Coordinate Suppression of ERBB2 and ERBB3 by Enforced Expression of Micro-RNA miR-125a or miR-125b*

By G. Scott, A. Goga, D. Bhaumik, C. Berger, C. S. Sullivan, C. Benz. Journal of Biological Chemistry, 2007

671 citations recorded by the source corpus.

Deregulation of micro-RNAs (miRNAs) is emerging as a major aspect of cancer etiology because their capacity to direct the translation and stability of targeted transcripts can dramatically influence cellular physiology. To explore the potential of exogenously applied miRNAs to suppress oncogenic proteins, the ERBB oncogene family was chosen with a bioinformatics search identifying targeting seed sequences for miR-125a and miR-125b within the 3′-untranslated regions of both ERBB2 and ERBB3. Using the human breast cancer cell line SKBR3 as a model for ERBB2 and ERBB3 dependence, infection of these cells with retroviral constructs expressing either miR-125a or miR-125b resulted in suppression of ERBB2 and ERBB3 at both the transcript and protein level. Luciferase constructs containing the 3′ 3′-untranslated regions of ERBB2 and ERBB3 demonstrated ∼35% less activity in miR-125a- and miR-125b-expressing cells relative to controls. Additionally, phosphorylation of ERK1/2 and AKT was suppressed in SKBR3 cells overexpressing either miR-125a or miR-125b. Consistent with suppression of both ERBB2 and ERBB3 signaling, miR-125a-or miR-125b-overexpressing SKBR3 cells were impaired in their anchorage-dependent growth and exhibited reduced migration and invasion capacities. Parallel studies performed on MCF10A cells demonstrated that miR-125a or miR-125b overexpression produced only marginal influences on the growth and migration of these non-transformed human mammary epithelial cells. These results illustrate the feasibility of using miRNAs as a therapeutic strategy to suppress oncogene expression and function.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0c5a4b0774c10184d5a8baf7ddfc83c38c406f3b

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Citations in the corpus

MicroRNA expression profiling in prostate cancer. (2007, background): “Of the differentially expressed miRNAs detected in this study, the let-7 family has been shown to target the RAS oncogene (22), miR-16 to repress the antiapoptotic factor BCL2 (21), and miR-125a and miR-125b to suppress the oncogenes ERBB2 and ERBB3 ( 47 ).”
MicroRNAs in development and disease. (2011, background): “Meanwhile, miR-125a inhibits cell proliferation and migration via targeting the RNA-binding protein HuR (224), and ErbB2 and ErbB3 family members of the EGFR (539).”
MicroRNA signatures in human ovarian cancer. (2007, background): “Using the DianaTarbase,(6) we looked for confirmed targets of some of the most significant miRNAs resulting from our analyses, finding some interesting data: ERBB2 and ERBB3 receptors, for example, are targeted by miR-125 (32); miR101 , down-modulated in ovarian carcinoma, has been shown targeting t”
Modulation of miR-155 and miR-125b Levels following Lipopolysaccharide/TNF-α Stimulation and Their Possible Roles in Regulating the Response to Endotoxin Shock1 (2007, background): “Taking into account that LPS stimulation also results in the activation of the Tpl2/ERK1/2 pathway, which is needed to permit the transport of nuclear TNF- mRNAs toward the cytoplasm and thus allow their translation (9), the physiological signification of down-regulating miR-125b levels upon LPS cha”
Salivary microRNA: Discovery, Characterization, and Clinical Utility for Oral Cancer Detection (2009, background): “Through transient transfection studies, miR-125a along with it homologue miR-125b, have been shown to reduce ERBB2 and ERBB3 oncogenic protein levels in SKBR3 cells, a human breast cancer cell line (32).”
Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer. (2017, background): “In addition, both of these miRNAs have been reported to be tumor suppressors [24,25].”
MicroRNA function in cancer: oncogene or a tumor suppressor? (2009, background): “In addition, SKBR3 cells overexpressing miR-125a and miR-125b exhibited decreased cell growth, migration, and invasion associated with decreased levels of pERK1/2 and p-AKT [72].”
MicroRNAs in cancer: small molecules with a huge impact. (2009, background): “Conversely, downregulated microRNAs, as miR-125b and miR205, regulate oncogenes as tyrosine kinase receptors HER-2 and HER-3, respectively.(21,22) Ectopic expression of miR-205 in a breast cancer cell line decreases proliferation and improves the responsiveness to tyrosine kinase inhibitors as gefit”
A SNP in a let-7 microRNA complementary site in the KRAS 3′UTR Increases Non-Small Cell Lung Cancer Risk (2008, background): “For example, SNPs in miRNAs important in cancer have been identified; mir-125a , shown to be altered in breast cancer (5, 6), has a variant allele at a SNP in the mature miRNA sequence that decreases expression (7).”