MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression

Frampton, Adam E, Castellano, Leandro, Colombo, Teresa, Giovannetti, Elisa, Krell, Jonathan, Jacob, Jimmy, Pellegrino, Loredana, Roca-Alonso, Laura, Funel, Niccola, Gall, Tamara M H, De Giorgio, Alexander, Pinho, Filipa G, Fulci, Valerio, Britton, David J, Ahmad, Raida, Habib, Nagy A, Coombes, R Charles, Harding, Victoria, Knösel, Thomas, Stebbing, Justin and Jiao, Long R (2014) MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression. Gastroenterology, 146 (1). 268-277.e18. ISSN 0016-5085

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Abstract

BACKGROUND & AIMS

There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes.

METHODS

We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis.

RESULTS

We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection.

CONCLUSIONS

In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Leandro Castellano
Date Deposited: 15 Jun 2018 11:53
Last Modified: 15 Jun 2018 11:53
URI: http://sro.sussex.ac.uk/id/eprint/76531
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