TY - JOUR
T1 - A systematic approach to defining the microrna landscape in metastasis
AU - Mudduluru, Giridhar
AU - Abba, Mohammed
AU - Batliner, Jasmin
AU - Patil, Nitin
AU - Scharp, Maike
AU - Lunavat, Taral R.
AU - Leupold, Jörg Hendrik
AU - Oleksiuk, Olga
AU - Juraeva, Dilafruz
AU - Thiele, Wilko
AU - Rothley, Melanie
AU - Benner, Axel
AU - Ben-Neriah, Yinon
AU - Sleeman, Jonathan
AU - Allgayer, Heike
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84939541380&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-0997
DO - 10.1158/0008-5472.CAN-15-0997
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C2 - 26069251
AN - SCOPUS:84939541380
SN - 0008-5472
VL - 75
SP - 3010
EP - 3019
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -
