Overexpression of F-box only protein 31 predicts poor prognosis and deregulates p38α- and JNK-mediated apoptosis in esophageal squamous cell carcinoma.

Abstract

F-box only protein 31 (FBXO31), a subunit of the Skp1-Cul1-F box ubiquitin ligase, plays a crucial role in DNA damage response and tumorigenesis. Yet its expression and function vary in different types of human cancer. The expression of FBXO31 in esophageal squamous cell carcinoma (ESCC) and its association with clinicopathological features is not well studied. The underlying mechanism by which deregulated FBXO31 contributes to ESCC tumorigenesis is largely unknown. By immunohistochemical analysis of a tissue microarray containing 85 cases of ESCC and matched adjacent noncancerous tissue and an additional 10 cases of ESCC tissue samples, we found that FBXO31 was overexpressed in ESCC, and that its expression was significantly correlated with histological grade (p = 0.04) and clinical stage (p = 0.022). Higher expression of FBXO31 was associated with poor prognosis in univariate (p = 0.013) and multivariate (p = 0.014) analyses. We found that FBXO31 functioned as an antiapoptotic molecule in ESCC cells exposed to different types of genotoxic stress. Knockdown of FBXO31 inhibited serum-starved cell viability and decreased tumorigenicity of ESCC cells. In addition, the antiapoptotic effects of FBXO31 were associated with deactivation of stress-induced MAPK p38α and JNK. Furthermore, in vitro and in vivo data showed that silencing of FBXO31-sensitized ESCC cells and tumors to cisplatin treatment. Taken together, in addition to revealing that FBXO31 is an independent prognostic marker for ESCC, our findings substantiate a novel regulatory role of FBXO31 in tumorigenesis and drug resistance of ESCC.