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

journal contribution
posted on 2023-06-09, 13:47 authored by Adam E Frampton, Leandro CastellanoLeandro Castellano, Teresa Colombo, Elisa Giovannetti, Jonathan Krell, Jimmy Jacob, Loredana Pellegrino, Laura Roca-Alonso, Niccola Funel, Tamara M H Gall, Alexander De Giorgio, Filipa G Pinho, Valerio Fulci, David J Britton, Raida Ahmad, Nagy A Habib, R Charles Coombes, Victoria Harding, Thomas Knösel, Justin Stebbing, Long R Jiao
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Gastroenterology

ISSN

0016-5085

Publisher

Elsevier

Issue

1

Volume

146

Page range

268-277.e18

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2018-06-15

First Compliant Deposit (FCD) Date

2021-03-09

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