The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease

Ran Weissman; Eli L. Diamond; Julien Haroche; Nir Pillar; Guy Shapira; Benjamin H. Durham; Justin Buthorn; Fleur Cohen; Michelle Ki; Galia Stemer; Gary A. Ulaner; Zahir Amoura; Jean François Emile; Roei D. Mazor; Noam Shomron; Omar I. Abdel-Wahab; Ofer Shpilberg; Oshrat Hershkovitz-Rokah

doi:10.3390/cancers12113240

The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease

Ran Weissman
, Eli L. Diamond
, Julien Haroche
, Nir Pillar
, Guy Shapira
, Benjamin H. Durham
, Justin Buthorn
, Fleur Cohen
, Michelle Ki
, Galia Stemer
, Gary A. Ulaner
, Zahir Amoura
, Jean François Emile
, Roei D. Mazor
, Noam Shomron
, Omar I. Abdel-Wahab
, Ofer Shpilberg
, Oshrat Hershkovitz-Rokah

Ariel University
Assuta Medical Center
Department of Neurology
Memorial Sloan-Kettering Cancer Center
Service de Médecine Interne
Sorbonne Université
Department of Pathology
Hebrew University of Jerusalem
Tel Aviv University
Human Oncology and Pathogenesis Program
Department of Pathology
HaEmek Medical Center
Emek Medical Center
Department of Radiology
Université Paris-Saclay
Pathology Department
Hôpital Ambroise Paré
Translational Research Lab
Department of Medicine
Department of Molecular Biology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p,-15b-5p,-21-5p,-107,-221-3p,-320e,-630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.

Original language	English
Article number	3240
Pages (from-to)	1-20
Number of pages	20
Journal	Cancers
Volume	12
Issue number	11
DOIs	https://doi.org/10.3390/cancers12113240
State	Published - 3 Nov 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Funding

This work was supported by the Histiocytosis Association of America research grant. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Funding: This work was supported by the Histiocytosis Association of America research grant. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Funders	Funder number
Histiocytosis Association of America
NIH/NCI
National Institutes of Health
National Cancer Institute	P30 CA008748
Histiocytosis Association

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Erdheim–Chester disease
Histiocytosis
MAPK/ERK pathway
MicroRNA

Access to Document

10.3390/cancers12113240

Cite this

Weissman, R., Diamond, E. L., Haroche, J., Pillar, N., Shapira, G., Durham, B. H., Buthorn, J., Cohen, F., Ki, M., Stemer, G., Ulaner, G. A., Amoura, Z., Emile, J. F., Mazor, R. D., Shomron, N., Abdel-Wahab, O. I., Shpilberg, O., & Hershkovitz-Rokah, O. (2020). The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease. Cancers, 12(11), 1-20. Article 3240. https://doi.org/10.3390/cancers12113240

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title = "The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim{\textendash}chester disease",

abstract = "The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim{\textendash}Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95\% of which were downregulated. MiRNAs-15a-5p,-15b-5p,-21-5p,-107,-221-3p,-320e,-630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.",

keywords = "Erdheim{\textendash}Chester disease, Histiocytosis, MAPK/ERK pathway, MicroRNA",

author = "Ran Weissman and Diamond, \{Eli L.\} and Julien Haroche and Nir Pillar and Guy Shapira and Durham, \{Benjamin H.\} and Justin Buthorn and Fleur Cohen and Michelle Ki and Galia Stemer and Ulaner, \{Gary A.\} and Zahir Amoura and Emile, \{Jean Fran{\c c}ois\} and Mazor, \{Roei D.\} and Noam Shomron and Abdel-Wahab, \{Omar I.\} and Ofer Shpilberg and Oshrat Hershkovitz-Rokah",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = nov,

day = "3",

doi = "10.3390/cancers12113240",

language = "אנגלית",

volume = "12",

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Weissman, R, Diamond, EL, Haroche, J, Pillar, N, Shapira, G, Durham, BH, Buthorn, J, Cohen, F, Ki, M, Stemer, G, Ulaner, GA, Amoura, Z, Emile, JF, Mazor, RD, Shomron, N, Abdel-Wahab, OI, Shpilberg, O & Hershkovitz-Rokah, O 2020, 'The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease', Cancers, vol. 12, no. 11, 3240, pp. 1-20. https://doi.org/10.3390/cancers12113240

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T1 - The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease

AU - Weissman, Ran

AU - Diamond, Eli L.

AU - Haroche, Julien

AU - Pillar, Nir

AU - Shapira, Guy

AU - Durham, Benjamin H.

AU - Buthorn, Justin

AU - Cohen, Fleur

AU - Ki, Michelle

AU - Stemer, Galia

AU - Ulaner, Gary A.

AU - Amoura, Zahir

AU - Emile, Jean François

AU - Mazor, Roei D.

AU - Shomron, Noam

AU - Abdel-Wahab, Omar I.

AU - Shpilberg, Ofer

AU - Hershkovitz-Rokah, Oshrat

PY - 2020/11/3

Y1 - 2020/11/3

N2 - The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p,-15b-5p,-21-5p,-107,-221-3p,-320e,-630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.

AB - The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p,-15b-5p,-21-5p,-107,-221-3p,-320e,-630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.

KW - Erdheim–Chester disease

KW - Histiocytosis

KW - MAPK/ERK pathway

KW - MicroRNA

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ER -

The contribution of micrornas to the inflammatory and neoplastic characteristics of erdheim–chester disease

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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