Lu Ai-Qing, Lv Bin, Qiu Fei, Wang Xiao-Yun, Cao Xiao-Hua
Department of Ultrasound, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
Department of Gastrointestinal Surgery, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
Oncol Rep. 2017 Apr;37(4):2071-2078. doi: 10.3892/or.2017.5498. Epub 2017 Mar 10.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. More than 80% of patients with HCC are not good candidates for curative surgical resection due to advanced liver cirrhosis caused by underlying chronic hepatitis virus (B or C) infection. Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced HCC. Although, sorafenib currently sets the new standard for advanced HCC treatment, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical. In the present study, we found that adenine nucleotide translocator 2 (ANT2) was upregulated in sorafenib‑resistant HCC Huh7 cells (Huh7-R) and its overexpression promoted sorafenib resistance. ANT2 induced the formation of cancer-initiating cell (CIC) phenotypes and promoted metastasis-associated traits in the Huh7 cells. Silencing of miR-137 upregulated ANT2 protein expression in the Huh7 cells. miR-137 was downregulated in the Huh7-R cells, compared with that in the Huh7 cells and its restoration reversed sorafenib resistance in the Huh7-R cells. Restoration of miR-137 inhibited formation of CIC traits and attenuated the abilities of migration and invasion in the Huh7-R cells. Moreover, we demonstrated that high-intensity focused ultrasound (HIFU) in unresectable HCC upregulated serum miR-137. Combining HIFU and sorafenib may be a wise option for advanced and unresectable HCC.
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一。由于潜在的慢性乙型或丙型肝炎病毒感染导致晚期肝硬化，超过80%的HCC患者不适合进行根治性手术切除。索拉非尼是一种口服多激酶抑制剂，是唯一被批准用于治疗晚期HCC的药物。尽管索拉非尼目前为晚期HCC治疗设定了新标准，但肿瘤反应率通常相当低。了解索拉非尼耐药的潜在机制至关重要。在本研究中，我们发现腺嘌呤核苷酸转运体2（ANT2）在索拉非尼耐药的HCC Huh7细胞（Huh7-R）中上调，其过表达促进了索拉非尼耐药。ANT2诱导Huh7细胞中癌症起始细胞（CIC）表型的形成，并促进转移相关特征。miR-137的沉默上调了Huh7细胞中ANT2蛋白的表达。与Huh7细胞相比，miR-137在Huh7-R细胞中表达下调，其恢复逆转了Huh7-R细胞中的索拉非尼耐药。miR-137的恢复抑制了Huh7-R细胞中CIC特征的形成，并减弱了其迁移和侵袭能力。此外，我们证明了不可切除HCC中的高强度聚焦超声（HIFU）上调了血清miR-137。联合HIFU和索拉非尼可能是晚期不可切除HCC的明智选择。
