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

• Published in: Cancer science 2018-04, Vol.109 (4), p.1121-1134
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antioxidants; Antioxidants - metabolism; ARNT; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Basal cells; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomarkers, Tumor - metabolism; Cancer therapies; Carcinoma, Squamous Cell - metabolism; Cell culture; Cell Differentiation - physiology; Cell Line, Tumor; Cell survival; Chemoradiotherapy; Deoxyribonucleic acid; differentiation; DNA; DNA microarrays; DNA repair; DNA Repair - physiology; Down syndrome; Enzymes; Epithelial-Mesenchymal Transition - physiology; Esophageal cancer; Esophageal Neoplasms - metabolism; Esophageal Squamous Cell Carcinoma; Esophagus; Female; Gene expression; Gene Expression Regulation - physiology; Histology; Humans; Hydrocarbons; Hydrogen peroxide; Hypoxia; Medical prognosis; Mesenchyme; Metastasis; Mice; Original; Penicillin; R&D; Research & development; Roles; SIM2; Squamous cell carcinoma; Survival Rate; Transfection - methods; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13531

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 H2O2 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. In esophageal squamous cell carcinoma, we identified that expression of a transcriptional factor, single‐minded 2 (SIM2), is highly associated with favorable prognosis. A series of in vitro and in vivo studies showed SIM2 as a differentiation regulator and that SIM2 and ARNT cooperatively reduce PDPN‐positive malignant basal cells through differentiation and improve CRT sensitivity in squamous cell carcinoma.