ErbB2-intronic MicroRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling

Abstract

Although the role of the ErbB2/HER2 oncogene in cancers has been extensively studied, how ErbB2 is regulated remains poorly understood. A novel microRNA, mir-4728, was recently found within an intron of the ErbB2 gene. However, the function and clinical relevance of this intronic miRNA are completely unknown. Here, we demonstrate that mir-4728 is a negative regulator of MAPK signaling through directly targeting the ERK upstream kinase MST4 and exerts numerous tumor-suppressive properties in vitro and in animal models. Importantly, our patient sample study shows that mir-4728 was under-expressed in breast tumors compared with normal tissue, and loss of mir-4728 correlated with worse overall patient survival. These results strongly suggest that mir-4728 is a tumor-suppressive miRNA that controls MAPK signaling through targeting MST4, revealing mir-4728's significance as a potential prognostic factor and target for therapeutic intervention in cancer. Moreover, this study represents a conceptual advance by providing strong evidence that a tumor-suppressive miRNA can antagonize the canonical signaling of its host oncogene.

Coamplification of miR-4728 protects HER2 -amplified breast cancers from targeted therapy

“…We inhibited miR-4728-3p after transfection of MD-MB-361 and BT-474 cells with a specific pLV-hsa-miR-4728-3p locker plasmid or a scrambled vector control ( 38 ). As demonstrated in Fig.…”

Analysis of the miRNA Profiles of Melanoma Exosomes Derived Under Normoxic and Hypoxic Culture Conditions

“…miR-21 is embedded in a regulatory circuit with miR-4728, one of the miRNAs with increased exosomal levels under hypoxia. miR-4728 is encoded in an intron of the human epidermal growth factor receptor 2 (HER2) gene, a well-known oncogene in breast cancer (48). miR-4728 was identified as tumor suppressor in breast cancer antagonizing MAPK signaling.…”

HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5

“…Since mir-4728 has been suggested to regulate factors downstream of HER2 9 , we wanted to test if HER2 signalling could control PAPD5 and thus cause the observed downregulation of miR-21-5p upon blocking of miR-4728-3p. MicroRNA-4728 is a 5′ tailed half-mirtron with its 3′ end coinciding with the 5′ splice site of the HER2 exon 24 (NM_004448.3).…”

“…HER2 transcription simultaneously produces HER2 mRNA as well as mir-4728 to the point that expression of mir-4728 has been suggested to accurately mark HER2 status and to work as a non-invasive biomarker in HER2-positive breast and gastric cancer 7 . Among other functions, miR-4728-3p has been shown to modulate expression of oestrogen receptor alpha (ERα) 8 and may act as a negative feedback mechanism for HER2 signalling by regulating the MAPK pathway 9 .…”