MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer

Roberto Dinami; Luca Pompili; Eleonora Petti; Manuela Porru; Carmen D'Angelo; Serena Di Vito; Angela Rizzo; Virginia Campani; Giuseppe De Rosa; Alejandra Bruna; Violeta Serra; Miguel Mano; Mauro Giacca; Carlo Leonetti; Gennaro Ciliberto; Madalena Tarsounas; Antonella Stoppacciaro; Stefan Schoeftner; Annamaria Biroccio

doi:10.15252/emmm.202216033

MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer

Roberto Dinami, Luca Pompili, Eleonora Petti, Manuela Porru, Carmen D'Angelo, Serena Di Vito, Angela Rizzo, Virginia Campani, Giuseppe De Rosa, Alejandra Bruna, Violeta Serra, Miguel Mano, Mauro Giacca, Carlo Leonetti, Gennaro Ciliberto, Madalena Tarsounas, Antonella Stoppacciaro, Stefan Schoeftner, Annamaria Biroccio^*

^*Corresponding author for this work

SCMMS Denmark Hill

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

31 Citations (Scopus)

Abstract

The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

Original language	English
Journal	EMBO Molecular Medicine
DOIs	https://doi.org/10.15252/emmm.202216033
Publication status	Accepted/In press - 2022

Keywords

miR-182-3p
target therapy
telomeres
TRF2
triple-negative breast cancer

UN SDGs

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

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10.15252/emmm.202216033

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Dinami, R., Pompili, L., Petti, E., Porru, M., D'Angelo, C., Di Vito, S., Rizzo, A., Campani, V., De Rosa, G., Bruna, A., Serra, V., Mano, M., Giacca, M., Leonetti, C., Ciliberto, G., Tarsounas, M., Stoppacciaro, A., Schoeftner, S., & Biroccio, A. (Accepted/In press). MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.202216033

@article{792a9e98be9a46ac9a0d1b680ff736eb,

title = "MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer",

abstract = "The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.",

keywords = "miR-182-3p, target therapy, telomeres, TRF2, triple-negative breast cancer",

author = "Roberto Dinami and Luca Pompili and Eleonora Petti and Manuela Porru and Carmen D'Angelo and {Di Vito}, Serena and Angela Rizzo and Virginia Campani and {De Rosa}, Giuseppe and Alejandra Bruna and Violeta Serra and Miguel Mano and Mauro Giacca and Carlo Leonetti and Gennaro Ciliberto and Madalena Tarsounas and Antonella Stoppacciaro and Stefan Schoeftner and Annamaria Biroccio",

note = "Funding Information: The research leading to these results has been funded by Italian Association for Cancer Research (AIRC # 21579) and Ministry of Health (CO‐2019‐12369662) to AB. This work was financially supported by Ministry of Health Ricerca Corrente 2022 and intramural grant‐in‐aid to EP. RD, LP and EP were supported by AIRC fellowships. Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2022",

doi = "10.15252/emmm.202216033",

language = "English",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

publisher = "Wiley-Blackwell",

}

Dinami, R, Pompili, L, Petti, E, Porru, M, D'Angelo, C, Di Vito, S, Rizzo, A, Campani, V, De Rosa, G, Bruna, A, Serra, V, Mano, M , Giacca, M, Leonetti, C, Ciliberto, G, Tarsounas, M, Stoppacciaro, A, Schoeftner, S & Biroccio, A 2022, 'MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.202216033

TY - JOUR

T1 - MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer

AU - Dinami, Roberto

AU - Pompili, Luca

AU - Petti, Eleonora

AU - Porru, Manuela

AU - D'Angelo, Carmen

AU - Di Vito, Serena

AU - Rizzo, Angela

AU - Campani, Virginia

AU - De Rosa, Giuseppe

AU - Bruna, Alejandra

AU - Serra, Violeta

AU - Mano, Miguel

AU - Giacca, Mauro

AU - Leonetti, Carlo

AU - Ciliberto, Gennaro

AU - Tarsounas, Madalena

AU - Stoppacciaro, Antonella

AU - Schoeftner, Stefan

AU - Biroccio, Annamaria

N1 - Funding Information: The research leading to these results has been funded by Italian Association for Cancer Research (AIRC # 21579) and Ministry of Health (CO‐2019‐12369662) to AB. This work was financially supported by Ministry of Health Ricerca Corrente 2022 and intramural grant‐in‐aid to EP. RD, LP and EP were supported by AIRC fellowships. Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022

Y1 - 2022

N2 - The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

AB - The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

KW - miR-182-3p

KW - target therapy

KW - telomeres

KW - TRF2

KW - triple-negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85142739303&partnerID=8YFLogxK

U2 - 10.15252/emmm.202216033

DO - 10.15252/emmm.202216033

M3 - Article

C2 - 36426578

AN - SCOPUS:85142739303

SN - 1757-4676

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

ER -

MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer

Abstract

Keywords

UN SDGs

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