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Serine protease 3 (PRSS3), a trypsin\u2010like protease with four spliced variants (\n                    <jats:italic>PRSS3\u2010SVs<\/jats:italic>\n                    :\n                    <jats:italic>PRSS3\u2010V1<\/jats:italic>\n                    to\n                    <jats:italic>V4<\/jats:italic>\n                    ), plays diverse biological roles in cancer progression. Herein, we systematically analyzed the expression patterns and functional implications of\n                    <jats:italic>PRSS3\u2010SVs<\/jats:italic>\n                    in gastric cancer (GC) using an integrative approach that combined bioinformatic analyses, CpG site\u2010specific methylation detection, splice\u2010specific qPCR, isoform\u2010based methodologies, and multiple functional assays. Our findings revealed that differentially expressed\n                    <jats:italic>PRSS3<\/jats:italic>\n                    isoforms, predominantly PRSS3\u2010V1 and PRSS3\u2010V2, are regulated by intragenic methylation and exert pleiotropic roles in GC. Overexpression of\n                    <jats:italic>PRSS3<\/jats:italic>\n                    transcripts suppressed GC cell proliferation via the NF\u2010\u03baB signaling pathway, while exerting distinct effects on matrix metalloproteinase\u2010associated cell migration and invasion. Clinically, patients with low\n                    <jats:italic>PRSS3\u2010V1<\/jats:italic>\n                    or high\n                    <jats:italic>PRSS3\u2010V2<\/jats:italic>\n                    expression exhibited poorer survival outcomes, and the expression difference between these two transcripts was identified as an independent prognostic indicator for GC patients. Epigenetically, differential methylation patterns within\n                    <jats:italic>PRSS3<\/jats:italic>\n                    enabled stratification of GC patients into subgroups characterized by either high\u2010methylation with low\u2010expressed\n                    <jats:italic>PRSS3\u2010SVs<\/jats:italic>\n                    or low\u2010methylation with high\u2010expressed\n                    <jats:italic>PRSS3\u2010SVs<\/jats:italic>\n                    . The UHRF1\/DNMT1 complex was found to mediate CpG site methylation and regulate\n                    <jats:italic>PRSS3<\/jats:italic>\n                    transcripts, particularly silencing\n                    <jats:italic>PRSS3\u2010V1<\/jats:italic>\n                    through intragenic CpG methylation. This methylation pattern was associated with reduced survival rates and further validated its correlation with tumor metastasis in an independent cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009243). Our study elucidates that methylation\u2010regulated alternative splicing contributes to phenotypic heterogeneity in GC, highlighting its potential advantage over differentially expressed genes in improving stratification strategies for precision oncology.\n                  <\/jats:p>","DOI":"10.1111\/cas.70227","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T06:14:27Z","timestamp":1761804867000},"page":"33-49","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>CpG<\/scp>\n                    Methylation\u2010Driven Pleiotropic Spliced Isoforms of\n                    <scp>\n                      <i>PRSS3<\/i>\n                    <\/scp>\n                    Facilitate Gastric Intratumor Heterogeneity and Metastasis"],"prefix":"10.1111","volume":"117","author":[{"given":"Mengdi","family":"Pang","sequence":"first","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"},{"name":"Department of Gastroenterology Beijing Chest Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanli","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duoduo","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichuan","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongmeng","family":"Tian","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gu","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafisa","family":"Alimu","sequence":"additional","affiliation":[{"name":"School of Stomatology Xinjiang Medical University  Urumqi Xinjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EnKai","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Sciences &amp; Bioengineering Beijing Jiaotong University  Beijing 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