Abstract 4723: Improving prognosis or promoting progression? Double sword of S100A8 in colorectal cancer

Abstract

Abstract Tumor tissues are heterogeneous, including cancer cells, cancer stem cells and immune cells. The immune states are involved in malignancy and prognosis in colorectal carcinomas (CRC). S100A8, which represented granulocytes and monocytes, was identified as a favorable indicator for survival by previous work. Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) play critical roles on tumor cell malignancy and metastasis. The immune states, CSC and EMT should be regarded as integrity, which is important for clinical efforts and the mechanism investigation. For better understanding the associations among immune cells, CSC and EMT in CRC, S100A8 as along with CSC (Lgr5, Nanog, ALDH1 and CD44v6) and EMT (E-cadherin and Snail) markers were detected in the tumor invasive front (TF) and tumor center (TC) respectively by immunohistochemistry in 419 CRCs and survival analysis was done. Furthermore, functions of S100A8 in EMT were verified in vitro. S100A8+TF count was positively correlated with Lgr5TC (r=0.162, p=0.004) and cytoplasmic SnailTF expression (r=0.116, p=0.043), while it was not correlated with other stem cell markers wherever they were located, and not associated with E-cadherinTC or E-cadherinTF, or cytoplasmic snailTC or nucleic SnailTC and SnailTF expression (p>0.005). After combining S100A8+TF and Lgr5TC, three groups were got. It showed S100A8+TFhigh Lgr5TChigh had the best 5-year survival, while S100A8+TFlow Lgr5TClow had the worst 5-year survival. After joining with cytoplasmic snailTF into S100A8+TF and Lgr5TC, six groups were got. Finally, three groups with similar outcome were merged as A, B, and C, called SLS (S100A8, Lgr5 and snail). Kaplan-Meier survival curve analysis showed group C, with S100A8lowLgr5lowsnailhigh had the worst 5-year survival. SLS was also an independent predictor for 5-year survival. S100A8 was not only stained in granulocytes and monocytes but also in tumor cells. Then S100A8 was overexpressed by lentiviral vector in DLD1 and sw620 CRC cell lines to further investigate its intracellular functions. On the contrary, overexpression of S100A8 in tumor cells not only facilitated tumor cell proliferation, migration and invasion but also converted cells to EMT phenotype. Western blot showed E-cadherin was down-regulated and Vimentin, MMP9 and snail were up-regulated in S100A8 overexpressed cells. The transcription factor USF2 was verified to interact with S100A8 by luciferase reporter gene. Western blot showed overexpression of USF2 increased S100A8 expression, while overexpression of S100A8 had no effect on USF2. In conclusion, S100A8 from immune cells or tumor cells has opposing effects on cancer progression. S100A8 in immune cells predicts good prognosis. However, S100A8 in tumor cells, which could be regulated by USF2, promotes proliferation, migration and invasion, along with EMT transformation. Citation Format: Si Li, Fangying Xu, Lili Wang, Hui Li, Maode Lai. Improving prognosis or promoting progression? Double sword of S100A8 in 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 4723. doi:10.1158/1538-7445.AM2017-4723