Liu Kai, Lin Dongdong, Ouyang Yabo, Pang Lijun, Guo Xianghua, Wang Shanshan, Zang Yunjin, Chen Dexi
1 Beijing Institute of Hepatology, Capital Medical University affiliated Beijing You An Hospital, Beijing, P.R. China.
2 Capital Medical University affiliated Beijing You An Hospital, Beijing, P.R. China.
Tumour Biol. 2017 Mar;39(3):1010428317695026. doi: 10.1177/1010428317695026.
Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus-induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy.
p53凋亡刺激蛋白2（ASPP2）的过表达通过增强p53的反式激活活性诱导肝癌细胞（如HepG2细胞）发生凋亡性细胞死亡，但长期ASPP2过表达未能诱导更多凋亡，因为表皮生长因子/表皮生长因子受体/SOS1途径的激活损害了ASPP2的促凋亡作用。在本研究中，在重组腺病毒-ASPP2感染的HepG2细胞中，ASPP2过表达以p53依赖的方式诱导双调蛋白表达。虽然双调蛋白最初有助于ASPP2诱导的凋亡，但它最终通过激活表皮生长因子/表皮生长因子受体/SOS1途径损害ASPP2的促凋亡功能，导致凋亡抗性。此外，用中和抗体阻断可溶性双调蛋白也显著增加了甲磺酸甲酯、顺铂或重组p53腺病毒处理导致的HepG2细胞凋亡性细胞死亡，提示双调蛋白参与抑制凋亡的功能可能是肝癌细胞逃避刺激诱导凋亡的常见机制。因此，我们的数据阐明了肝细胞癌中的一种凋亡逃避机制，对肝细胞癌治疗具有潜在意义。
