{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T14:21:56Z","timestamp":1772720516076,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:00:00Z","timestamp":1736812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells\/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion\/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L\/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.<\/jats:p>","DOI":"10.3390\/cells14020111","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T03:29:43Z","timestamp":1736825383000},"page":"111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5394-8004","authenticated-orcid":false,"given":"Lukas","family":"Geisler","sequence":"first","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"},{"name":"Department of Biology, Humboldt University of Berlin, 10099 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Detjen","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Hellberg","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlene","family":"Kohlhepp","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-3087","authenticated-orcid":false,"given":"Carsten","family":"Gr\u00f6tzinger","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Knorr","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Eichhorn","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2403-4275","authenticated-orcid":false,"given":"Raphael","family":"Mohr","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"Holtmann","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-2552","authenticated-orcid":false,"given":"Bertram","family":"Wiedenmann","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Roderburg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2968-1335","authenticated-orcid":false,"given":"Alexander","family":"Wree","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr. 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