HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3
HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3
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HBV/前基因组 RNA 通过与胰岛素样生长因子 2 mRNA 结合蛋白 3 的相互调节增加干性并促进 HBV 相关 HCC 的发展
DOI：
10.1002/hep.31850
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发表时间：
2021-07-29
期刊：
影响因子：
13.5
通讯作者：
Yuan, Sheng-xian
中科院分区：
文献类型：
--
作者：
Ding, Wen-bin;Wang, Meng-chao;Yuan, Sheng-xian
HBV-pgRNA（前基因组RNA）已被提出用于预测核苷(t)类似物（NA）治疗的反应，指导NA治疗的停止和监测病毒突变的出现。然而，HBV-pgRNA在HCC中的作用仍有待研究。方法和结果从长期接受na治疗（>= 48周）的hbv相关HCC患者中获得血清HBV-DNA检测不到（低于检测下限）的血清样本双中心队列。分析血清pgRNA浓度与HCC预后的相关性。在体外和体内评估pgRNA在HCC发展中的作用。我们的研究结果显示，对于长期接受NA治疗且血清HBV-DNA检测不到的患者，血清pgRNA高表达的患者总体生存率较低，肝切除术后累积复发率较高。实验证明pgRNA促进HCC细胞的增殖、干性和致瘤性。在机制上，我们发现pgRNA可以在转录后水平上调胰岛素样生长因子2 mrna结合蛋白3 （IGF2BP3）的表达，这是一种已被证实的癌蛋白。此外，干扰素(IFN)- α -2a可以通过增加其n6 -甲基腺苷（m6A） RNA修饰来降低pgRNA的稳定性。总的来说，我们的研究结果表明，血清pgRNA可以作为一种潜在的生物标志物，用于预测长期接受NA治疗且血清HBV-DNA检测不到的HCC患者的预后和复发；pgRNA-IGF2BP3轴在hbv相关HCC的发展中起重要作用。此外，ifn - α -2a可以通过增加pgRNA的m6A RNA修饰水平来降低pgRNA的稳定性，从而抑制hbv相关HCC的发展。总之，我们的研究揭示了HBV-pgRNA在增加干性特征中的意义和机制，并为hbv相关性HCC提供了潜在的预后标志物和治疗靶点。
Background and Aims HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. Approach and Results Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (>= 48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-alpha-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-alpha-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. Conclusions In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.