Liu Jia, Lv Liang, Gong Jian, Tan Yuyong, Zhu Yun, Dai Yinghuan, Pan Xin, Huen Michael S Y, Li Bin, Tsao Sai Wah, Huo Jirong, Cheung Annie L M
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China.
Center of Medical Research, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
Int J Cancer. 2018 Jan 1;142(1):145-155. doi: 10.1002/ijc.31040. Epub 2017 Sep 28.
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.
F盒蛋白31（FBXO31）是Skp1-Cul1-F盒泛素连接酶的一个亚基，在DNA损伤反应和肿瘤发生中起关键作用。然而，其在不同类型人类癌症中的表达和功能存在差异。FBXO31在食管鳞状细胞癌（ESCC）中的表达及其与临床病理特征的关系尚未得到充分研究。FBXO31失调促进ESCC肿瘤发生的潜在机制在很大程度上尚不清楚。通过对包含85例ESCC及匹配的癌旁非癌组织的组织芯片以及另外10例ESCC组织样本进行免疫组化分析，我们发现FBXO31在ESCC中过表达，且其表达与组织学分级（p = 0.04）和临床分期（p = 0.022）显著相关。在单因素（p = 0.013）和多因素（p = 0.014）分析中，FBXO31的高表达与预后不良相关。我们发现FBXO31在暴露于不同类型基因毒性应激的ESCC细胞中作为抗凋亡分子发挥作用。敲低FBXO31可抑制血清饥饿诱导的细胞活力并降低ESCC细胞的致瘤性。此外，FBXO31的抗凋亡作用与应激诱导的丝裂原活化蛋白激酶p38α和JNK的失活有关。此外，体外和体内数据表明，沉默FBXO31可使ESCC细胞和肿瘤对顺铂治疗敏感。综上所述，除了揭示FBXO31是ESCC的独立预后标志物外，我们的研究结果证实了FBXO31在ESCC肿瘤发生和耐药中的新调控作用。
