Open AccessMultiple roles of single‐minded 2 in esophageal squamous cell carcinoma and its clinical implications
Author(s) -
Tamaoki Masashi,
Komatsuzaki Rie,
Komatsu Masayuki,
Minashi Keiko,
Aoyagi Kazuhiko,
Nishimura Takao,
Chiwaki Fumiko,
Hiroki Tomoko,
Daiko Hiroyuki,
Morishita Kazuhiro,
Sakai Yoshiharu,
Seno Hiroshi,
Chiba Tsutomu,
Muto Manabu,
Yoshida Teruhiko,
Sasaki Hiroki
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13531
Subject(s) - aryl hydrocarbon receptor nuclear translocator , gene knockdown , cancer research , biology , cellular differentiation , tissue microarray , malignant transformation , cell , apoptosis , chemistry , transcription factor , immunohistochemistry , gene , immunology , aryl hydrocarbon receptor , biochemistry , genetics
Degree of histological differentiation is an important characteristic of cancers and may be associated with malignant potential. However, in squamous cell carcinomas, a key transcriptional factor regulating tumor differentiation is largely unknown. Chemoradiotherapy (CRT) is a standard treatment for locally advanced esophageal squamous cell carcinoma; however, the survival rate is still below 40%. From microarray data, single‐minded 2 ( SIM2) was overexpressed in the epithelial subtype. Here, we investigated the correlation between SIM2 expression and its clinical implication, and in vitro and in vivo functions of SIM2 in tumor differentiation and in CRT sensitivity. Although SIM2 was suppressed in cancerous tissues, SIM2 ‐high ESCC showed a favorable prognosis in CRT. Transient SIM2 expression followed by 3D culture induced expression of differentiation markers and suppressed epithelial‐mesenchymal transition‐ and basal‐cell markers. Levels of PDPN‐high tumor basal cells and of expression of genes for DNA repair and antioxidant enzymes were reduced in stable transfectants, and they showed high CDDP and H 2 O 2 sensitivities, and their xenografts showed a well‐differentiated histology. Reduction of tumor basal cells was restored by knockdown of aryl hydrocarbon receptor nuclear translocator (ARNT) that interacted with SIM2. Together, SIM2 increases CRT sensitivity through tumor differentiation by cooperation with ARNT.