Multiple roles of single-minded 2 in esophageal squamous cell carcinoma and its clinical implications.

Abstract

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 H2 O2 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.

• Authors: Masashi Tamaoki, Rie Komatsuzaki, Masayuki Komatsu, Keiko Minashi, Kazuhiko Aoyagi, Takao Nishimura, Fumiko Chiwaki, Tomoko Hiroki, Hiroyuki Daiko, Kazuhiro Morishita, Yoshiharu Sakai, Hiroshi Seno, Tsutomu Chiba, Manabu Muto, Teruhiko Yoshida, Hiroki Sasaki
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 4 Pg. 1121-1134 (Apr 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 29427302 (Publication Type: Journal Article)
• Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antioxidants
• Basic Helix-Loop-Helix Transcription Factors
• Biomarkers, Tumor
• SIM2 protein, human
• Aryl Hydrocarbon Receptor Nuclear Translocator

Topics

• Animals
• Antioxidants (metabolism)
• Aryl Hydrocarbon Receptor Nuclear Translocator (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Squamous Cell (metabolism)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• DNA Repair (physiology)
• Epithelial-Mesenchymal Transition (physiology)
• Esophageal Neoplasms (metabolism)
• Esophageal Squamous Cell Carcinoma
• Female
• Gene Expression Regulation (physiology)
• Humans
• Mice
• Survival Rate
• Transfection (methods)