CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma
CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma
复制标题
CD147通过增加肝细胞癌中Bip的转录诱导UPR抑制细胞凋亡和化疗敏感性
DOI：
10.1038/cdd.2012.60
复制
发表时间：
2012-11-01
影响因子：
12.4
通讯作者：
Chen, Z-N
中科院分区：
文献类型：
--
作者：
Tang, J.;Guo, Y-S;Chen, Z-N
未折叠蛋白反应（unfolded protein response，UPR）通常在实体瘤中被激活，导致肿瘤细胞抗凋亡和耐药。然而，肿瘤特异性UPR转换器在很大程度上是未知的。在本研究中，我们确定了CD 147，一种癌症生物标志物，作为肝细胞癌（HCC）的UPR诱导剂。在人肝癌组织中，UPR的主要靶点Bip的表达与CD 147呈正相关。通过使FAK和Src磷酸化，CD 147增强TFII-I在Tyr 248处的酪氨酸磷酸化。CD 147还诱导p-TFII-I核定位并与Bip启动子结合，其中内质网（ER）应激反应元件1（ERSE 1）（− 82/− 50）是三种ERSE中最有效的靶标，从而增加Bip的转录。此外，CD 147通过诱导UPR抑制肝癌细胞凋亡，降低细胞对阿霉素的化疗敏感性，从而降低荷瘤裸鼠的生存率。总之，这些结果揭示了CD 147在调节HCC中UPR中的关键作用，并提高了CD 147是促进HCC细胞凋亡和增加肿瘤对抗癌药物敏感性的靶点的可能性。因此，CD 147抑制提供了增强现有药物疗效的机会，并代表了HCC治疗的新靶点。
The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1)(− 82/− 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment.