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Oncol.","Current Oncology"],"abstract":"<jats:p>The role of Signal Transducer and Activator of Transcription 2 (STAT2) in cancer remains poorly understood. STAT2 is a key mediator of type I interferon (IFN) signaling, activating the expression of IFN-stimulated genes with antiviral and antiproliferative effects. However, emerging evidence suggests that STAT2 can also promote tumor growth. Here, we show that high STAT2 mRNA expression in colon cancer tumors correlates with reduced overall survival in patients. In preclinical models, deletion of STAT2 in tumor cells suppressed tumor growth, whereas STAT2 overexpression enhanced tumor growth, supporting its pro-tumorigenic role. To determine whether this function depends on type I IFN receptor (IFNAR1) signaling, we generated IFNAR1 knockout (IFNAR1 KO) colon carcinoma cells and compared their growth with parental and STAT2-deficient (STAT2 KO) tumor cells. Loss of type I IFN signaling was confirmed by western blot and qPCR analyses. In vitro, IFNAR1 KO and STAT2 KO tumor cells proliferated at similar rates. However, in xenograft tumor transplantation models, IFNAR1 KO cells formed larger tumors while STAT2 KO tumor cells formed smaller ones compared to parental tumor cells. These findings indicate that STAT2 promotes colorectal cancer growth through mechanisms independent of IFNAR1 signaling.<\/jats:p>","DOI":"10.3390\/curroncol32120707","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:00:26Z","timestamp":1765882826000},"page":"707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["STAT2 Promotes Tumor Growth in Colorectal Cancer Independent of Type I IFN Receptor Signaling"],"prefix":"10.3390","volume":"32","author":[{"given":"Jorge","family":"Canar","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7871-1488","authenticated-orcid":false,"given":"Madeline","family":"Bono","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Amy","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Michael","family":"Slifker","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1024-9128","authenticated-orcid":false,"given":"Giovanni","family":"Sitia","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-1415","authenticated-orcid":false,"given":"Ana M.","family":"Gamero","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: From bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct. 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