Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma
Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma
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DOI：
10.3892/ol.2020.11696
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发表时间：
2020-08-01
期刊：
影响因子：
2.9
通讯作者：
Masaki, Tsutomu
中科院分区：
文献类型：
--
作者：
Kohno, Tomoki;Morishita, Asahiro;Masaki, Tsutomu
肝细胞癌（HCC）是全球第三大癌症相关死亡原因。临床治疗改善了早期肝癌的预后，但晚期肝癌的预后仍然很差。索拉非尼是一种口服多激酶抑制剂，为晚期HCC提供了一种治疗选择，并作为晚期HCC患者的一线治疗延长了生存期并抑制了肿瘤进展。在这项研究中，我们研究了特定的microRNA是否可以作为索拉非尼有效性的预测生物标志物，并指示转换为二线治疗的最佳时间。索拉非尼对Li-7、Hep 3B、HepG 2和Huh 7肝癌细胞株的增殖有抑制作用（有效组），对HLE、HLF和ALEX肝癌细胞株的增殖无抑制作用（无效组）。进行微RNA（miRNA/miR）分析，比较索拉非尼有效和无效细胞系以及来自索拉非尼有效（完全响应/部分响应）和索拉非尼无效（进行性疾病）组的HCC患者在索拉非尼施用之前的血清样品，并检测在体内和体外样品中常见的三种差异表达的miRNA。hsa-miR-30 d在培养基中的增加率（有效/无效）高于在癌细胞中的增加率。hsa-miR-30 d在有效组HCC患者血清和exosomes中的表达高于无效组。此外，与无效组相比，有效组中癌细胞系培养基中的hsa-miR-30 d表达高度上调。这些结果表明，hsa-miR-30 d可能由癌细胞通过exosomes分泌到血清中。我们鉴定了一种特异性循环miRNA，其与索拉非尼治疗下的难治性HCC相关。因此，hsa-miR-30 d可作为索拉非尼治疗HCC疗效的预测性生物标志物。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Clinical management has improved the prognosis of early HCC, but that of advanced HCC remains poor. Sorafenib, an oral multikinase inhibitor, provided a treatment option for advanced-stage HCC, and prolonged the survival and inhibited tumor progression as first-line therapy in patients with advanced HCC. In this study, we investigated if specific microRNAs could act as predictive biomarkers of sorafenib effectiveness and indicate the best time to switch to second-line therapies. Sorafenib inhibited the proliferation of the Li-7, Hep3B, HepG2 and Huh7 liver cancer cell lines (effective group), but not that of the HLE, HLF and ALEX cancer cell lines (non-effective group). A microRNA (miRNA/miR) analysis was performed comparing sorafenib-effective and non-effective cells lines as well as serum samples from patients with HCC from sorafenib-effective (complete response/partial response) and -non-effective (progressive disease) groups before sorafenib administration and detected three differentially-expressed miRNAs that were common among the in vivo and in vitro samples. The increase rate (effective/non-effective) of hsa-miR-30d in the medium was higher than that in the cancer cells. hsa-miR-30d was highly expressed in the serum and exosomes of patients with HCC in the effective group when compared to those of the non-effective group. Additionally, the hsa-miR-30d expression in the medium of cancer cell lines was highly upregulated in the effective group compared with the non-effective group. These results suggested that hsa-miR-30d might be secreted by the cancer cells to the serum through the exosomes. We identified a specific circulating miRNA that is related to refractory HCC under sorafenib therapy. Therefore, hsa-miR-30d might serve as a predictive biomarker for the efficacy of sorafenib therapy in HCC.