{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:36:48Z","timestamp":1786977408446,"version":"build-2736575974"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,4,2]],"date-time":"2023-04-02T00:00:00Z","timestamp":1680393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K16578"],"award-info":[{"award-number":["19K16578"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K15398"],"award-info":[{"award-number":["21K15398"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Lung adenocarcinoma progresses stepwise from atypical adenomatous hyperplasia to adenocarcinoma in situ (AIS), followed by minimally invasive adenocarcinoma (MIA), and then obvious invasive adenocarcinoma. In this study, we examined the protein expression profiles of early and epidermal growth factor receptor (EGFR) mutation\u2010positive lung adenocarcinomas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fifteen cases of small and EGFR mutation\u2010positive adenocarcinomas were collected, including AIS, MIA, and small invasive adenocarcinoma (SIA). We examined their protein expression profiles by tandem mass tag (TMT)\u2010labeling liquid chromatography\u2010mass spectrometry (LC\u2013MS\/MS) and compared the results between AIS and MIA versus SIA. The differentially expressed proteins were then verified by Western blot analysis and immunohistochemistry (IHC). The clinicopathological implications of the proteins were also examined by IHC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 4220 proteins were identified by LC\u2013MS\/MS analysis. Pathway analysis of the differentially expressed proteins revealed that pathways related to interferon \u03b1\/\u03b2 signaling, glutamate and glutamine metabolism, and gluconeogenesis were upregulated in SIA relative to AIS. Among the 13 differentially expressed proteins, cellular retinoic acid binding protein 2 (CRABP2), delta(24)\u2010sterol reductase (DHCR24), and adenylate kinase 4 (AK4) were expressed significantly more strongly in SIA than in AIS. Patients with high expression of CRABP2, DHCR24, and AK4 showed a significantly poorer outcome than those with low expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In comparison with AIS, SIA shows differences in several different protein expression pathways. Furthermore, CRABP2, DHCR24, and AK4 are useful IHC markers for diagnosis of lung adenocarcinoma invasiveness and may be associated with malignant progression of AIS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.5766","type":"journal-article","created":{"date-parts":[[2023,4,2]],"date-time":"2023-04-02T07:34:25Z","timestamp":1680420865000},"page":"10755-10767","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["In\u2010depth proteomics reveals the characteristic developmental profiles of early lung adenocarcinoma with epidermal growth factor receptor mutation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9221-840X","authenticated-orcid":false,"given":"Tomoko","family":"Dai","sequence":"first","affiliation":[{"name":"Tsukuba Human Tissue Biobank Center University of Tsukuba Hospital  Ibaraki Japan"},{"name":"Tsukuba Human Tissue Diagnostic Center University of 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