<p>miR-3 Encoded by Hepatitis B Virus Downregulates PTEN Protein Expression and Promotes Cell Proliferation</p>

Abstract

Purpose Chronic hepatitis B virus (HBV) infection is a key determinant of hepatocellular carcinoma (HCC). However, the mechanism by which HBV contributes to the development of HCC remains to be further explored. HBV-encoded miR-3 (HBV-miR-3) is a newly discovered microRNA that can affect the replication of HBV, but its influence on host genes is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is expressed at low levels in most cancer cells. How HBV-miR-3 acts on PTEN to induce tumorigenesis has not been clarified. Materials and Methods PTEN protein expression was evaluated in HBV-miR-3-transfected cells and HBV-related liver cancer and paracancerous tissues. A luciferase reporter assay was employed to identify the HBV-miR-3 binding site on the 3ʹ-untranslated region (3ʹ-UTR) of PTEN. Cell apoptosis was assessed by flow cytometry. Cell proliferation was evaluated by colony formation assays. Transwell assays were used to detect cancer cell invasion. Results HBV-miR-3 was identified only in HBV-replicating HCC cells and HBV-infected patients. HBV-miR-3 expression in liver cancer tissues was higher than that in paracancerous tissues, and the corresponding PTEN expression was significantly decreased. Wild-type HBV-miR-3 bound to the 3ʹ-UTR of PTEN and downregulated its protein expression in a dose-dependent manner. Moreover, the inhibition of HBV-miR-3 rescued PTEN protein expression. Furthermore, HBV-miR-3 reduced liver cancer cell apoptosis, enhanced cell invasion, and promoted cell proliferation. Conclusion HBV-miR-3 binds to the 3ʹ-UTR of PTEN mRNA and downregulates PTEN protein expression, thereby reducing cell apoptosis and enhancing cell invasion and proliferation. These results indicate that HBV-miR-3 contributes to the development of HBV-related HCC and may be a therapeutic target for this cancer.

miRNAs as Potential Biomarkers for Viral Hepatitis B and C

“…HBV-miR-3 enhances IFN production, activates JAK/STAT signaling, affects macrophages polymerization/depolarization, and induces the production of interferons and IL-6 by repressing SOCS5/STAT1 pathway ( Figure 3 A) [ 31 ]. Moreover, HBV-miR-3 interacts directly with the Protein phosphatase 1A (PPM1A) and Phosphatase and TENsin homolog (PTEN), silences these human genes, and enhances cell invasion and proliferation in HCC development [ 30 , 32 ]. Furthermore, HBV attenuates its replication targeting its HBV 3,5 kb mRNA transcript with HBV-miR-3 to reduce the expression of HBV core proteins (HBc) and the level of pgRNA [ 28 ].…”

Role of m6A RNA methylation in the development of hepatitis B virus‐associated hepatocellular carcinoma

“…HBV may promote HCC development through HBV‐encoded RNA, which can regulate HBV replication and induce hepatic fibrosis and carcinogenesis 127,128 . HBV‐encoded RNA may interact with host RNAs and genes to promote the proliferation of liver cancer cells 129–132 . Recently, some studies found that m6A modification of HBV RNA also played important roles in the regulation of hepatocarcinogenesis 133 .…”

Effects of Exosomal Viral Components on the Tumor Microenvironment

“…They also found that HBV-miR-3 promoted polarization of M1 macrophages after downregulating SOCS5 and activating the STAT1 signaling pathway. Furthermore, HBV-miR-3 can downregulate PTEN and PPMIA protein expression, enhance HCC cell proliferation and invasion, and promote the development of HBV-related HCC [ 110 , 111 ]. A recent study found that HBV-miR-3 is only present in peripheral blood exosomes of chronic hepatitis B (CHB) patients, so it could be used for monitoring of HBV infection [ 112 ].…”