Abstract
Objective
This research analyzes the potential of long non-coding RNAs (lncRNAs) as markers in determining the necessity of antiviral treatment in pregnant women by examining alterations in the expression profile of serum lncRNAs in pregnant women with elevated hepatitis B viral load (HBVL) under antiviral and non-antiviral treatment regimens between the second trimester and delivery.
Methods
Serum was obtained from 6 s-trimester pregnant women with high HBVL and no intrauterine infection. Then, 3 of these women were randomly selected for antiviral treatment, with the remaining 3 women undergoing non-antiviral treatment as control. Serum samples were again collected from these 6 women before delivery. The expression profile of lncRNAs was analyzed with microarray technology, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The axes of hub lncRNA-miRNA-mRNA were identified based on the competing endogenous RNA (ceRNA) network.
Results
The expression profile of serum lncRNAs in pregnant women with high HBVL changed significantly from the second trimester of pregnancy until delivery under antiviral or non-antiviral treatment. The Venn diagram was utilized to screen out the jointly up-regulated and down-regulated lncRNAs in the serum of pregnant women under antiviral and non-antiviral treatment before delivery. Additionally, the KEGG pathway enrichment analysis results showed that lncRNAs might mediate the Hippo pathway in HBV infection. Based on the ceRNA network, 3 hub lncRNAs (CATG00000076041.1, LINC01310, and G014655) were found to potentially regulate the key gene TP73 in the Hippo pathway.
Conclusion
In this study, we retrieved co-differentially expressed lncRNAs in pregnant women with high HBVL under antiviral or non-antiviral treatment, which may be used as markers for evaluating whether pregnant women with high HBVL may be free of antiviral treatment. This study may provide a basis for preventing potential adverse effects of antiviral treatment on maternal and fetal health.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12884-024-06907-z.
Keywords: Hepatitis B viral load, Perinatal transmission, LncRNAs, Hippo pathway
Introduction
Chronic hepatitis B virus (HBV) infection in newborns primarily occurs through mother-to-child transmission, with over 90% of infected infants developing chronic HBV [1]. In China, 6-8% of women of childbearing age have chronic HBV, being the main source of perinatal transmission [2]. HBV infection can occur through intrauterine, intrapartum, or postpartum transmission [3]. Although intrapartum and postpartum transmissions can be effectively prevented with hepatitis B immunoglobulin and vaccines, intrauterine transmission remains a challenge [4]. Antiviral therapy is a typical method to prevent intrauterine HBV infection during the second and third trimesters [5]. However, for women with high hepatitis B viral load (HBVL), the intrauterine transmission rate without intervention is only 5–20% [3]. According to the 2020 guidelines, most mother-to-child transmissions occur during or after delivery, rather than intrauterinely [6]. Extensive use of antiviral drugs during pregnancy can waste resources, increase economic burdens, and potentially harm both the mother and fetus [4]. Therefore, it is crucial to explore more effective and safer methods by understanding the mechanisms, identifying predictive indicators, and targeting antiviral therapies, thereby preventing intrauterine HBV transmission.
Previously, long non-coding RNAs (lncRNAs) were widely recognized as a group of functionless RNAs with the main function of governing gene transcription and RNA processing [7]. Accumulating studies have indicated that long non-coding RNAs (lncRNAs) play a crucial role in HBV-related diseases. For example, HOTTIP inhibits HBV replication by suppressing the production of pregenomic RNA through HOXA13 [8]. LINC01431 binds to PRMT1 to prevent HBx-mediated degradation of PRMT1, thereby inhibiting covalently closed circular DNA (cccDNA) transcription [9]. HOXA-AS2 restricts HBV replication by binding to cccDNA and recruiting deacetylase complexes, which reduces histone acetylation [10]. NKILA can suppress HBV replication by inhibiting NF-κB activity, while HBV downregulates NKILA expression to promote its replication [11]. Therefore, it is crucial to explore the underlying mechanisms of lncRNAs, as they could significantly contribute to the prevention and treatment of intrauterine infections. Notably, advancements in microarray and high-throughput RNA sequencing technologies offer a more comprehensive analysis of lncRNA expression and regulatory mechanisms, providing valuable and precise data to aid in the prevention of intrauterine infections.
Method
Collection of clinical serum samples
Initially, blood samples were collected from 6 pregnant women with high HBVL and normal liver function in the second trimester (24–28 weeks) who had not undergone antiviral therapy. Thereafter, 3 of these women were randomly selected to receive antiviral treatment during pregnancy, while the remaining 3 women underwent non-antiviral intervention. Approximately 5 mL blood samples were aseptically obtained by puncturing a needle into the Cubital vein and subsequently placed in sterile centrifuge tubes, followed by 5-minute centrifugation at 300 g to separate serum. The serum samples were then aliquoted into 2 mL centrifuge tubes (0.5 mL per tube) labeled with sample number, date, and time. The samples were stored in a -80 °C refrigerator to prevent repeated freezing and thawing, ensuring the integrity of lncRNAs in the serum. All experiments involving human beings were conducted following the ethical standards of the national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethics Committee of the People’s Hospital of Guangxi Zhuang Autonomous Region (No. KY-GZR-2019-061). All specimens were collected with the written consent of patients and ethical approval.
Arraystar LncRNA 5.0 chip
After RNA extraction, RNA integrity and concentration were subjected to quality assessment with the Agilent ND-1000. Next, RNA was labeled with the Arraystar Flash RNA Labeling Kit and then hybridized with Agilent SureHyb. The chip was washed and scanned with an Agilent microarray scanner, followed by collecting the chip probe signal values with the Agilent Feature Extraction Software (v11.0.0.1). The Agilent GeneSpring GX v12.1 software was employed to standardize the chips and select differentially expressed lncRNAs. The false discovery rate (FDR) was controlled using a Benjamini-Hochberg correction. Differential expression was considered significant at an adjusted p-value (FDR) of < 0.05. The differentially expressed lncRNAs were annotated with pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The p-value indicated the likelihood that the observed association between the gene set and the pathway occurred by chance. Pathways with p < 0.05 were statistically significant, highlighting the key biological processes that were potentially impacted by the differentially expressed genes.
LncRNA-mRNA co-expression network
Based on the normalized signal intensities of the mRNA and lncRNA expression levels, the lncRNA-mRNA co-expression network was constructed to identify interactions between differentially expressed mRNAs and differentially expressed lncRNAs. Pearson’s correlation coefficients were calculated to determine the strength and direction of the linear relationships between lncRNA and mRNA expression levels to establish this co-expression network.
Statistical analysis
The unpaired t-test was employed to evaluate differential gene expression between groups. Fisher’s exact test was utilized to assess the enrichment of differentially expressed lncRNAs in specific biological pathways. Pearson’s correlation analysis was conducted to calculate the linear relationships between lncRNA and mRNA expression levels, thus facilitating the construction of the lncRNA-mRNA co-expression network. All statistical analyses were performed using the R software (version 4.1.1). A p-value of less than 0.05 indicated a statistically significant difference.
Results
Changes in the expression profile of serum lncRNAs in pregnant women with high HBVL from the second trimester until delivery
First, the serum of pregnant women with high HBVL was collected in the second trimester and before delivery for analyzing the expression profile of lncRNAs using lncRNA microarray technology. The heat map of overall differential genes indicated that both pregnancy and antiviral treatment affected the expression of serum lncRNAs (Fig. 1a). Next, the intersection of differentially expressed serum lncRNAs between patients without and with antiviral therapy was analyzed from the second trimester to delivery, and 331 down-regulated lncRNAs (Fig. 1b, Table S1) and up-regulated 134 lncRNAs (Fig. 1c, Table S2) were identified. These jointly up-regulated or down-regulated lncRNAs indicated that the clinical outcome of patients with antiviral treatment was consistent with that of patients without antiviral treatment (no intrauterine infection). Furthermore, lncRNAs can predict to a certain extent that antiviral treatment is unnecessary for pregnant women with high HBVL in the second trimester, which reduces the impact of antiviral drugs on fetal growth and development.
Fig. 1.
The expression profile of serum lncRNAs in pregnant women with high hepatitis B virus load (HBVL). a The heat map shows the lncRNA expression profile of each group; G1 and G2 represent the expression profile of serum lncRNAs in pregnant women in the second trimester of pregnancy who did not receive antiviral treatment; D1 represents the expression profile of serum lncRNAs in second-trimester pregnant women in G1 who did not receive antiviral treatment before delivery; D2 stands for the expression profiles of serum lncRNAs in second-trimester pregnant women of G2 who received antiviral treatment from pregnancy to delivery; (b-c) Venn diagrams exhibit jointly down-regulated or up-regulated lncRNAs in the serum of second-trimester and prepartum pregnant women with and without antiviral treatment. P value < 0.05 and |log2 (fold change)| > 1 were used as the criteria to filter genes that were significantly regulated
Effects of antiviral treatment on the expression profile of serum lncRNAs and pathways in pregnant women before delivery
It is extensively accepted that antiviral treatment can significantly repress virus replication and transmission. However, it remains uncertain whether antiviral treatment influences the expression of serum lncRNAs in pregnant women with high HBVL before delivery. The expression of serum lncRNAs changed significantly before delivery in terms of copy number in pregnant women after antiviral treatment, showing 1056 up-regulated lncRNAs and 1212 down-regulated lncRNAs (Fig. 2a, Table S3). Moreover, the pathways enriched by these differentially expressed lncRNAs were the thyroid hormone pathway, Renin − angiotensin system, glycerolipid metabolism, GABAergic synapse, Fanconi anemia pathway, ECM − receptor interaction, complement and coagulation cascades, and cholinergic synapse (Fig. 2b). These results illustrated that antiviral treatment before delivery may decrease the risk of fetal intrauterine infection via lncRNAs and related pathways.
Fig. 2.
The effect of antiviral treatment before delivery on the expression of lncRNAs and the enriched pathways. a Changes in the copy number of differential lncRNAs displayed on chromosomes; b KEGG pathway enrichment analysis of differential lncRNAs
Differences in serum lncRNA expression and pathways of pregnant women under antiviral treatment and non-antiviral treatment
Subsequently, the differentially expressed serum lncRNAs were displayed on the chromosomes of pregnant women who received antiviral treatment from the second trimester until delivery, yielding 2197 up-regulated lncRNAs and 2808 down-regulated lncRNAs (Fig. 3a, Table S4). According to the KEGG pathway enrichment analysis results, pathways enriched by these differentially expressed lncRNAs primarily included tyrosine metabolism, ribosome, primary bile acid biosynthesis, phenylalanine metabolism, other glycan degradation, Hippo pathway, cellular senescence, and C − type lectin receptor pathway. This suggested that HBV modulated multiple pathways through differential lncRNAs to affect the transmission and immunosuppressive effects of viruses in the body (Fig. 3b).
Fig. 3.
Changes in lncRNA expression of patients from the second trimester to delivery in different states. a Serum differential lncRNA copy number changes of pregnant women who did not receive antiviral treatment from the second trimester to delivery on chromosome; b KEGG pathway enrichment analysis showed changes in pathways from the second trimester to delivery who did not receive antiviral treatment; c Changes in the copy number of serum lncRNAs in pregnant women who received antiviral therapy from the second trimester to prepartum on the chromosome; d KEGG pathway enrichment analysis showed changes in signaling pathways from the second trimester until delivery who received antiviral therapy
Meanwhile, the differentially expressed serum lncRNAs were displayed on the chromosomes of pregnant women with antiviral treatment from the second trimester to delivery, yielding 2102 up-regulated lncRNAs and 1138 down-regulated lncRNAs (Fig. 3c, Table S5). The KEGG pathway enrichment analysis results unraveled that the pathways significantly enriched by these differentially expressed lncRNAs in patients with antiviral treatment primarily included RNA degradation, pyrimidine metabolism, pantothenate and CoA biosynthesis, Hippo pathway, fatty acid metabolism, fatty acid elongation, biosynthesis of unsaturated fatty acids, autoimmune thyroid disease, and Allograft rejection (Fig. 3d). Among them, the Hippo pathway was significantly enriched in pregnant women without and with antiviral treatment in the absence of intrauterine infection. The results indicated that the Hippo pathway may be the key pathway in pregnant women with high HBVL in the absence of intrauterine infection and may emerge as a novel promising target for the prevention of intrauterine infection and antiviral therapy.
CeRNA network analysis of the hub lncRNA-miRNA-mRNA regulatory axis
Subsequently, the ceRNA network analysis was conducted on the jointly differential genes (CRB1, CSNK1D, RASSF6, SMAD1, and TP73) in the Hippo pathway in patients with and without antiviral treatment to retrieve lncRNAs that regulated these differential genes (Fig. 4a, Table S6). Next, these differential lncRNAs were intersected with differentially expressed lncRNAs in patients with and without antiviral treatment before delivery to screen potential markers of no intrauterine infection without antiviral treatment. As indicated by the results, CATG00000076041.1, LINC01310, and G014655 jointly regulated the key gene TP73 in the Hippo pathway (Fig. 4b). However, the ceRNA regulatory network still requires further verification through in-vivo and in-vitro experiments.
Fig. 4.
Construction of ceRNA regulatory network. a Protein-protein interaction displayed the lncRNA-miRNA-mRNA regulatory network relationship; b Venn diagram elucidated the intersection of jointly differential genes in G1 vs. D1 and G2 vs. D2 and no differential genes in D1 vs. D2
Discussion
Prior research has demonstrated that serum lncRNAs may be involved in the multiple aspects of viral infection, such as diagnosis, treatment, and pathophysiological mechanisms [12]. For instance, a prior study on individuals with chronic hepatitis B revealed a significant correlation between serum lncRNA GAS5 expression and the onset and progression of liver fibrosis [13, 14]. The current research unraveled that HBV infection markedly affected the expression profile of serum lncRNAs from the second trimester until delivery, indicating the potential involvement of serum lncRNAs in viral infection mechanisms. Furthermore, the identified jointly up-regulated or down-regulated lncRNAs were closely associated with the virus infection process, which further evidenced that HBV infection could modulate the expression of lncRNAs to affect the immune system of the host.
Furthermore, the effect of antiviral treatment on the expression profile of serum lncRNAs was assessed in pregnant women with high HBVL before delivery, concordant with previous studies. For example, a prior study on HBV-infected patients revealed that antiviral treatment substantially altered the expression profile of serum lncRNAs and that some of these differential lncRNAs were closely related to the pathophysiological mechanism of HBV infection [15]. Furthermore, our results elaborated that before delivery, antiviral treatment significantly changed the expression profile of serum lncRNAs in pregnant women and enriched in multiple pathways. These findings illustrated that antiviral treatment exhibited a broad impact on the expression profile of serum lncRNAs in pregnant women before delivery and may regulate the physiological state and immune response of pregnant women via mediating many pathways.
The Hippo pathway is a crucial factor in the development and regeneration of the liver and the onset of liver cancer [16]. Prior studies have demonstrated that the inactivation of the Hippo pathway shared a significant association with the occurrence and progression of liver cancer [17, 18]. Additionally, the Hippo pathway is also a key player in the regulation of apoptosis, autophagy, and immunity [19]. Moreover, the Hippo pathway is implicated in the modulation of viral infections, including HBV infection and hepatitis C virus infection [20–26].
Tumor protein p73 (TP73), a tumor-related gene, is a member of the p53 family [27], which regulates the Hippo pathway by interacting with the core regulatory factors YES-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ). YAP and TAZ are pivotal downstream effectors of the Hippo pathway, whose activity is modulated by the Hippo pathway. Reportedly, when the activity of the Hippo pathway is reduced, YAP and TAZ enter the nucleus and bind to transcription factors to up-regulate target genes, ultimately facilitating cell proliferation and tissue growth [28]. The present study elucidated that the Hippo pathway was vital for HBV infection and might serve as a novel potential target for antiviral intervention. Furthermore, 3 lncRNAs, including CATG00000076041.1, LINC01310, and G014655, were identified as potential regulators of the key gene TP73 in the Hippo pathway. Our results further evidenced the crucial involvement of the Hippo pathway in viral infections and may offer novel insights into the treatment and management of HBV infections.
This study provides novel insights into the impact of antiviral treatment on serum lncRNA expression in pregnant women with high HBVL. However, there are several limitations. The small sample size of this study limits the generalizability of the findings, and the observational design cannot establish causality. Larger and more diverse cohorts should be involved in future research to validate these results and explore the underlying mechanisms. Additionally, although lncRNAs are identified to be linked to the Hippo pathway, their precise roles in HBV infection and antiviral treatment need further exploration through in-vivo and in-vitro studies. Further investigation is needed to explore the potential of targeting the Hippo pathway as a therapeutic approach in clinical settings.
In conclusion, this study sheds new light on the effect of antiviral treatment on the expression of serum lncRNAs in pregnant women, reveals the involved pathways, and furnishes essential information for developing new anti-infection strategies. Nonetheless, further studies are required to verify these results and to probe the long-term effects of antiviral treatment on pregnant women and fetuses. Additionally, this study was limited by a small sample size. Studies with a larger sample size are warranted in the future to verify the reliability and generalizability of our results. Importantly, our results have certain implications for clarifying the mechanism of HBV infection and antiviral therapy.
Conclusion
This study preliminarily clarified the jointly up-regulated or down-regulated lncRNAs in the serum of pregnant women with or without antiviral treatment by analyzing the changes in the expression profile of serum lncRNAs in pregnant women with high HBVL in different states. These lncRNAs, to a certain extent, can be used as markers for determining that pregnant women with high HBVL in the second trimester may not receive antiviral treatment, thus suppressing the impact of antiviral drugs on fetal growth and development. Hence, more attention should be paid to the detection and application of lncRNAs for the prevention and treatment of HBV-infected pregnant women in future clinical practice.
Supplementary Information
Supplementary Material 1. Table S1. Jointly down-regulated serum lncRNAs in pregnant women with or without antiviral treatment from the second trimester until delivery.
Supplementary Material 2. Table S2. Jointly up-regulated lncRNAs in the serum of pregnant women with our without antiviral treatment from the second trimester until delivery.
Supplementary Material 3. Table S3. Before delivery, maternal serum lncRNA expression is significantly altered in terms of copy number after antiviral treatment.
Supplementary Material 4. Table S4. Differential expression of lncRNA copy number in the serum of pregnant women without antiviral treatment from the second trimester until delivery.
Supplementary Material 5. Table S5. Differential expression of lncRNA copy number in the serum of pregnant women with antiviral treatment in the second trimester of antiviral treatment to delivery.
Supplementary Material 6. Table S6. CeRNA network analysis of the hub-lncRNA-miRNA-mRNA regulatory axis.
Author’ contributions
Contributions: (I) Conception and design: Cuimin Wang, Xuxia, Liang; (II) Data analysis and interpretation: Zaiming Jia; (III) Collection and assembly of data: Yuting Huang, Hui Chen, Haitang Wei; (IV) Administrative support: Yin Huang; (V) Provision of study materials or patients: Xizhen Huang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Funding
This study was funded by National Natural Science Foundation of China (No.: 81960117); Scientific research project of Health Commission of Guangxi Zhuang Autonomous Region (No.: Z20200028); Key research and development plan project of Qingxiu District Science and Technology Bureau of Nanning City (No.: 2021014).
Data availability
All the data are deposited in GEO databases GSE238157 (https://www.ncbi.nlm.nih.gov/geo/). The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Ethics Committee of the People's Hospital of Guangxi Zhuang Autonomous Region (No. KY-GZR-2019-061).
Informed consent was obtained from all individual participants included in the study.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Cuimin Wang, Email: wcmwcmlove@yeah.net.
Xuxia Liang, Email: 1345067634@qq.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1. Table S1. Jointly down-regulated serum lncRNAs in pregnant women with or without antiviral treatment from the second trimester until delivery.
Supplementary Material 2. Table S2. Jointly up-regulated lncRNAs in the serum of pregnant women with our without antiviral treatment from the second trimester until delivery.
Supplementary Material 3. Table S3. Before delivery, maternal serum lncRNA expression is significantly altered in terms of copy number after antiviral treatment.
Supplementary Material 4. Table S4. Differential expression of lncRNA copy number in the serum of pregnant women without antiviral treatment from the second trimester until delivery.
Supplementary Material 5. Table S5. Differential expression of lncRNA copy number in the serum of pregnant women with antiviral treatment in the second trimester of antiviral treatment to delivery.
Supplementary Material 6. Table S6. CeRNA network analysis of the hub-lncRNA-miRNA-mRNA regulatory axis.
Data Availability Statement
All the data are deposited in GEO databases GSE238157 (https://www.ncbi.nlm.nih.gov/geo/). The data supporting the findings of this study are available from the corresponding author upon reasonable request.