Pairing a prognostic target with potential therapeutic strategy for head and neck cancer
Sze Min Lek, Ke Li, Qiu Xuan Tan, Nicholas B. Shannon, Wai Har Ng, Josephine Hendrikson, Joey Wee‐Shan Tan, Hui Jun Lim, Yudong Chen, Kelvin K.N. Koh, Thakshayeni Skanthakumar, Xue Lin Kwang, Fui Teen Chong, Hui Sun Leong, Gerald Tay, Natascha Ekawati Putri, Tony Kiat Hon Lim, Jacqueline Siok Gek Hwang, Mei‐Kim Ang, Daniel Shao-Weng Tan, Ngian Chye Tan, Hiang Khoon Tan, Oi Lian Kon, Khee Chee Soo, N. Gopalakrishna Iyer, Chin‐Ann Johnny Ong
Abstract
OBJECTIVES: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC. MATERIALS AND METHODS: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting. RESULTS: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels. CONCLUSION: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3.