Wen-Bin Ding1,2,3, Meng-Chao Wang1,2,3, Jian Yu1,2,3, Gang Huang1,2,3, Da-Peng Sun1,2,3, Lei Liu1,2,3, Jia-Ning Zhang1,2,3, Yuan Yang1,2,3, Hui Liu1,2,3, Wei-Ping Zhou1,2,3, Fu Yang4, Sheng-Xian Yuan1,2,3. 1. The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. 2. Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China. 3. Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China. 4. The Department of Medical Genetics, Second Military Medical University, Shanghai, China.
Abstract
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)-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. 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.
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)-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. 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.