Chuan Xu, Dan Xie, Shi-Cang Yu, Xiao-Jun Yang, Li-Ru He, Jing Yang, Yi-Fang Ping, Bin Wang, Lang Yang, Sen-Lin Xu, Wei Cui, Qing-Liang Wang, Wen-Juan Fu, Qing Liu, Cheng Qian, You-Hong Cui, Jeremy N Rich, Hsiang-Fu Kung, Xia Zhang, Xiu-Wu Bian
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.
Cancer research 2013 May 15Cancer 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. ©2013 AACR.
Chuan Xu, Dan Xie, Shi-Cang Yu, Xiao-Jun Yang, Li-Ru He, Jing Yang, Yi-Fang Ping, Bin Wang, Lang Yang, Sen-Lin Xu, Wei Cui, Qing-Liang Wang, Wen-Juan Fu, Qing Liu, Cheng Qian, You-Hong Cui, Jeremy N Rich, Hsiang-Fu Kung, Xia Zhang, Xiu-Wu Bian. β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma. Cancer research. 2013 May 15;73(10):3181-9
PMID: 23539445
View Full Text