CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma
CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma
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DOI：
10.1007/s12072-019-09960-5
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发表时间：
2019-07-01
影响因子：
6.6
通讯作者：
Jia, Qingan
中科院分区：
文献类型：
--
作者：
Liao, Xia;Bu, Yang;Jia, Qingan
背景肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内第二大恶性肿瘤死亡原因.化疗是晚期HCC的替代治疗方法，但化疗耐药性使癌症治疗无法获得稳定和完全的反应。了解化疗耐药的潜在机制是提高HCC疗效的关键。MethodsId-1和CCN 2的表达水平在大队列的HCC检测，Id-1和CCN 2的功能分析在体外和体内进行。用cDNA微阵列技术检测CCN 2过表达的肝癌细胞表达谱的变化。结果Id-1和CCN 2的高表达与肝癌奥沙利铂耐药密切相关。CCN 2和Id-1的上调与HCC患者的生存期缩短和复发增加独立相关，并显著增强奥沙利铂耐药性和促进体内肺转移，而敲低其表达显著逆转化疗耐药性并抑制HCC细胞的干细胞性。cDNA微阵列和PCR结果显示Id-1和MAPK通路是CCN 2的下游信号通路。结论CCN 2/MAPK/Id-1环反馈放大参与了奥沙利铂耐药的发生，奥沙利铂联合CCN 2或MAPK信号通路抑制剂可能是改善肝癌奥沙利铂耐药的有效途径。
BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC.MethodsThe expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role ofdownstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored.ResultsThe increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner.ConclusionsCCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC.