Suppression of cancer stemness by upregulating Ligand-of-Numb protein X1 in colorectal carcinoma

Cancer stem-like cells (CSCs) have been reported to play major roles in tumorigenesis, tumor relapse, and metastasis after therapy against colorectal carcinoma (CRC). Therefore, identification of colorectal CSC regulators could provide promising targets for CRC. Ligand-of-Numb protein X1 (LNX1) is one E3 ubiquitin ligase which mediates the ubiquitination and degradation of Numb. Although several studies indicate LNX1 could be a potential suppressor of cancer diseases, the functions of LNX1 in mediating cancer stemness remain poorly understood. In this study, LNX1 was identified as a negative regulator of cancer stemness in CRC, which was downregulated in colonospheres or side population (SP) cells. Furthermore, the coxsackievirus and adenovirus receptor (CXADR) was found to be one critical downstream mediator of cancer stemness regulated by LNX1. Interestingly, the anti-breast cancer drug tamoxifen was found to be an agonist of LNX1 and suppress cancer stemness in CRC. In sum, this study provided the evidences that LNX1 signaling plays important roles in regulating the stemness of colon cancer cells.

已有研究证实，癌症干细胞样细胞（Cancer stem-like cells，CSCs）在结直肠癌（colorectal carcinoma，CRC）的肿瘤发生、肿瘤复发及治疗后转移过程中发挥核心作用。因此，鉴定结直肠癌CSCs的调控因子可为结直肠癌治疗提供极具潜力的干预靶点。Numb蛋白配体X1（Ligand-of-Numb protein X1，LNX1）是一类可介导Numb蛋白泛素化修饰与降解的E3泛素连接酶（E3 ubiquitin ligase）。尽管多项研究提示LNX1可能作为癌症疾病的潜在抑癌因子，但其在调控癌症干细胞干性中的功能仍有待深入阐明。本研究鉴定发现，LNX1是结直肠癌中癌症干细胞干性的负调控因子，其在结肠球形成细胞及侧群细胞（side population cells，SP细胞）中表达下调。进一步研究表明，柯萨奇病毒与腺病毒受体（coxsackievirus and adenovirus receptor，CXADR）是LNX1调控癌症干细胞干性的关键下游介导分子之一。有趣的是，抗乳腺癌药物他莫昔芬被证实可作为LNX1的激动剂，进而抑制结直肠癌中的癌症干细胞干性。综上，本研究提供的实验证据表明，LNX1信号通路在调控结肠癌细胞干性过程中发挥重要作用。