining to assess the relationship between ADAMTS12 expression and the clinicopathologic factors and to study the prognostic significance of ADAMTS12 in colorectal cancer patients.Results: ADAMTS12 expression was mainly localized in the fibroblasts adjacent to the tumor cells or in macrophages in front of the invasive cancer margins. The ADAMTS12 expression was significantly correlated with the tumor histological grade, depth of tumor invasion, lymph node metastasis, and Dukes' stage. Patients with low or no ADAMTS12 expression in the tumor stroma had a significantly poor overall survival or disease-free survival.Conclusion: The expression of ADAMTS12 in colorectal cancer stroma plays an important role in inhibiting tumor development. Patients with ADAMTS12 expression showed better prognosis than those without ADAMTS12 expression. Thus, ADAMTS12 expression may be a good prognostic marker for colorectal cancer. [ABSTRACT FROM AUTHOR]

The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the role of ADAMTS7 and ADAMTS12 on atherosclerosis and inflammation in prediabetic and diabetic patients. Patients & methods: Serum ADAMTS7 and ADAMTS12 levels were compared with the atherosclerotic and inflammatory markers in diabetic (n = 65, female 30.9%, mean age = 53 years), prediabetic (n = 55, female 36.6%, mean age = 49 years) and control groups (n = 55, females 32.5%, mean age = 49 years). Serum ADAMTS levels were determined by a human enzyme-liked immunoassay. Results: In terms of ADAMTS7, there was no significant difference between diabetic, prediabetic and control groups (50.93, 44.34, 59.07, respectively; p > 0.05). ADAMTS12 is lower in diabetics (p < 0.05), whereas it is similar in prediabetics and controls (14.53, 20.76, 25.05, respectively; p > 0.05). ADAMTS7 and ADAMTS12 levels did not differ in diabetic nephropathy, retinopathy and neuropathy (p > 0.05). Conclusion: While ADAMTS12 was significantly lower in diabetics and prediabetics, ADAMTS7 and ADAMTS12 were not related to diabetic complications (nephropathy, retinopathy and neuropathy).

Background: ADAMTS12, a member of the ADAMTS family, is reported to be associated with the clinic outcome of colorectal cancer (CRC) patients. However, the functions and precise mechanism in CRC progression have yet to be fully understood., Methods: By analyzing The Cancer Genome Atlas (TCGA) database, we examined the mRNA level of ADAMTS12 and assessed the prognostic value of ADAMTS12 in CRC patients using a tissue microarray containing 41 CRC patient samples. Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays were used to quantify the impact of ADAMTS12 on cell proliferation and migration in ADAMTS12-overexpressing and ADAMTS12-deficient cell lines. The signaling pathways that ADAMTS12 mediated were identified by dual-luciferase reporter assays, and confirmed by western blotting and quantitative teal-time polymerase chain reaction (qRT-PCR)., Results: The ADAMTS12 mRNA level was upregulated in CRC tissues, and CRC patients with a high level of ADAMTS12 showed worse prognosis when compared with the patients with a low level of ADAMTS12. In vitro functional assays demonstrated that overexpression of ADAMTS12 significantly boosted cell proliferation and migration while ADAMTS12 deficiency remarkably impaired both tumor cell behaviors. Mechanical studies further verified that ADAMTS12 overexpression enhanced the transcriptional activity of β-catenin in the Wnt/β-catenin signaling pathway. In the ADAMTS12-deficient context, the downstream gene expression of myc and cyclin D1 was significantly reduced compared with that in wild-type cancer cells., Conclusions: ADAMTS12 fulfills the tumor-promotor role by activating Wnt/β-catenin signaling pathway in colon cells and may represent a new option in CRC target treatment., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Colorectal cancer, a common gastrointestinal malignant tumor, has been a leading cause of cancer related deaths. Long non-coding RNAs (lncRNAs) play an important role in regulating cancer development. The aim of this study was to investigate the role and potential mechanism of lncRNA AK001058 in colorectal cancer. To establish tumor xenografts, BALB/c nude mice received subcutaneously injection of SW480 cells with transfection targeting AK001058 (overexpression or knockdown). Tumor growth was observed and recorded. The relative gene expression levels were determined by quantitative real-time PCR or western blot. Cell apoptosis was determined by tunnel analysis. Microvessel morphology changes were detected by H&E staining. Methylation level of CpG island was analyzed using methylation specific PCR. The results showed that AK001058 overexpression notably accelerated tumor growth. AK001058 overexpression also decreased cell apoptosis, worsened microvessel morphology and increased the expression of VEGFA and angiopoietin II. Moreover, AK001058 decreased the expression of ADAMTS12 by increasing its methylation level. Nevertheless, AK001058 knockdown exerted the opposite function. Therefore, AK001058 knockdown could effectively inhibit tumor growth mostly accounting for decreased cell apoptosis and tumor angiogenesis, which was partly dependent on the high methylation level of ADATS12. These data provided a novel therapeutic strategy of colorectal cancer., Competing Interests: None., (AJTR Copyright © 2019.)

Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)