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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.
Highlights
Lung cancer is the leading cause of cancer-related human deaths with increasing incidence and less than 14% of the overall 5-year survival rate worldwide [1]
We examined the correlation of insulin-like growth factor I receptor (IGF-IR) expression with Cancer stem-like cells (CSLC) markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) in specimens excised from patients with lung adenocarcinoma
We show that IGF-IR–mediated POU5F1 expression to form a complex with SOX2 is crucial for the self-renewal of lung adenocarcinoma stem-like cells (LACSLC) in the initiation of lung adenocarcinoma, and the expressions of IGF-IR, b-catenin, and POU5F1 predict poor prognosis in patients with lung adenocarcinoma
Summary
Lung cancer is the leading cause of cancer-related human deaths with increasing incidence and less than 14% of the overall 5-year survival rate worldwide [1]. Non–small cell lung cancers (NSCLC), which can be subdivided into adenocarcinoma, squamous cell, and large cell carcinomas, account for approximately 85% of all lung cancers [2]. Authors' Affiliations: 1Institute 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; 2State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China; 3Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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