Abstract 4780: Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer

Colorectal cancer (CRC) is a major type of human cancers in terms of incidence and mortality worldwide. Chemotherapy is one of the standard protocols for the treatment of CRC but drug resistance is recognized as the main cause of treatment failure. Resistance to anticancer therapy is a multifactorial event involving a number of interrelated or independent mechanisms. Growing evidence supports a critical role of cancer stem cell (CSC) in development, progression, and resistance to anticancer therapies in CRCs. However, the molecular and cellular mechanisms underlying the CSC9s chemoresistance are not completely defined, and a comprehensive understanding of the biology of the CSCs is urgently needed. We have investigated mechanisms of chemoresistance, focusing on those mediated by CSCs, through the employment of CRC stem-like cell populations that are: 1) sorted out by using well-characterized stemness markers; ii) established via serial passage through increasing doses of oxaliplatin or 5-FU; or iii) enriched by culturing in sphere forming condition. We then assessed changes involved in CSC maintenance and found a novel role of S100A14 in CSCs of CRC. We found that transcriptional down-regulations of S100A14 expression conferred phenotypes of CSCs in the stem-like cell populations of CRC. Consistently, elevation of S100A14 expression sensitized the stem-like cell populations to the treatment with 5-FU in vitro and in vivo. Mechanistically, S100A14 directly interacted with STAT3 and promoted its degradation via the ubiquitin-proteasome pathway, leading to decreases in STAT3 target gene expression and colony forming capacity of the stem-like cell populations. Further, S100A14 expression was markedly downregulated in human CRC tissue specimens compared with their normal counterparts. Moreover, the expression level of S100A14 was inversely correlated with clinical outcomes in patients with CRC. These results collectively suggest that S100A14 is a novel target for the treatment of colorectal cancer by targeting CSCs. Citation Format: Jaebeom Cho, Hye-Young Min, Ji-Sun Lee, Ho-Young Lee. Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4780. doi:10.1158/1538-7445.AM2017-4780