The Novel Protein ADAMTS16 Promotes Gastric Carcinogenesis by Targeting IFI27 through the NF-κb Signaling Pathway

Li, Tuoyang; Zhou, Jianhua; Jiang, Yingming; Zhao, Yandong; Huang, Jintuan; Li, Weiyao; Huang, Zhenze; Chen, Zijian; Tang, Xiaocheng; Chen, Hao; Yang, Zhaohui

doi:10.3390/ijms231911022

Cited by 9 publications

(14 citation statements)

References 46 publications

(56 reference statements)

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“…Furthermore, ADAMTS16 and BMP2 were selected from the enriched genes associated with embryonic kidney development for follow-up studies. ADAMTS16 belongs to the ADAMTS family and it has been demonstrated to promote the proliferation and invasion of gastric cancer ( 41 ) and esophageal cancer ( 15 ) cells. However, to the best of our knowledge, the function of ADAMTS16 has not yet been studied in HCC.…”

Section: Discussionmentioning

confidence: 99%

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Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

Jiang

Zhang

et al. 2023

Oncol Lett

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Tumor budding (TB) has become a crucial factor for predicting the malignancy grade and prognostic outcome for multiple types of solid cancer. Studies have investigated the prognostic value of TB in hepatocellular carcinoma (HCC). However, its molecular mechanism in HCC remains unclear. To the best of our knowledge, the present study was the first to compare the expression of differentially expressed genes (DEGs) between TB-positive (TB-pos) and TB-negative HCC tissues. In the present study, total RNA was extracted from 40 HCC tissue specimens and then sequenced. According to Gene Ontology (GO) functional annotation, upregulated DEGs were markedly associated with embryonic kidney development-related GO terms, which suggested that the TB process may at least partly mimic the process of embryonic kidney development. Subsequently, two genes, a disintegrin and metalloproteinase domain with thrombospondin motifs 16 (ADAMTS16) and bone morphogenetic protein 2 (BMP2), were screened and verified through immunohistochemical analysis of HCC tissue microarrays. According to the immunohistochemical results, ADAMTS16 and BMP2 were upregulated in TB-pos HCC samples, and BMP2 expression was increased in budding cells compared with the tumor center. Additionally, through cell culture experiments, it was demonstrated that ADAMTS16 and BMP2 may promote TB of liver cancer, thus promoting the malignant progression of liver cancer. Further analysis revealed that ADAMTS16 expression was associated with necrosis and cholestasis, and BMP2 expression was associated with the Barcelona Clinic Liver Cancer stage and the vessels encapsulating tumor clusters. Overall, the findings of the present study provided insights into the possible mechanisms of TB in HCC and revealed potential anti-HCC therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

“…And TB is considered to be an EMT-like process ( 10 ). It has been documented that ADAMTS16 may promote cell migration and invasion through the NF-κB pathway ( 41 ). In addition, BMP2 also enhances the migration, invasion and EMT of tumor cells through the m-TOR signaling pathway ( 45 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

Jiang

Zhang

et al. 2023

Oncol Lett

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“…After thorough washing with PBS, an HRP-conjugated secondary antibody was applied, and the visualization of the antibody-antigen complex was achieved through the use of a DAB substrate. The final staining scores were determined using an established H-score method [ 26 ]. Based on their immunoreactivity scores, the GC patients were divided into two distinct groups, i.e., those with low expression (H-score < 7) and those with high expression (H-score ≥ 7).…”

Section: Methodsmentioning

confidence: 99%

Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Tang,

Huang,

Jiang

et al. 2023

J Transl Med

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Background Gastric cancer (GC) is a fatal cancer with unclear pathogenesis. In this study, we explored the function and potential mechanisms of intercellular adhesion molecule 2 (ICAM2) in the development and advancement of GC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to quantify ICAM2 expression in harvested GC tissues and cultured cell lines. Immunohistochemical analyses were conducted on a GC tissue microarray to quantify ICAM2 expression and explore its implication on the prognosis of GC patients. In vitro experiments were carried out to reveal the biological functions of ICAM2 in GC cell lines. Further, in vivo experiments were conducted using xenograft models to assess the impact of ICAM2 on GC development and metastasis. Western blot, immunofluorescence, immunoprecipitation, luciferase assay, chromatin immunoprecipitation, and ubiquitination analysis were employed to investigate the underlying mechanisms. Results ICAM2 expression was downregulated in GC, positively correlating with advanced T stage, distant metastasis, advanced clinical stage, vessel invasion, and shorter patient survival time. ICAM2 overexpression suppressed the proliferation, migration, invasion, metastasis of GC cells as well as their ability to form tumors, whereas ICAM2 knockdown yielded opposite results. Erythroblast transformation-specific-related gene (ERG) as a transcription factor promoted the transcription of ICAM2 by binding to the crucial response element localized within its promoter region. Further analysis revealed that ICAM2 reduced radixin (RDX) protein stability and expression. In these cells, ICAM2 bound to the RDX protein to promote the ubiquitination and degradation of RDX via NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L), and this post-translational modification resulted in the inhibition of GC. Conclusions In summary, this study demonstrates that ICAM2, which is induced by ERG, suppresses GC progression by enhancing the ubiquitination and degradation of RDX in a NEDD4L-dependent manner. Therefore, these results suggest that ICAM2 is a potential prognostic marker and a therapeutic target for GC.

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“…In our previous studies 19,22 , we obtained 195 primary cancer tissue samples collected from the Sixth A liated Hospital of Sun Yat-Sen University, Guangzhou, China, from December 2007 to March 2012. These tissue specimens were constructed using tissue microarrays (TMAs) for IHC, and overall survival and the clinicopathological characteristics were obtained as in our previous study 19,22,23,27 . To study chemoresistance caused by ADAMTS12, we also received another 36 tumor tissues of patients who have accepted neoadjuvant chemotherapy.…”

Section: Methodsmentioning

confidence: 99%

ADAMTS12 mediates vascular abnormality to enhance chemoresistance via the MAPK/VEGF signaling pathway in gastric cancer

Jiang¹,

Huang²,

Huang³

et al. 2023

Preprint

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Purpose: A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is involved in the angiogenesis and tumorigenesis of gastrointestinal cancer. However, the exact molecular and biological mechanisms of ADAMTS12 in gastric cancer (GC) remain unclear. This study aims to explore the exact underlying mechanisms of ADAMTS12 and provide a biomarker for prognosis and chemotherapy in GC. Methods: Gain- and loss-of-function assays were used to reveal the effect of ADAMTS12 on cell proliferation, migration, invasion, tube formation and chemoresistance in vitro and in vivo. IHC was used to analyze the expression and the correlation between ADAMTS12, VEGF and CD31 in gastric cancer tissues with or without neoadjuvant chemotheraphy. Results: ADAMTS12 promotes cell proliferation, angiogenesis and chemoresistance in vitro and in vivo. ADAMTS12 upregulates VEGF expression through ERK activation, which in turn, promoting angiogenesis and reducing sensitivity to oxaliplatin in GC. In GC tissues, ADAMTS12 was positively correlated with VEGF and microvessel density (MVD). Furthermore, patients with high ADAMTS12 level had poor overall survival (OS) and poor response to neoadjuvant chemotherapy. Conclusion: ADAMTS12 enhances chemoresistance to oxaliplatin in normoxic and hypoxic microenvironments via the MAPK/VEGF signaling pathway in GC. High ADAMTS12 levels have prognostic significance for poor survival, and indicator of vascular abnormality and chemoresistance in GC.

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The Novel Protein ADAMTS16 Promotes Gastric Carcinogenesis by Targeting IFI27 through the NF-κb Signaling Pathway

Cited by 9 publications

References 46 publications

Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

ADAMTS12 mediates vascular abnormality to enhance chemoresistance via the MAPK/VEGF signaling pathway in gastric cancer

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