Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Mol Carcinog. 2018 Jun;57(6):722-734. doi: 10.1002/mc.22793. Epub 2018 Feb 27.
5-FU-based chemotherapy is recently most recommended as the first-line treatment for gastric cancer (GC). However, 5-FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5-FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5-FU. Moreover, dehydrogenase/reductase 2 (DHRS2) was identified as a downstream gene of HOXA13. HOXA13 played a role of carcinogenesis through directly down-regulating DHRS2 to increase MDM2. Furthermore, HOXA13 conferred 5-FU resistance through MRP1 by a p53-dependent pathway. Therefore, HOXA13 might serve as a potential signature that recognized patients who were insensitive to 5-FU, and timely recommended them to other chemotherapy regimens.
5-FU 为基础的化疗最近被推荐为胃癌（GC）的一线治疗方法。然而，5-FU 耐药在许多术后 GC 患者中很常见。同源盒 A13（HOXA13）是一种在许多人类肿瘤中高表达的同源盒基因家族的成员。其在 GC 中对 5-FU 耐药的潜在作用和机制尚不清楚。在这项研究中，我们发现 HOXA13 在体内和体外均发挥致癌作用。HOXA13 过表达的患者与预后不良密切相关，且更易对 5-FU 耐药。此外，脱氢酶/还原酶 2（DHRS2）被鉴定为 HOXA13 的下游基因。HOXA13 通过直接下调 DHRS2 增加 MDM2 发挥致癌作用。此外，HOXA13 通过 p53 依赖途径通过多药耐药相关蛋白 1（MRP1）赋予 5-FU 耐药性。因此，HOXA13 可能作为一种潜在的标志物，识别对 5-FU 不敏感的患者，并及时推荐他们使用其他化疗方案。
