title: β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.
abstract: Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Xu
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Shi-Cang
authors.initials: SC
authors.lastname: Yu
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yang
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: He
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Ping
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Lang
authors.initials: L
authors.lastname: Yang
authors.forename: Sen-Lin
authors.initials: SL
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Qing-Liang
authors.initials: QL
authors.lastname: Wang
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Fu
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: You-Hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3