title: STAT3 expression in activating EGFR-driven adenocarcinoma of the lung.
abstract: Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1cm, 1-2 cm, and ≥2 cm in diameter, respectively, were analyzed. Of the 24 tumors ≤2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p<0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p=0.017). In the tumors ≤2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p=0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n=17) and 82% of the wild-type tumors (n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued.
authors.affiliation: Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Saburo
authors.initials: S
authors.lastname: Takata
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Segawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubo
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kozuki
authors.forename: Norihiro
authors.initials: N
authors.lastname: Teramoto
authors.forename: Motohiro
authors.initials: M
authors.lastname: Yamashita
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases