A systematic approach to defining the microrna landscape in metastasis

Giridhar Mudduluru, Mohammed Abba, Jasmin Batliner, Nitin Patil, Maike Scharp, Taral R. Lunavat, Jörg Hendrik Leupold, Olga Oleksiuk, Dilafruz Juraeva, Wilko Thiele, Melanie Rothley, Axel Benner, Yinon Ben-Neriah, Jonathan Sleeman, Heike Allgayer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of N-cadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues.

Original languageAmerican English
Pages (from-to)3010-3019
Number of pages10
JournalCancer Research
Volume75
Issue number15
DOIs
StatePublished - 1 Aug 2015

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

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