Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

Arianna Bellazzo; Giulio Di Minin; Elena Valentino; Daria Sicari; Denis Torre; Luigi Marchionni; Federica Serpi; Michael B. Stadler; Daniela Taverna; Gaia Zuccolotto; Isabella Monia Montagner; Antonio Rosato; Federica Tonon; Cristina Zennaro; Chiara Agostinis; Roberta Bulla; Miguel Mano; Giannino Del Sal; Licio Collavin

doi:10.1038/s41418-018-0088-5

Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

Arianna Bellazzo, Giulio Di Minin, Elena Valentino, Daria Sicari, Denis Torre, Luigi Marchionni, Federica Serpi, Michael B. Stadler, Daniela Taverna, Gaia Zuccolotto, Isabella Monia Montagner, Antonio Rosato, Federica Tonon, Cristina Zennaro, Chiara Agostinis, Roberta Bulla, Miguel Mano, Giannino Del Sal, Licio Collavin^*

^*Corresponding author for this work

Cardiovascular Sciences

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

31 Citations (Scopus)

Abstract

The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

Original language	English
Pages (from-to)	1224-1238
Number of pages	15
Journal	CELL DEATH AND DIFFERENTIATION
Volume	25
Issue number	7
DOIs	https://doi.org/10.1038/s41418-018-0088-5
Publication status	Published - 1 Jul 2018

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Bellazzo, A., Di Minin, G., Valentino, E., Sicari, D., Torre, D., Marchionni, L., Serpi, F., Stadler, M. B., Taverna, D., Zuccolotto, G., Montagner, I. M., Rosato, A., Tonon, F., Zennaro, C., Agostinis, C., Bulla, R., Mano, M., Del Sal, G., & Collavin, L. (2018). Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells. CELL DEATH AND DIFFERENTIATION, 25(7), 1224-1238. https://doi.org/10.1038/s41418-018-0088-5

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title = "Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells",

abstract = "The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.",

author = "Arianna Bellazzo and {Di Minin}, Giulio and Elena Valentino and Daria Sicari and Denis Torre and Luigi Marchionni and Federica Serpi and Stadler, {Michael B.} and Daniela Taverna and Gaia Zuccolotto and Montagner, {Isabella Monia} and Antonio Rosato and Federica Tonon and Cristina Zennaro and Chiara Agostinis and Roberta Bulla and Miguel Mano and {Del Sal}, Giannino and Licio Collavin",

note = "Funding Information: Funding This work was funded by AIRC (Italian Association for Cancer Research) Investigator Grant (IG 14173) and Universit{\`a} di Trieste (FRA 2015) to LC, and AIRC Special Program Molecular Clinical Oncology “5 per mille” (Grant no. 10016) to GDS and AR. This study was also supported by NIH-NCI Grant R01CA200859 to LM. AB was supported by a “Guglielmina Lucatello e Gino Mazzega” postdoctoral fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro). FT and CZ were supported by Fondazione la Nuova Speranza ONLUS - Lotta alla Glomerulosclerosi Focale, Rho (Milano). Publisher Copyright: {\textcopyright} 2018 ADMC Associazione Differenziamento e Morte Cellulare.",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41418-018-0088-5",

language = "English",

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journal = "CELL DEATH AND DIFFERENTIATION",

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Bellazzo, A, Di Minin, G, Valentino, E, Sicari, D, Torre, D, Marchionni, L, Serpi, F, Stadler, MB, Taverna, D, Zuccolotto, G, Montagner, IM, Rosato, A, Tonon, F, Zennaro, C, Agostinis, C, Bulla, R, Mano, M, Del Sal, G & Collavin, L 2018, 'Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells', CELL DEATH AND DIFFERENTIATION, vol. 25, no. 7, pp. 1224-1238. https://doi.org/10.1038/s41418-018-0088-5

TY - JOUR

T1 - Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

AU - Bellazzo, Arianna

AU - Di Minin, Giulio

AU - Valentino, Elena

AU - Sicari, Daria

AU - Torre, Denis

AU - Marchionni, Luigi

AU - Serpi, Federica

AU - Stadler, Michael B.

AU - Taverna, Daniela

AU - Zuccolotto, Gaia

AU - Montagner, Isabella Monia

AU - Rosato, Antonio

AU - Tonon, Federica

AU - Zennaro, Cristina

AU - Agostinis, Chiara

AU - Bulla, Roberta

AU - Mano, Miguel

AU - Del Sal, Giannino

AU - Collavin, Licio

N1 - Funding Information: Funding This work was funded by AIRC (Italian Association for Cancer Research) Investigator Grant (IG 14173) and Università di Trieste (FRA 2015) to LC, and AIRC Special Program Molecular Clinical Oncology “5 per mille” (Grant no. 10016) to GDS and AR. This study was also supported by NIH-NCI Grant R01CA200859 to LM. AB was supported by a “Guglielmina Lucatello e Gino Mazzega” postdoctoral fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro). FT and CZ were supported by Fondazione la Nuova Speranza ONLUS - Lotta alla Glomerulosclerosi Focale, Rho (Milano). Publisher Copyright: © 2018 ADMC Associazione Differenziamento e Morte Cellulare.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

AB - The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

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U2 - 10.1038/s41418-018-0088-5

DO - 10.1038/s41418-018-0088-5

M3 - Article

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AN - SCOPUS:85044294102

SN - 1350-9047

VL - 25

SP - 1224

EP - 1238

JO - CELL DEATH AND DIFFERENTIATION

JF - CELL DEATH AND DIFFERENTIATION

IS - 7

ER -

Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

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