The HER2-encoded miR-4728-3p regulates ESR1 through a non-canonical internal seed interaction.
Since the early 1980s remarkable progress has been made in understanding the role of the HER2 locus in carcinogenesis, but many details of its regulatory network are still elusive. We recently reported the finding of 367 new human microRNA (miRNA) genes of which one, mir-4728, is encoded in an intron of the HER2 gene. Here, we confirm that the HER2 oncogene is a bi-functional locus encoding the membrane receptor and a functional miRNA gene. We further show that miR-4728-3p has alternative functionalities depending on the region used for interaction with its target; the canonical seed between nucleotides 2-8 or a novel, more internal seed shifted to nucleotides 6-12. Analysis of public data shows that this internal seed region, although rare compared to the far more abundant canonical 2-8 seed interaction, can also direct targeted down-regulation by other miRNAs. Through the internal seed, miR-4728-3p regulates expression of estrogen receptor alpha, an interaction that would have remained undetected if classic rules for miRNA-target interaction had been applied. In summary, we present here an alternative mode of miRNA regulation and demonstrate this dual function of the HER2 locus, linking the two major biomarkers in breast cancer.
BioCare, Strategic Cancer Research Program, Lund, Sweden; Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Inga
I
Newie
BioCare, Strategic Cancer Research Program, Lund, Sweden; Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Rolf
R
Søkilde
Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Helena
H
Persson
Department of Pathology, Skåne University Hospital, Lund, Sweden.
Dorthe
D
Grabau
Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Natalia
N
Rego
Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Anders
A
Kvist
BioCare, Strategic Cancer Research Program, Lund, Sweden; Department of Laboratory Medicine, Lund University Cancer Center, Lund, Sweden.
Kristoffer
K
von Stedingk
BioCare, Strategic Cancer Research Program, Lund, Sweden; Department of Laboratory Medicine, Lund University Cancer Center, Lund, Sweden.
Håkan
H
Axelson
BioCare, Strategic Cancer Research Program, Lund, Sweden; CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden; Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Åke
Å
Borg
CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden; Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Johan
J
Vallon-Christersson
BioCare, Strategic Cancer Research Program, Lund, Sweden; CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden; Department of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
Carlos
C
Rovira
D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009711:Nucleotides / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D009711:Nucleotides; D018719:Erb-b2 Receptor Tyrosine Kinases; C506487:ESR1 protein, human; C000605129:MIRN4728 microRNA, human; C508053:ERBB2 protein, human