title: SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity.
abstract: Recently, the SOX2 gene has been reported to be amplified in human lung squamous cell carcinomas. However, its roles in human lung adenocarcinomas are still elusive. In this study, we analyzed the functions of SOX2 in cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) derived from human lung adenocarcinoma. Human lung CSCs/CICs were isolated as higher tumorigenic side population (SP) cells using Hoechst 33342 dye from several lung cancer cell lines. Four of nine lung cancer cell lines were positive for SP cells (LHK2, 1-87, A549, Lc817). The ratios of SP cells ranged from 0.4% for Lc817 to 2.8% for LHK2. To analyze the molecular aspects of SP cells, we performed microarray screening and RT-PCR analysis, and isolated SOX2 as one of a SP cell-specific gene. SOX2 was expressed predominantly in LHK2 and 1-87 SP cells, and was also expressed in several other cancer cell lines. The expression of SOX2 protein in primary human lung cancer tissues were also confirmed by immunohistochemical staining, and SOX2 was detected in more than 80% of primary lung cancer tissues. To address SOX2 molecular functions, we established a SOX2-overexpressed LHK2 and A549 cell line (LHK2-SOX2 and A549-SOX2). LHK2-SOX2 cells showed higher rates of SP cells and higher expression of POU5F1 compared with control cells. LHK2-SOX2 and A549-SOX2 cells showed relatively higher tumorigenicity than control cells. On the other hand, SOX2 mRNA knockdown of LHK2 SP cells by gene-specific siRNA completely abrogated tumorigenicity in vivo. These observations indicate that SOX2 has a role in maintenance of stemness and tumorigenicity of human lung adenocarcinoma CSCs/CICs and is a potential target for treatment.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.forename: Akari
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Satoko
authors.initials: S
authors.lastname: Inoda
authors.forename: Masaki
authors.initials: M
authors.lastname: Murase
authors.forename: Hiroko
authors.initials: H
authors.lastname: Asanuma
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Rena
authors.initials: R
authors.lastname: Morita
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Michifuri
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058985:Side-Population Cells / Q000378:metabolism*
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors