MicroRNA signature constituted of miR-30d, miR-93, and miR-181b is a promising prognostic marker in primary central nervous system lymphoma

Takashima, Yasuo; Kawaguchi, Atsushı; Iwadate, Yasuo; Hondoh, Hiroaki; Fukai, Junya; Kajiwara, Koji; Hayano, Azusa

doi:10.1371/journal.pone.0210400

Cited by 26 publications

(29 citation statements)

References 40 publications

(44 reference statements)

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“…Random survival forests analysis was performed to determine variable importance factors distinguishing expression of genes with survival times, which was estimated by randomly permutating its values and recalculating the predictive accuracy of the model that were expressed as the log rank test statistics using the randomForestSRC package in R [17].…”

Section: Methodsmentioning

confidence: 99%

CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

2019

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Glioma is the most common type of primary brain tumor, accounting for 40% of malignant brain tumors. Although a single gene may not be a marker, an expression profiling and multivariate analyses for cancer immunotherapy must estimate survival of patients. In this study, we conducted expression profiling of immunotherapy-related genes, including those in Th1/2 helper T and regulatory T cells, and stimulatory and inhibitory checkpoint molecules associated with survival prediction in 571 patients with malignant and aggressive form of gliomas, glioblastoma multiforme (GBM). Expression profiling and Random forests analysis of 21 immunosuppressive genes and Kaplan-Meier analysis in 158 patients in the training data set suggested that CD276, also known as B7-H3, could be a single gene marker candidate. Furthermore, prognosis prediction formulas, composed of Th2 cell-related GATA transcription factor 3 (GATA3) and immunosuppressive galactose-specific lectin 3 (LGALS3), based on 67 immunotherapy-related genes showed poor survival with high scores in training data set, which was also validated in another 413 patients in the test data set. The CD276 expression helped distinguish survival curves in the test data set. In addition, inhibitory checkpoint genes, including T cell immunoreceptor with Ig and ITIM domains, V-set domain containing T cell activation inhibitor 1, T-cell immunoglobulin and mucin-domain containing 3, and tumor necrosis factor receptor superfamily 14, showed potential as secondary marker candidates. These results suggest that CD276 expression and the gene signature composed of GATA3 and LGALS3 are effective for prognosis in GBM and will help us understanding target pathways for immunotherapy in GBM.

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Section: Methodsmentioning

confidence: 99%

CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

2019

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“…Investigation of miR-93 expression prolife reveals that patients with low expression of miR-93 have poor prognosis that is maybe due to its impact on PDCD1LG2. This study demonstrates that miR-93 can be considered as a reliable biomarker for prediction of prognosis of patients with PCNSL [128]. Gliomas are one of the most common malignant tumors of brain with high aggressiveness [129,130].…”

Section: Brain Tumorsmentioning

confidence: 63%

Flaming the fight against cancer cells: the role of microRNA-93

et al. 2020

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There have been attempts to develop novel anti-tumor drugs in cancer therapy. Although satisfying results have been observed at a consequence of application of chemotherapeutic agents, the cancer cells are capable of making resistance into these agents. This has forced scientists into genetic manipulation as genetic alterations are responsible for generation of a high number of cancer cells. MicroRNAs (miRs) are endogenous, short non-coding RNAs that affect target genes at the post-transcriptional level. Increasing evidence reveals the potential role of miRs in regulation of biological processes including angiogenesis, metabolism, cell proliferation, cell division, and cell differentiation. Abnormal expression of miRs is associated with development of a number of pathologic events, particularly cancer. MiR-93 plays a significant role in both physiological and pathological mechanisms. At the present review, we show how this miR dually affects the proliferation and invasion of cancer cells. Besides, we elucidate the oncogenesis or oncosuppressor function of miR-93.

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“…Interestingly, in cerebrospinal fluid samples from patients with primary and secondary CNSL, microRNA (miR)-30c acts a diagnostic biomarker 24 . Besides, miR-30d, miR-93, and miR-181b are constituted of prognosis factors in PCNSL tumors 25 . While, miR-101, miR-548b, miR-554, and miR-1202 are associated with cancer immunity in PCNSL tumors 26 .…”

Section: Discussionmentioning

confidence: 99%

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Takashima¹,

Hamano

Fukai

et al. 2020

Sci Rep

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Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin's B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. these results suggest that the GSeA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances. Primary central nervous system lymphoma (PCNSL) is a rare subtype of cerebral malignant non-Hodgkin's B-cell lymphoma with a median overall survival (OS) of approximately four years, which accounts for 3% of all primary brain tumors and 1% of non-Hodgkin's lymphomas (NHLs) in adults 1,2. Methotrexate (MTX) is an antifolate that inhibits dihydrofolate (DHF) reductase (DHFR) activity in purine and thymidine syntheses and regulates the expression of glucocorticoid receptors α and β in human blood cells in vitro 3,4. High-dose MTX (HD-MTX) is used as a first-line treatment in PCNSL 5. Second-line treatments are also required for 10-35% of patients with refractory diseases and for another 35-60% or more who have relapse-acquired MTX resistances 6. Thus, almost PCNSLs recur with MTX resistances despite standard treatments 7. MTX is an antifolate that inhibits DNA synthesis 4. DHFR converts DHF to tetrahydrofolate (THF), a basic form of reduced folate coenzymes 8. MTX resistances are acquired through alternative intrinsic mechanisms in malignant cells, which include decreased drug transport due to mutations and reduced transcription activity of folate carrier genes, dysregulated DHFR activity and affinity, and decreased polyglutamination of MTX due to decreased folylpolyglutamate synthetase (FPGS) activity and increased γ-glutamyl hydrolase (GGH) activity 9-11. MTX exposure induces the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocystein...

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MicroRNA signature constituted of miR-30d, miR-93, and miR-181b is a promising prognostic marker in primary central nervous system lymphoma

Cited by 26 publications

References 40 publications

CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

Flaming the fight against cancer cells: the role of microRNA-93

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

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