title: SIX1 maintains tumor basal cells via transforming growth factor-β pathway and associates with poor prognosis in esophageal cancer.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5-year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial-mesenchymal transition (EMT) by transforming growth factor-β (TGF-β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1-transfectants. Furthermore, the SIX1-transfectants highly expressed tumor basal cell markers such as NGFR, SOX2, ALDH1A1, and PDPN. Although mock-transfectants had only a 20% PDPN-high population, SIX1-transfectants had 60-70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF-β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN-positive tumor basal cell population. The present results suggest that SIX1 accelerates self-renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tamaoki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Komatsuzaki
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.affiliation: Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Department of Clinical Trial Promotion, Chiba Cancer Center, Chiba, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Minashi
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Chiwaki
authors.affiliation: Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C117468:PDPN protein, human; D000098853:Podoplanin; C099236:SIX1 protein, human
keywords: Epithelial-mesenchymal transition; SIX1; esophageal cancer; prognosis; transforming growth factor-β