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      ADAMTS7 Enhances Gastric Cancer Growth and Metastasis by Triggering the NF-κB Signaling Pathway

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          Abstract

          The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of metalloproteinases plays a vital role in various biological and pathological processes, including tissue remodeling, angiogenesis, and cancer progression. Among the 19 ADAMTS family members, our research focused on ADAMTS7, which exhibited significant overexpression in gastric cancer (GC). This overexpression was strongly correlated with poor clinical outcomes, including reduced overall survival and heightened metastatic potential. To investigate the role of ADAMTS7 in GC, we employed an integrated approach encompassing bioinformatics analysis, Western blotting, immunofluorescence, as well as in vitro and in vivo functional analyses. Our results showed that silencing ADAMTS7 expression significantly inhibited the proliferation, migration, and invasion of GC cells, and furthermore, silencing ADAMTS7 significantly inhibited the growth and metastasis of tumour cells in vivo in nude mice, highlighting its critical role in driving the malignant behaviour of GC cells. Further mechanistic studies identified the NF-κB signaling pathway as a key downstream target of ADAMTS7, with ADAMTS7 silencing resulting in a notable reduction in NF-κB pathway activity. These findings establish ADAMTS7 as a significant contributor to the aggressiveness of GC and a pivotal activator of the NF-κB pathway, a major regulator of inflammation and tumor progression. Consequently, ADAMTS7 emerges as a promising therapeutic target and prognostic biomarker for GC. Our study opens new avenues for the development of targeted therapies aimed at inhibiting ADAMTS7 activity, thereby potentially improving treatment outcomes and survival rates for patients with GC.

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          Gastric cancer

          Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
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            The nuclear factor NF-kappaB pathway in inflammation.

            The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-kappaB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway. NF-kappaB has long been considered the "holy grail" as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease. In this article, we discuss the role of NF-kappaB in inflammation in light of these recent studies.
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              Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

              Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2025
                1 January 2025
                : 16
                : 3
                : 1008-1019
                Affiliations
                [1 ]Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China.
                [2 ]Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China.
                [3 ]Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China.
                [4 ]High Quality Development Assessment Office, Affiliated Hospital of Nantong University, No 20, Xisi Road, Nantong 226001, China.
                Author notes
                ✉ Corresponding authors: Zhenyu Sha, High Quality Development Assessment Office, Affiliated Hospital of Nantong University, No 20, Xisi Road, Nantong 226001, China. E-mail: 14738384@ 123456qq.com . Junjie Chen, Department of Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, 226001, China. E-mail: ntfyCJJ@ 123456ntu.edu.cn .

                *These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav16p1008
                10.7150/jca.103093
                11705055
                abe8121f-7ad8-42da-a4db-8c5f0f84156f
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See https://ivyspring.com/terms for full terms and conditions.

                History
                : 1 September 2024
                : 14 December 2024
                Categories
                Research Paper

                Oncology & Radiotherapy
                adamts7,gastric cancer,nf-κb,metastasis,proliferation
                Oncology & Radiotherapy
                adamts7, gastric cancer, nf-κb, metastasis, proliferation

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