miR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer

Abstract

IntroductionERBB3, one of the four members of the ErbB family of receptor tyrosine kinases, plays an important role in breast cancer etiology and progression. In the present study, we aimed to identify novel miRNAs that can potentially target ERBB3 and their biological functions.MethodThe expression levels of miR-143/145 and target mRNA were examined by relative quantification RT-PCR, and the expression levels of target protein were detected by Western blot. We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Luciferase reporter plasmids were constructed to confirm direct targeting. Furthermore, the biological consequences of the targeting of ERBB3 by miR-143/145 were examined by cell proliferation and invasion assays in vitro and by the mouse xenograft tumor model in vivo.ResultsWe identified an inverse correlation between miR-143/145 levels and ERBB3 protein levels, but not between miR-143/145 levels and ERBB3 mRNA levels, in breast cancer tissue samples. We identified specific targeting sites for miR-143 and miR-145 (miR-143/145) in the 3’-untranslated region (3’-UTR) of the ERBB3 gene and regulate ERBB3 expression. We demonstrated that the repression of ERBB3 by miR-143/145 suppressed the proliferation and invasion of breast cancer cells, and that miR-143/145 showed an anti-tumor effect by negatively regulating ERBB3 in the xenograft mouse model. Interestingly, miR-143 and miR-145 showed a cooperative repression of ERBB3 expression and cell proliferation and invasion in breast cancer cells, such that the effects of the two miRNAs were greater than with either miR-143 or miR-145 alone.ConclusionTaken together, our findings provide the first clues regarding the role of the miR-143/145 cluster as a tumor suppressor in breast cancer through the inhibition of ERBB3 translation. These results also support the idea that different miRNAs in a cluster can synergistically repress a given target mRNA.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-220) contains supplementary material, which is available to authorized users.

Predicting associations between microRNAs and target genes in breast cancer by bioinformatics analyses

“…miR-100 has been reported to inhibit tumorigenesis in oral squamous cell carcinoma, ovarian cancer and breast cancer by interfering with proliferation and survival signaling (24)(25)(26). Additionally, miR-143 and miR-145 have been observed to synergistically regulate v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3 to suppress cell proliferation and invasion in breast cancer (27). Moreover, miR-197 and miR-21 were noted to be prominently upregulated in male breast cancer (28).…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…90,91 Bischoff et al found that miR-148b, miR-149, miR-326, and miR-520a-3p directly reduced HER3 mRNA and protein levels. 85 Yan et al 92 provided insights into the role of the miR-143/145 cluster as a tumor suppressor in breast cancer; that is, they suggested that it inhibits HER3 translation in vivo. Yu et al 93 suggested that miR-148a attenuates angiogenesis by inhibiting HER3.…”

Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1

“…3 Emerging evidence has shown that miRNAs are involved in cancer initiation and progression. 4 MiR-145 has been reported as an important tumor suppressor gene in ovarian carcinoma, 5,6,7 malignant pleural mesothelioma, 8 breast cancer, 9 pancreatic cancer, 10,11 liposarcoma, 12 colorectal cancer, 13,14,15,16 neuroblastoma, 17 breast cancer, 18,19,20,21 esophageal cancer, 22 bladder cancer, 23,24 urothelial cancer, 25 prostate cancer, 26,27 gastric cancer, 28 and head and neck cancer, 29 and other types. MiR-145 was also implicated in the progression of NSCLC; 30,31,32 however, its exact mechanism is not well established.…”