Multiple roles of SIM2 in esophageal squamous cell carcinoma and its clinical implications

Summary

The degree of histological differentiation is an important characteristic of cancers and may be associated with their malignant potentials. However, in squamous cell carcinomas, a key transcriptional factor to regulate tumor differentiation is largely unknown. Chemoradiotherapy (CRT) is a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC); however, the survival rate is still below 40%. From microarray data, 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 ESCCs showed a favorable prognosis in CRT. Transient SIM2 expression followed by 3D culture induced expression of differentiation markers and suppressed EMT- and basal cell-markers. The levels of the PDPN-high tumor basal cells and of expression of genes for DNA repair and antioxidant enzymes were reduced in the stable transfectants, and they exhibited high CDDP- and H₂O₂-sensitivities, and their xenografts showed a well-differentiated histology. Reduction of the tumor basal cells was restored by knockdown of ARNT that interacted with SIM2. Together, SIM2 increases CRT sensitivity through the tumor differentiation by cooperation with ARNT.

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