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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
- Source :
- Hepatology. 74:1480-1495
- Publication Year :
- 2021
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2021.
-
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.
- Subjects :
- Male
Hepatitis B virus
Carcinoma, Hepatocellular
medicine.medical_treatment
Mrna binding
Antiviral Agents
Hepatitis B, Chronic
In vivo
Interferon
Cell Line, Tumor
medicine
Humans
RNA Processing, Post-Transcriptional
Cell Proliferation
Hepatology
biology
business.industry
Growth factor
Pregenomic rna
Liver Neoplasms
RNA-Binding Proteins
Hep G2 Cells
Middle Aged
Prognosis
digestive system diseases
In vitro
HEK293 Cells
Gene Knockdown Techniques
Insulin-like growth factor 2
DNA, Viral
Neoplastic Stem Cells
Cancer research
biology.protein
RNA, Viral
Female
Hepatectomy
business
medicine.drug
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....18f310d6c4945eb58c53a537ddc4c790