Beijing Youan Hospital, Beijing Institute of Hepatology, Capital Medical University, Beijing, 100069, China; Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao City, 266003, China.
Department of Clinical Laboratory, Haidian Maternal&Child Health Hospital, 100080, Beijing, China.
Biochem Biophys Res Commun. 2019 Jan 15;508(3):769-774. doi: 10.1016/j.bbrc.2018.11.181. Epub 2018 Dec 6.
Apoptosis stimulated protein of p53-2 (ASPP2) induces the transcription of p53-targeted genes to stimulates its pro-apoptosis function. The poor chemotherapeutic sensitivity is associated with the decreased ASPP2 expression in many human cancers. Here, multiple genes real-time RT-PCR array and western blotting analysis show that ASPP2 suppress the expression of X-linked inhibitor of apoptosis protein (XIAP), determinant of chemoresistance in cancer, in hepatocellular carcinoma (HCC) in a p53-independent manner. Further experiments with ASPP2-rAd and ASPP2-Lv confirmed that ASPP2 enhanced sensitivity of sorafenib to HCC via suppressing XIAP expression. XIAP mainly found on the cytoplasm and perinuclear areas of ASPP2 over-expressed HepG2 cells, while both cytoplasm and nucleus in ASPP2 shut down HepG2 cells. The association of poor sensitivity of sorafenib and XIAP expression was also found both in ASPP2 shut down and overexpress mice, where liver tissue with decreased or increased ASPP2 displayed less or more apoptosis, respectively. Finally, ASPP2 and XIAP expression analyzed in 43 hepatocellular carcinoma tumors and 44 adjacent normal tissues from 38 hepatocellular carcinoma patients for fully understand their expression within HCC patients. Compared with the tumor tissues, ASPP2 mRNA levels were increased, and XIAP levels decreased in the adjacent normal tissues. Taken together, XIAP suppressed ASPP2 increased tumor sensitivity to chemotherapy in a p53-independent manner, which was associated with chemotherapy resistance, suggesting that p53 activation and XIAP suppression were two independent ways that ASPP2 enhance the sensitivity of chemotherapy.
p53 凋亡刺激蛋白 2（ASPP2）诱导 p53 靶向基因的转录，从而刺激其促凋亡功能。许多人类癌症中 ASPP2 表达降低与化疗敏感性降低有关。在这里，通过实时 RT-PCR 阵列和 Western blot 分析多个基因显示，ASPP2 以 p53 非依赖性方式抑制肝癌（HCC）中细胞凋亡抑制蛋白（XIAP）的表达，XIAP 是癌症化疗耐药的决定因素。使用 ASPP2-rAd 和 ASPP2-Lv 的进一步实验证实，ASPP2 通过抑制 XIAP 表达增强了索拉非尼对 HCC 的敏感性。XIAP 主要存在于 ASPP2 过表达 HepG2 细胞的细胞质和核周区，而在 ASPP2 失活的 HepG2 细胞中则存在于细胞质和核内。在 ASPP2 失活和过表达的小鼠中也发现了索拉非尼敏感性差和 XIAP 表达之间的关联，其中 ASPP2 减少或增加的肝组织分别显示出较少或更多的细胞凋亡。最后，在 38 名肝癌患者的 43 个肝癌肿瘤组织和 44 个相邻正常组织中分析了 ASPP2 和 XIAP 的表达，以充分了解它们在 HCC 患者中的表达情况。与肿瘤组织相比，ASPP2 的 mRNA 水平在相邻的正常组织中增加，而 XIAP 水平降低。综上所述，XIAP 以 p53 非依赖性方式抑制 ASPP2 增加肿瘤对化疗的敏感性，与化疗耐药有关，提示 p53 激活和 XIAP 抑制是 ASPP2 增强化疗敏感性的两种独立方式。
