CeRNA Network of lncRNA/miRNA as Circulating Prognostic Biomarkers in Non-Hodgkin Lymphomas: Bioinformatic Analysis and Assessment of Their Prognostic Value in an NHL Cohort.

Mara Fernandes,Rui Medeiros,Herlander Marques,Ana Luísa Teixeira

doi:10.3390/ijms23010201

Abstract

Research has been focusing on identifying novel biomarkers to better stratify non-Hodgkin lymphoma patients based on prognosis. Studies have demonstrated that lncRNAs act as miRNA sponges, creating ceRNA networks to regulate mRNA expression, and its deregulation is associated with lymphoma development. This study aimed to identify novel circulating prognostic biomarkers based on miRNA/lncRNA-associated ceRNA network for NHL. Herein, bioinformatic analysis was performed to construct ceRNA networks for hsa-miR-150-5p and hsa-miR335-5p. Then, the prognostic value of the miRNA–lncRNA pairs’ plasma levels was assessed in a cohort of 113 NHL patients. Bioinformatic analysis identified MALAT1 and NEAT1 as hsa-miR-150-5p and has-miR-335-5p sponges, respectively. Plasma hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 levels were significantly associated with more aggressive and advanced disease. The overall survival and progression-free survival analysis indicated that hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 pairs’ plasma levels were remarkably associated with NHL patients’ prognosis, being independent prognostic factors in a multivariate Cox analysis. Low levels of hsa-miR-150-5p and hsa-miR-335-5p combined with high levels of the respective lncRNA pair were associated with poor prognosis of NHL patients. Overall, the analysis of ceRNA network expression levels may be a useful prognostic biomarker for NHL patients and could identify patients who could benefit from more intensive treatments.

Highlights

Non-Hodgkin lymphomas (NHL) are a heterogenous class of lymphoproliferative malignancies, characterized by infiltration of lymphoid tissues [1]
Highly associated with miRNA deregulation, all central signal analysis of highly hsa-miR-335-5p targets pathways, we find PI3K/Akt and pathways, associated with through miRNAand deregulation, all central signaling pathways pathways involved in the development progression ofcould involved in the development and progression of NHL
Given the ability of lncRNA to sponge miRNAs and inhibiting their inhibitory function over target mRNAs, in this study, we investigated the prognostic value of lncRNAs and miRNAs by analyzing lncRNAs–miRNAs pairs’ expression in plasma samples of NHL lymphomas

Summary

Introduction

Non-Hodgkin lymphomas (NHL) are a heterogenous class of lymphoproliferative malignancies, characterized by infiltration of lymphoid tissues [1]. The latest GLOBOCAN data indicate that NHL represents the most common hematological malignancy worldwide, corresponding to approximately 3% of cancer diagnoses and cancer deaths [2]. The standard therapy regime for NHL treatment remains the anthracycline-containing chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone—CHOP) combined with anti-CD20 agent, Rituximab (R-CHOP) [1]. Despite the improvement in patients’ outcome after Rituximab introduction, approximately 20–50% of patients are refractory ab initio or relapse, with these patients presenting only a 20–40% 2-year overall survival rate [3,4,5]. The advance of gene-expression profiling and next-generation sequencing provided substantial insights about the etiology and the molecular background of the different entities comprising NHL, but the underlying molecular mechanisms still remain unclear. One of the main challenges in NHL management continues to be the ability to reliably stratify patients according to their risk of recurrence

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