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HBV-pgRNA increases the stemness and promotes the development of HBV-related HCC through reciprocal regulation with IGF2BP3.

HBV-pgRNA has been proposed for predicting the response of NAs treatment, guiding discontinuation of NAs therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain largely unknown. Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NAs-treated (at least 48 weeks) of 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 underwent long-term NAs therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had 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 IGF2BP3, a well-proved oncoprotein, at post-transcriptional level. Furthermore, IFN-α-2a could degrade the stability of pgRNA through increasing its 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 NAs therapy with undetectable serum HBV-DNA; And 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.