PDF(Pubmed)
Abstract：
Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.
摘要：
尽管治疗取得了显着进展，但许多肝细胞癌（HCC）患者对放疗的反应较差。迫切需要更深入地了解HCC对这种疗法的敏感性机制。已证明RECQL4在HCC患者的恶性细胞中上调。升高的RECQL4水平通过修复辐射诱导的双链DNA(dsDNA)片段降低HCC对放射治疗的敏感性。机械上,RECQL4对放疗的抑制作用是由于肿瘤微环境（TME）中树突状细胞和CD8+T细胞的募集减少。RECQL4通过抑制树突状细胞中的cGAS-STING途径来破坏辐射诱导的TME向杀肿瘤小生境的转化。敲除树突状细胞中的STING可以阻断RECQL4对HCC放射敏感性的影响。值得注意的是,在多个独立队列中,HCC中RECQL4的高表达与不良预后显著相关.总之,这项研究强调了HCC衍生的RECQL4如何通过DNA修复破坏树突状细胞中的cGAS-STING途径激活，从而降低HCC的放射敏感性。这些发现为HCC的临床治疗提供了新的视角。
