The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.
Hepatology. 2021 Sep;74(3):1480-1495. doi: 10.1002/hep.31850. Epub 2021 Jul 29.
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.
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)-α-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-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC.
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.
HBV-pgRNA（前基因组 RNA）已被提议用于预测核苷（酸）类似物（NA）治疗的反应，指导 NA 治疗的停药，并监测病毒突变的出现。然而，HBV-pgRNA 对 HCC 的贡献仍有待研究。
从长期接受 NA 治疗（≥48 周）的 HBV 相关 HCC 患者中获得了血清样本的双中心队列，这些血清样本的血清 HBV-DNA （低于检测下限）无法检测到。分析了血清 pgRNA 浓度与 HCC 预后的相关性。评估了 pgRNA 在 HCC 发展中的作用，包括在体外和体内。我们的研究结果表明，对于接受长期 NA 治疗且血清 HBV-DNA 无法检测到的患者，pgRNA 高表达的患者总体生存率更低，肝切除术后累积复发率更高。实验表明，pgRNA 可促进 HCC 细胞的增殖、干性和致瘤性。从机制上讲，我们发现 pgRNA 可以在上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，IGF2BP3 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。总之，我们的研究结果揭示了血清 pgRNA 可作为预测长期接受 NA 治疗且血清 HBV-DNA 无法检测到的 HCC 患者预后和复发的潜在生物标志物；pgRNA-IGF2BP3 轴在 HBV 相关 HCC 的发展中起重要作用。此外，IFN-α-2a 可以通过增加其 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 在增加干性特征方面的意义和机制，并为 HBV 相关 HCC 提供了一个潜在的预后标志物和治疗靶点。
