MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer.
While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.
Olson
Peter
P
Diabetes Center, University of California at San Francisco, San Francisco, California 94143, USA.
Lu
Jun
J
Zhang
Hao
H
Shai
Anny
A
Chun
Matthew G
MG
Wang
Yucheng
Y
Libutti
Steven K
SK
Nakakura
Eric K
EK
Golub
Todd R
TR
Hanahan
Douglas
D
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D018358:Neuroendocrine Tumors / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000503:physiopathology*; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D007211:Indoles; D035683:MicroRNAs; D011758:Pyrroles; D000077210:Sunitinib