RNA sequencing analysis reveals the competing endogenous RNAs interplay in resected hepatocellular carcinoma patients who received interferon-alpha therapy

Yibin Wu,Yiming Zhao,Lu Wang,Qi Pan,Xiaoshuang Wang,Jiamin Zhou,Ning Zhang,Anrong Mao,Longrong Wang,Weiping Zhu

doi:10.1186/s12935-021-02170-w

Yibin Wu, Yiming Zhao + Show 8 more

Open Access

https://doi.org/10.1186/s12935-021-02170-w

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Abstract

BackgroundInterferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in anti-HCC relapse are rarely understood.MethodsHCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) by RNA sequence, and significant differential expression (DE) of these types of RNAs were selected for further analysis. A ceRNA regulatory network was constructed to explore the potential mechanisms of IFN-α intervention on anti-HCC relapse. Finally, the potential prognostic associated genes among these DE RNAs were identified.ResultsTotally, 556 mRNAs, 120 circRNAs, 87 lncRNAs, and 96 miRNAs were differentially expressed in patients who received IFN-α treatment. A ceRNA regulatory network including a circRNA-miRNA-mRNA network which composed of 4 up- and 10 down-regulated circRNAs, 8 up- and 5 down-regulated miRNAs, 28 up- and 9 down-regulated mRNAs, and a lncRNA-miRNA-mRNA network which composed of 10 up- and 3 down-regulated lncRNAs, 11 up- and 5 down-regulated miRNAs, 28 up- and 10 down-regulated mRNAs was constructed. Gene enrichment and pathway analysis revealed that the ceRNA network was associated with immune-related pathway and corresponding molecular function in patients who accepted IFN-α treatment. Next, we identified 3 most relevant to IFN-α treatment to HCC among these DE RNAs, namely FAM20A, IGFBP4 and MARCH3, as the prognostic associated genes for HCC. Furthermore, MARCH3 expression correlated with infiltrating levels of tumor infiltrating immune cells (TICCs) in HCC. MARCH3 expression also showed strong correlations with the gene markers of diverse immune cells in HCC.ConclusionOur data discovered a novel ceRNA network in HCC patients receiving IFN-α therapy, which might lay the foundation for better understand the regulatory mechanism of IFN-α treatment.

Highlights

Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC)
Analysis of TISIDB database, we aimed to depict the immunological role of Membrane associated ring-CHtype finder 3 (MARCH3) are critical in determining the subpopulation of HCC patients that may benefit from target-MARCH3 immunotherapy
The results showed that the copy number variation (CNV) pattern of MARCH3 including arm-level deletion, diploid/normal, arm-level gain and high amplication was correlated with the infiltrating levels of TIICs

Summary

Introduction

Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). IFN-α is an antiviral cytokine which has anti-proliferation and immunomodulatory properties against malignant tumors [5], and has been reported that it could inhibit tumor metastasis in HCC xenografts model [6], and in our clinical trials [7]. The characteristics of patients who can benefit from IFN-α are not consistent. Have reported that the increased expression of IFIT3 in tumor tissue can be regarded as an indicator for predicting the response of IFN-α therapy [8]. Patients with low RIG-I expression always presented shorter survival and to poorer response IFN-α therapy [9]. Many researches have stratified the potential patients who might benefit from IFN-α therapy, no agreement has been reached

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