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2017 ; 108
(2
): 216-225
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SIX1 maintains tumor basal cells via transforming growth factor-? pathway and
associates with poor prognosis in esophageal cancer
#MMPMID27987372
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
Cancer Sci
2017[Feb]; 108
(2
): 216-225
PMID27987372
show ga
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-? (TGF-?) 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-? 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.