RRC ID 49314
Author Nishimura T, Tamaoki M, Komatsuzaki R, Oue N, Taniguchi H, Komatsu M, Aoyagi K, Minashi K, Chiwaki F, Shinohara H, Tachimori Y, Yasui W, Muto M, Yoshida T, Sakai Y, Sasaki H.
Title SIX1 maintains tumor basal cells via transforming growth factor-β pathway and associates with poor prognosis in esophageal cancer.
Journal Cancer Sci
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.
Volume 108(2)
Pages 216-225
Published 2017-2-1
DOI 10.1111/cas.13135
PMID 27987372
PMC PMC5329162
MeSH Carcinoma, Squamous Cell / metabolism* Carcinoma, Squamous Cell / mortality Carcinoma, Squamous Cell / pathology Cell Line, Tumor Epithelial-Mesenchymal Transition* Esophageal Neoplasms / metabolism* Esophageal Neoplasms / mortality Esophageal Neoplasms / pathology Homeodomain Proteins / genetics Homeodomain Proteins / metabolism* Humans Membrane Glycoproteins / metabolism Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Prognosis Receptors, Transforming Growth Factor beta / genetics Receptors, Transforming Growth Factor beta / metabolism* Transfection Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism*
IF 4.966
Times Cited 13
DNA material pcDNA3.1(+)-SIX1 (RDB15335)