Zhang Yihao, Zhang Ting, Wu Chao, Xia Quan, Xu Dujuan
School of Pharmacy, Anhui Medical University, Hefei, China.
The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Lab Invest. 2017 Jan;97(1):53-69. doi: 10.1038/labinvest.2016.127. Epub 2016 Dec 5.
Chemotherapy is the main treatment method of patients with advanced liver cancer. However, drug resistance is a serious problem in the treatment of hepatocellular carcinoma (HCC). Acid sensing ion channel 1a (ASIC1a) is a H-gated cation channel; it mediates tumor cell migration and invasion, which suggests that it is involved in the development of malignant tumors. Therefore, we studied the relationship between ASIC1a and drug resistance in human hepatocellular carcinoma. In our study, we found that ASIC1a is highly expressed in human HCC tissue, and that its levels were significantly increased in resistant HCC cells Bel7402/FU and HepG2/ADM. Inhibiting the activity of ASIC1a enhances the chemosensitivity of Bel7402/FU and HepG2/ADM cells. The overexpression of ASIC1a contributed to drug resistance in Bel7402 and HepG2 cells, whereas knockdown of ASIC1a overcame drug resistance in Bel7402/FU and HepG2/ADM cells. We further demonstrated that ASIC1a mediated calcium influx, which resulted in the activation of PI3K/AKT signaling and increased drug resistance. These data suggest that ASIC1a/Ca/PI3K/AKT signaling represents a novel pathway that regulates drug resistance, thus offering a potential target for chemotherapy of HCC.
化疗是晚期肝癌患者的主要治疗方法。然而，耐药性是肝细胞癌（HCC）治疗中的一个严重问题。酸敏感离子通道1a（ASIC1a）是一种H⁺门控阳离子通道；它介导肿瘤细胞的迁移和侵袭，这表明它参与了恶性肿瘤的发生发展。因此，我们研究了ASIC1a与人类肝细胞癌耐药性之间的关系。在我们的研究中，我们发现ASIC1a在人类肝癌组织中高表达，并且其在耐药肝癌细胞Bel7402/FU和HepG2/ADM中的水平显著升高。抑制ASIC1a的活性可增强Bel7402/FU和HepG2/ADM细胞的化疗敏感性。ASIC1a的过表达导致Bel7402和HepG2细胞产生耐药性，而敲低ASIC1a可克服Bel7402/FU和HepG2/ADM细胞的耐药性。我们进一步证明，ASIC1a介导钙内流，从而导致PI3K/AKT信号通路激活并增加耐药性。这些数据表明，ASIC1a/Ca²⁺/PI3K/AKT信号通路代表了一条调节耐药性的新途径，从而为肝癌化疗提供了一个潜在靶点。
