Pairing a prognostic target with potential therapeutic strategy for head and neck cancer. (December 2020)

• Record Type: Journal Article
• Authors: Lek, Sze Min; Li, Ke; Tan, Qiu Xuan; Shannon, Nicholas B.; Ng, Wai Har; Hendrikson, Josephine; Tan, Joey W.S.; Lim, Hui Jun; Chen, Yudong; Koh, Kelvin K.N.; Skanthakumar, Thakshayeni; Kwang, Xue Lin; Chong, Fui Teen; Leong, Hui Sun; Tay, Gerald; Putri, Natascha Ekawati; Lim, Tony Kiat Hon; Hwang, Jacqueline S.G.; Ang, Mei Kim; Tan, Daniel S.W.; Tan, Ngian Chye; Tan, Hiang Khoon; Kon, Oi Lian; Soo, Khee Chee; Iyer, N. Gopalakrishna; Ong, Chin-Ann J.
• Is Part Of: Oral oncology. Volume 111(2020)
• Publication Date: 2020-12
• Subjects: Head and neck neoplasms -- Squamous cell carcinoma of head and neck -- Immunohistochemistry -- ATP13A3 protein -- Aurora A kinase -- Molecular target therapy; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2020.105035
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. Previous study showed that a 3 gene IHC panel can prognosticate patients with HNSCC. Tumors with high ATP13A3 are associated with high AURK activity. Knockdown of ATP13A3 in HNSCC cell lines showed decrease in AURKA levels. AURKA inhibitors may potentially be applied to patients with ATP13A3 enriched HNSCC. 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.