染色质异常开放激活的STAT3/LINC01140/miR-34a信号轴在调控肝癌射频消融敏感性中的作用及机制研究

Radiofrequency ablation (RFA) is one of the major treatments for hepatocellular carcinoma(HCC). Nevertheless, its outcome varies even in patients with same cancer staging. Unfortunately, little knowledge is known about this phenomenon. Recently, epigenetic regulation is regarded as a key determinant for therapeutic response. Hence, we performed ATAC-seq in RFA sensitive and non-sensitive patients and surprisingly identified the unique open chromatin structures (accessible regions) with significant STAT3 enrichment. Moreover, our preliminary data showed that STAT3 binds on the enhancer region of LINC01140 gene and possibly triggers the enhancer/promoter interaction (looping) and subsequent transcriptional activation. Furthermore, the activated LINC01140 may function as a miRNA ‘sponge’ and inhibit its downstream target miR-34a to mediate RFA resistance in HCC. Overall, in this proposal, we aim to: (1) interrogate the roles of STAT3 and its inhibitor OPB-51602 (FDA approved drug under cancer clinical trials) in therapeutic sensitivity of RFA in HCC; (2) unravel the mechanisms of STAT3 in the regulation of therapeutic sensitivity of RFA in HCC; (3) establish a model based on STAT3 expression in tumor or exosomes (peripheral blood) to predict RFA sensitivity in HCC. We believe that this innovative proposal will open a new avenue for our understanding of RFA sensitivity in HCC and identify novel therapeutic targets.

射频消融（RFA）是肝癌最主要的治疗手段之一，但临床上发现即使病理分期相同的患者，RFA治疗的敏感性却差异甚远。遗憾的是，我们对这一现象的认识仍知之甚少。最近的研究表明表观遗传调控是决定治疗反应的关键因素之一。我们通过ATAC-seq发现RFA不敏感患者的癌细胞具有特征性的染色质开放结构（可接近性），且STAT3在其中显著富集，并可能通过调控LINC01140的增强子与启动子互作，促进其转录及调控其潜在下游靶标miR-34a的表达，从而介导RFA治疗抗性的发生。我们拟在这一项目中：（1）探讨STAT3对肝癌RFA治疗敏感性中的影响及其抑制剂在改善RFA治疗敏感性中的作用；（2）阐明STAT3调控RFA治疗敏感性的机制；（3）建立基于肿瘤/外周血外泌体STAT3的表达预测RFA治疗敏感性的模型。我们相信，这一创新性课题的探索必将为RFA治疗敏感性的认识打开一扇崭新的大门及挖掘新的治疗靶点。

射频消融（RFA）是肝癌最主要的治疗手段之一，但临床上发现即使病理分期相同的患者，RFA治疗的敏感性却差异甚远。遗憾的是，我们对这一现象的认识仍知之甚少。最近的研究表明表观遗传调控是决定治疗反应的关键因素之一。我们通过ATAC-seq发现RFA不敏感患者的癌细胞具有特征性的染色质开放结构（可接近性），且STAT3在其中显著富集，并可能通过调控非编码RNA的=促进其转录及调控其潜在下游靶标的表达，从而介导RFA治疗抗性的发生。我们拟在这一项目中：（1）探讨STAT3对肝癌RFA治疗敏感性中的影响（2）阐明lncRNA-MET对肝癌转移的作用及表观遗传机制（3）介导肝癌的机制，优化临床肝癌消融术后治疗模式。（4）肝癌细胞超级增强子相关的远端互作模式及特征系列研究。我们相信，这一创新性课题的探索必将为RFA治疗敏感性的认识打开一扇崭新的大门及挖掘新的治疗靶点。