microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Abstract

As an inhibitor of TGF-β signaling, SMAD7 was reported to play dual roles in breast cancer development and progression. It inhibited the cancer metastasis by blocking epithelial-mesenchymal transition, however, litter studies focused on its role in other cancer processes. In this study, miR-497 expression was found inversely correlated with SMAD7 expression in breast cancer tissues. Bioinformatics analyses defined a potential miR-497 response element within 3' untranslated region of SMAD7 that was validated in reporter gene experiments. Enforced miR-497 expression, accompanied with SMAD7 reduction, suppressed MDA-MB-231 and MCF-7 breast cancer cell growth by MTT and invasion assay, and, induced the S phase arrest detected by flow cytometry. Furthermore, upregulated miR-497 expression by mimics treatment significantly suppressed the tumor growth in the orthotopic nude mouse models. Finally, high expression of miR-497 conferred a better prognosis, indicated by Kaplan-Meier test, especially in HER2 overexpression and triple-negative breast cancer (TNBC). Taken together, our results identified the proliferation promoting role of SMAD7 in breast cancer and therefore established the regulations of SMAD7 in breast cancer by miR-497 through a posttranscriptional mechanism. Moreover, miR-497 might be deemed as a novel potential therapeutic target for the HER2 positive and TNBC in future.

MicroRNAs in the prognosis of triple-negative breast cancer

“…Twelve studies reported adjusted HRs; the models described in these studies included covariates such as age, tumor site, grade, or disease stage (Table 1). In the included articles, increased expression of miR-27a/b, [15,16,18,19] miR-34b, [20] miR-210, [14] miR-125b, [21] miR-655, [21] miR-21, [22,23] miR-18b, [24] miR-103, [24] miR-107, [24] miR-652, [24] miR-301a, [25] miR-30e, [15] miR-214 [26] and miR-454 [17] decreased expression of miR-155, [15,21,27,28] miR-16, [21] miR-374a/b, [19,21] miR-497, [15,29] miR-493, [15] miR-185, [30] miR-26a, [31] miR-126-3p, [19] miR-218-5p [19] and miR-361-5p [32] were associated with poor prognosis in TNBC. Among these miRs, 6 (miR-155, miR-21, miR-27a/b, miR-374a/b, miR-210, and miR-454) were reported by at least 2 studies (Table 2).…”

MicroRNA-497 inhibits cellular proliferation, migration and invasion of papillary thyroid cancer by directly targeting AKT3

“…For instance, previous studies have revealed that miR-497 is downregulated in breast cancer tissues and cell lines ( 27 – 29 ). Low expression levels of miR-497 indicate a poorer prognosis for patients with breast cancer ( 30 ). Wang et al ( 31 ) reported that miR-497 expression levels are reduced in colorectal cancer and correlate closely with clinical stage and lymph node metastases.…”

MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4

“…Relationships between miRNAs dysregulation and human disease are investigated from variable disease. MiR-497, being one of miR-15 family members, is mainly identified as a tumor suppressor in various cancers, such as hepatocellular carcinoma [5], osteosarcoma [6–7] and breast cancer [8]. Recently, miR-15 family members were identified as novel regulators in cardiac hypertrophy and fibrosis by inhibition of the TGFβ pathway [9].…”