In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis
In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis
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DOI：
10.1158/1078-0432.ccr-16-1464
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发表时间：
2017-07-15
影响因子：
11.5
通讯作者：
Gramantieri, Laura
中科院分区：
文献类型：
--
作者：
Fornari, Francesca;Pollutri, Daniela;Gramantieri, Laura
目的：miR-221的异常表达是包括肝细胞癌（HCC）在内的人类癌症的标志，并且其参与耐药性，连同抗miR-221分子的经证实的体内功效，加强了其作为肿瘤学领域中有吸引力的靶候选物的作用。预测治疗反应的生物标志物的发现代表了个性化治疗时代的临床挑战。本研究旨在探讨miR-221作为循环生物标志物在接受索拉非尼治疗的HCC患者中的可能作用，以及评估其对晚期HCC.Experimental Design中索拉非尼耐药的贡献：采用化学诱导的HCC大鼠模型和异种移植小鼠模型以及HCC衍生的细胞系来分析索拉非尼治疗对miR-221的调节。来自功能分析的数据在来自手术切除的HCC的组织样品中得到验证。在动物模型和两个独立的晚期HCC患者队列中测定了与索拉非尼治疗相关的循环miR-221水平的变化。结果：miR-221过表达与两个HCC动物模型中的索拉非尼耐药相关，caspase-3被鉴定为其靶基因，在索拉非尼给药后驱动miR-221抗凋亡活性。较低的治疗前miR-221血清水平被发现在随后经历响应索拉非尼和增加循环miR-221在两个月的评估中观察到在responsible patients.Conclusions：miR-221可能代表一个候选的生物标志物的可能性索拉非尼在肝癌患者中进行测试，在未来的研究。miR-221对Caspase-3的调节参与索拉非尼耐药。(C)2017年AACR。
Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. (C) 2017 AACR.