Abstract 3161: Novel evidence for Trefoil Factor 3 as an oncogenic mediator of disease progression, and a potential predictor for neoadjuvant chemotherapy in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. The increased incidence rates of CRC places a considerable burden on individuals and society in Asian countries. Although surgical resection remains the standard treatment for CRC patients, accumulating evidences showed advanced patients derived an additional benefit from molecular targeted agents. Therefore, there is a great need to identify novel cellular targets in CRC that can be exploited for therapeutic benefit. Trefoil factor 3 (TFF3), is a member of a family of small secretory proteins characterized by three intrachain disulfide bonds constituting the trefoil motif. TFF3 was initially found as a mediator of mucosal healing and play a critical role in epithelial restitution. Recent studies showed that TFF3 may contribute to tumorigenesis. However, its role in CRC remains unclear. Herein, the protein expression of TFF3 was measured in colorectal adenoma polyps (PLP, n=20), cancer tissues (n=20) and matched adjacent healthy tissues (n=20) by immunohistochemical (IHC) assay. We further evaluated serum and urine level of TFF3 from healthy volunteers (n=40), PLP patients (n=40) and CRC patients (n=40) by using ELISA assay. To investigate the functional or mechanistic role of TFF3 in CRC, we conducted several in vivo and in vitro approaches. The IHC showed that TFF3 was frequently overexpressed in cancer tissues (12/20, P<0.0001), while scarcely detected in PLP (2/20) or healthy tissues (3/20). In addition, serum or urine level of TFF3 was increased in CRC patients, compared to PLP patients or healthy volunteers (P=0.00032). Intriguingly, we found patients with lower serum TFF3 level are more sensitive to neoadjuvant chemotherapy than those with higher TFF3 level (with 3.4 fold increase, P<0.0001). With regard to biological function of TFF3, we found overexpression of TFF3 in CRC cell lines HCT-116 and SW480 significantly enhanced cell viability, invasion, and colony formation capacity. Subsequent mice model validated its oncogenic role in CRC, which TFF3 treatment remarkably enhances xenograft growth. In conjunction with its higher serum level in chemoresistant patients, we found overexpression of TFF3 endows HCT-116 cells with 5’-Fluorouracil resistant phenotype. Mechanistically, we observed overexpression of TFF3 is sufficient to activate Akt and Autophagy pathways in HCT-116 and SW480 cells, confirming its correlation with malignant clinical and biological phenotype. In conclusion, we identified TFF3 as a novel diagnostic marker in CRC and a promising predictor for neoadjuvant chemotherapy. Targeting TFF3 may provide an effective strategy for improving treatment of this malignancy. Note: This abstract was not presented at the meeting. Citation Format: Ying Long, Tsuyoshi Ozawa, Hanhua Li, Weijie Pan, Wenhao Weng. Novel evidence for Trefoil Factor 3 as an oncogenic mediator of disease progression, and a potential predictor for neoadjuvant chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3161.