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Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma

Yosuke Ooizumi MD, Keita Kojima MD, Kazuharu Igarashi MD, Yoko Tanaka MD, Hiroki Harada MD, Kazuko Yokota MD, Takeshi Kaida MD, Satoru Ishii MD, PhD, Toshimichi Tanaka MD, PhD, Keigo Yokoi MD, PhD, Nobuyuki Nishizawa MD, PhD, Marie Washio MD, Hideki Ushiku MD, PhD, Hiroshi Katoh MD, PhD, Yoshimasa Kosaka MD, PhD, Hiroaki Mieno MD, PhD, Kei Hosoda MD, PhD, Masahiko Watanabe MD, PhD, FACS, Chikatosh
Translational Research and Biomarkers
Volume 26, Issue 13 / December , 2019

Abstract

Background

OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer.

Methods

OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC).

Results

OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance.

Conclusion

Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

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