Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. There is an urgent demand for prognostic biomarkers that facilitate early tumor detection, as the incidence of HCC has tripled in the United States in the last three decades. Biomarkers to identify populations at risk would have significant impact on survival. We recently found that expression of Neuronal Calcium Sensor 1 (NCS1), a Ca2⁺-dependent signaling molecule, predicted disease outcome in breast cancer, but its predictive value in other cancer types is unknown. This protein is potentially useful because increased NCS1 regulates Ca2⁺ signaling and increased Ca2⁺ signaling is a hallmark of metastatic cancers, conferring cellular motility and an increasingly aggressive phenotype to tumors.Methods: We explored the relationship between NCS1 expression levels and patient survival in two publicly available liver cancer cohorts and a tumor microarray using data mining strategies.Results: High NCS1 expression levels are significantly associated with worse disease outcome in Asian patients within these cohorts. In addition, a variety of Ca2⁺-dependent and tumor growth-promoting genes are transcriptionally coregulated with NCS1 and many of them are involved in cytoskeleton organization, suggesting that NCS1 induced dysregulated Ca2⁺ signaling facilitates cellular motility and metastasis.Conclusions: We found NCS1 to be a novel biomarker in HCC. Furthermore, our study identified a pharmacologically targetable signaling complex that can influence tumor progression in HCC.Impact: These results lay the foundation for using NCS1 as a prognostic biomarker in prospective cohorts of HCC patients and for further functional assessment of the characterized signaling axis. Cancer Epidemiol Biomarkers Prev; 27(9); 1091-100. ©2018 AACR.

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