Whole transcriptome analysis reveals dysregulated oncogenic lncRNAs in natural killer/T-cell lymphoma and establishes MIR155HG as a target of PRDM1

Abstract

Natural killer/T-cell lymphoma is a rare but aggressive neoplasm with poor prognosis. Despite previous reports that showed potential tumor suppressors, such as PRDM1 or oncogenes associated with the etiology of this malignancy, the role of long non-coding RNAs in natural killer/T-cell lymphoma pathobiology has not been addressed to date. Here, we aim to identify cancer-associated dysregulated long non-coding RNAs and signaling pathways or biological processes associated with these long non-coding RNAs in natural killer/T-cell lymphoma cases and to identify the long non-coding RNAs transcriptionally regulated by PRDM1. RNA-Seq analysis revealed 166 and 66 long non-coding RNAs to be significantly overexpressed or underexpressed, respectively, in natural killer/T-cell lymphoma cases compared with resting or activated normal natural killer cells. Novel long non-coding RNAs as well as the cancer-associated ones such as SNHG5, ZFAS1, or MIR155HG were dysregulated. Interestingly, antisense transcripts of many growthregulating genes appeared to be transcriptionally deregulated. Expression of ZFAS1, which is upregulated in natural killer/ T-cell lymphoma cases, showed association with growth-regulating pathways such as stabilization of P53, regulation of apoptosis, cell cycle, or nuclear factor-kappa B signaling in normal and neoplastic natural killer cell samples. Consistent with the tumor suppressive role of PRDM1, we identified MIR155HG and TERC to be transcriptionally downregulated by PRDM1 in two PRDM1-null NK-cell lines when it is ectopically expressed. In conclusion, this is the first study that identified long non-coding RNAs whose expression is dysregulated in natural killer/T-cell lymphoma cases. These findings suggest that ZFAS1 and other dysregulated long non-coding RNAs may be involved in natural killer/T-cell lymphoma pathobiology through regulation of cancer-related genes, and loss-of-PRDM1 expression in natural killer/ T-cell lymphomas may contribute to overexpression of MIR155HG; thereby promoting tumorigenesis.

Identification and Validation of Two Novel Prognostic lncRNAs in Kidney Renal Clear Cell Carcinoma

“…lncRNA MIR155HG can suppress lymphoma by regulating the activity of NF-κB and mesenchymal genes [42]. However, the contribution of lncRNA DNM1P35 to the development of KIRC is still not known, and further studies are required to address these aspects.…”

“…Several studies have reported that lncRNA MIR155HG plays key roles in the development of myeloproliferative disorders, leukemia, lymphoma, and glioma [40][41][42]. lncRNA MIR155HG can suppress lymphoma by regulating the activity of NF-κB and mesenchymal genes [42].…”

Oncogenic Network and Hub Genes for Natural Killer/T-Cell Lymphoma Utilizing WGCNA

“…Kucuk et al (7) found that STAT3 and STAT5B were each mutated at 5.9% frequency (n = 51). Baytak et al (22) focused on the dysregulated oncogenic lncRNA (MIR155HG) in NKTCL by analyzing the SRP049695 dataset. In this study, we found that ECM receptor interaction pathway was significant in KEGG ( Figure 1D), PPI network (Figure 3), and GSEA (Figure 2A) analysis.…”

ZFAS1: a novel tumor-related long non-coding RNA

“…Guo et al [51] reported ZFAS1 was upregulated in AML cell lines compared with T lymphocytic leukemia cell line or Burkitt’s lymphoma cell line, then they found knockdown of ZFAS1 impeded proliferation, and promoted apoptosis of AML cell line. Baytak et al [52] found ZFAS1 was overexpressed in NKTCL tissues and ZFAS1 -associated genes are enriched in pathways regulating proliferation and survival. The above data showed ZFAS1 might act as a valuable prognostic biomarker and potential therapeutic target for Melanoma, NSCLC, OS, ESCC, AML and NKTCL.…”