{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:35:39Z","timestamp":1760146539996,"version":"build-2065373602"},"reference-count":66,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute of the National Institutes of Health","award":["R01CA157595","R01CA109385","P30CA023074"],"award-info":[{"award-number":["R01CA157595","R01CA109385","P30CA023074"]}]},{"name":"Experimental Mouse, Tissue Acquisition and Molecular Analysis, and Biostatistics Shared Resources","award":["R01CA157595","R01CA109385","P30CA023074"],"award-info":[{"award-number":["R01CA157595","R01CA109385","P30CA023074"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: The objective of this study was to assess the role of a secreted serine protease, kallikrein-related peptidase 6 (KLK6), during colorectal tumorigenesis driven by a mutant Adenomatous polyposis coli (APC) tumor suppressor gene. A first analysis of KLK6 expression in the intestinal tract of Apc-mutant multiple intestinal neoplasia (ApcMin\/+) mice revealed up to four-fold induction of Klk6 mRNA levels in adenomas relative to its level in the adjacent mucosa. Methods and Results: The presence of KLK6 protein in the adenomatous areas was confirmed by immunohistochemistry and optical coherence tomography\/laser-induced fluorescence (OCT\/LIF) imaging. To assess the contribution of the KLK6 expression on the Apc-mutant intestinal and colon tumorigenesis, we engineered a mouse with floxed alleles of the Klk6 gene (Klk6lox\/lox) and crossed it with a mouse expressing the truncated APC protein under control of the intestinal tract-specific human CDX2P9.5-NLS Cre transgene (CPC;Apcfl\/fl;Klk6+\/+). We found that CPC;Apcfl\/fl mice with disrupted Klk6 gene expression (CPC;Apcfl\/fl;Klk6fl\/fl) had a significantly smaller average size of the small intestinal and colon crypts (p &lt; 0.001 and p = 0.04, respectively) and developed a significantly fewer adenomas (p = 0.01). Moreover, a decrease in high-grade adenomas (p = 0.03) and adenomas with a diameter above 2 mm (p &lt; 0.0001) was noted in CPC;Apcfl\/fl;Klk6fl\/fl mice. Further molecular analysis showed that Klk6 gene inactivation in the small intestine and colon tissues of CPC;Apcfl\/fl;Klk6fl\/fl mice resulted in a significant suppression of transforming growth factor \u03b22 (TGF-\u03b22) protein (p \u2264 0.02) and mitogen-activated protein kinase (MAPK) phosphorylation (p \u2264 0.01). Conclusions: These findings demonstrate the oncogenic role of KLK6 in the mutant Apc-mediated intestinal tumorigenesis and suggest the utility of KLK6 for early diagnosis of colorectal tumors.<\/jats:p>","DOI":"10.3390\/cancers16223842","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T04:53:05Z","timestamp":1731991985000},"page":"3842","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a Mutant Adenomatous polyposis coli Gene"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-8714","authenticated-orcid":false,"given":"Teodora G.","family":"Georgieva","sequence":"first","affiliation":[{"name":"Genetically Engineered Mouse Models Core, The University of Arizona Bio5 Institute, Tucson, AZ 85721-0240, USA"},{"name":"Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724-5024, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1206-0655","authenticated-orcid":false,"given":"Dalila","family":"Darmoul","sequence":"additional","affiliation":[{"name":"Institut de Biologie Paris-Seine, Sorbonne Universit\u00e9, UMR CNRS 8256, INSERM ERL U1164, Biological Adaptation and Ageing, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hwudaurw","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724-5024, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724-5024, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7100-4023","authenticated-orcid":false,"given":"Photini F. S.","family":"Rice","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721-0240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer K.","family":"Barton","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721-0240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David G.","family":"Besselsen","sequence":"additional","affiliation":[{"name":"University Animal Care, The University of Arizona, Tucson, AZ 85721-0101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-1340","authenticated-orcid":false,"given":"Natalia A.","family":"Ignatenko","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724-5024, USA"},{"name":"Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85724-5024, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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