Hepatitis B virus P protein initiates glycolytic bypass in HBV-related hepatocellular carcinoma via a FOXO3/miRNA-30b-5p/MINPP1 axis

Abstract

Background Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied. Methods Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort. Results We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease. Conclusion Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.

The Mechanisms of HBV-Induced Hepatocellular Carcinoma

“…115 HBp protein can trigger glycolysis through the FoxO3/miRNA-30b-5p/ MINPP1 signaling axis, enhancing the proliferation and migration of tumor cells. 116 In addition to its influence on tumor cells, metabolic reprogramming induced by HBV may also play a role in promoting tumorigenesis by affecting the extracellular microenvironment. For example, HBV can help the virus evade innate immune recognition by activating glycolysis, promoting HK activity and lactic acid production, and blocking RLR signaling by inhibiting RIG-I/MAVS interactions.…”

“… 115 HBp protein can trigger glycolysis through the FoxO3/miRNA-30b-5p/MINPP1 signaling axis, enhancing the proliferation and migration of tumor cells. 116 …”

Extracellular Acidification Induces Lysosomal Dysregulation

“…One way to reverse and prevent this damage would be to replace these acid sensitive lipids with lipids that are better suited for, or protected from, acid exposure. It has been shown previously that cells adapted to an acidic extracellular environment have increased expression of LAMP2b and increased representation on the plasma membrane [ 13 , 52 , 53 , 54 ]. Due to the acidic nature of the lysosomal lumen, the lipid composition of the inner leaflet of the lysosomal membrane has an increased concentration of lipids that are resistant to acid hydrolysis.…”

Metabolic Control by DNA Tumor Virus-Encoded Proteins

“…MYC can form a complex with kaposin B, which is another KSHV latent protein, to modulate the expression of a wide variety of host microRNAs [ 120 ], some of which, such as miR-210 [ 121 , 122 , 123 , 124 , 125 ], miR-3188 [ 126 ], miR-483-3p [ 127 ], miR-3197 [ 128 ], miR-423-5p [ 129 ], let-7f-5p [ 130 ], miR-372-3p [ 131 ], miR-9-5p [ 132 , 133 ], miR-489-3p [ 134 ], miR-1271-5p [ 135 ], miR-7-5p [ 136 ] miR-942-3p [ 137 ] and miR-153-3p [ 138 , 139 ], have been linked to metabolism in other diseases. In addition, the KSHV latent protein vIRF3 can stimulate the transcriptional activity of MYC by interacting with Skp2, a transcriptional cofactor that stabilizes and upregulates MYC activity [ 140 ].…”