ADRB2信号通路在HIF-1α诱导的肝癌细胞化疗抵抗中的作用及机制研究

Primary hepatocellular carcinoma is one of the refractory malignant tumors. Liver cancer cells are not sensitive to chemotherapeutic drugs. Thus the role of chemotherapy in the treatment of liver cancer is controversial, which is a major problem in the field of comprehensive treatment of liver cancer. To solve this problem is of great significance to improve the prognosis of patients with advanced liver cancer. Hypoxia is of great importance in the resistance of tumor cells to chemotherapy, and hypoxia inducible factor -1 (HIF-1) plays an important role in it. The persistent activation of HIF-1α also plays an important role in the chemotherapy resistance of hepatocellular carcinoma. Therefore, it is of great clinical value to study the signaling pathway that inhibits the expression of HIF-1α and to develop drugs that regulates degradation of HIF-1. Our previous studies have found that beta 2 adrenergic receptor (ADRB2) signaling pathway can promote the development and progression of hepatocellular carcinoma (HCC) by inhibiting the autophagic degradation of HIF-1α. However, little is known about the effect of ADRB2 signaling pathway on the sensitivity of liver cancer cells to chemotherapeutic drugs. In this study, we will elaborate on the regulatory role of ADRB2 signaling pathway on HIF-1 induced chemoresistance of hepatocellular carcinoma (HCC) in vitro (in vitro) and in vivo (animal experiment), and further explore the potential role of propranolol (ADRB2 inhibitor), the clinical commonly used drugs, in enhancing the effect of chemotherapy, in order to provide new ideas and methods for the chemical treatment of hepatocellular carcinoma.

原发性肝细胞癌属于难治性恶性肿瘤之一。肝癌细胞对化疗药物极不敏感，化疗在肝癌治疗中的作用备受争议，这成为肝癌综合治疗领域的一大难题。研究解决这一难题，对改善中晚期肝癌患者预后具有重要意义。低氧在肿瘤细胞化疗抵抗中的作用至关重要，低氧诱导因子-1（HIF-1）在其中发挥重要作用。HIF-1α的持续激活在肝癌化疗抵抗中也扮演重要角色。因此，研究抑制HIF-1α表达的信号通路、开发促进HIF-1α降解的药物具有潜在的临床应用价值。我们前期研究首次发现ADRB2信号通路能够通过抑制HIF-1α自噬性降解促进肝癌的发生和发展。但ADRB2信号通路能否影响肝癌细胞对化疗药物的敏感性，目前知之甚少。本研究将阐述ADRB2信号通路对HIF-1α诱导的肝癌细胞化疗抵抗的调节作用及具体分子机制，并探索临床常用药物普萘洛尔（ADRB2抑制剂）增强肝癌化疗效果的潜在作用，为肝癌的化学治疗提供新的思路和方法。

背景：肝细胞癌（hepatocellularcarcinoma，HCC）的化疗耐药是一个重要的临床问题。有证据表明肾上腺素能信号与肿瘤的进展和化疗耐药密切相关。本研究旨在探讨β2肾上腺素能受体（ADRB2）信号通路在肝癌化疗耐药中的作用。.方法：检测化疗后肝癌细胞系中ADRB2阳性细胞比例的变化。通过体外增殖和凋亡实验检测抑制ADRB2信号对肝癌细胞顺铂和阿霉素耐药的影响。随后用免疫印迹法观察低氧诱导因子-1α（HIF-1α）的表达。此外，在稳定细胞中HIF-1α的表达后，再次检测抑制ADRB2信号对肝癌细胞顺铂耐药的影响。.结果：化疗后肝癌细胞系中ADRB2阳性细胞比例明显增加。ICI118,551介导的ADRB2信号抑制进一步降低了接受化疗的肝癌细胞的生存能力。同时，HIF-1α进一步下调。HIF-1α的稳定逆转了ADRB2信号通路对接受化疗的肝癌细胞活性抑制的影响。.结论：我们的数据揭示了抑制ADRB2信号通过降低HIF-1α表达，在抑制HCC化疗耐药中起到了关键作用。