Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma

Abstract

Context: Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model. Methodology:Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined. Results:Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P Ͻ .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis. Conclusions:Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. (J Clin Endocrinol Metab 98: E196 -E205, 2013)

MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer

“…Elucidation of sensitive biomarkers allowing for identification of such patients would significantly facilitate the treatment and monitoring of their health status. In PTC, miR-146b promotes cell migration and invasion and is associated with an increased risk of recurrence (50). Recently, it has been shown that PTC cases with overexpression of miR-146b-5p and miR-21 had significantly poorer disease-free survival rates.…”

An update on molecular biology of thyroid cancers

“…The candidate targets of these miRNAs could be p27kip1, a cell cycle progression inhibitor, and KIT, a receptor tyrosine kinase that plays important roles in cell growth and differentiation [143,148]. Interestingly, high expression levels of miR-146b were found to be correlated with lower overall survival and with the development of drug resistance [149]. A recent study demonstrated that miR-146b could cause thyroid cancer development by regulating TGF-␤ signaling, although the mechanisms of miR-146b-mediated tumor behavior in PTC are largely unknown [150].…”

“…There are several studies reporting overexpression of miRNAs including miR-222, miR-221, and miR-146b in PTC and these miRNAs may be of diagnostic potential [143][144][145][146][147][148][149][150][151]. In a recent study, a panel of seven miRNAs was used in thyroid FNAB samples [223].…”

Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

“…Different miRNA expression profiles have been observed in ATC, with elevated expressions of miR-17, miR-221, miR-222 and decreased let-7, miR-30 and miR-29 expressions as compared to normal thyroid tissue (Mancikova et al 2015). Moreover, the differential expression of some of these and other miRNAs is associated with TC aggressiveness, epithelial-mesenchymal transition, vascular invasion, lymph node dissemination, risk of recurrence and dedifferentiation, including increased expression of miR-9, miR-21 and miR-146b, HMGB1-induced miR-221 and miR-222 upregulation and miR-204 downregulation (Braun et al 2010, Mardente et al 2012, Chou et al 2013, Cancer Genome Atlas Research Network 2014, Guo et al 2015, Sondermann et al 2015. By specifically downregulating hNIS expression, miR-339 and miR-146b are identified to promote TC dedifferentiation and RAI resistance (Lakshmanan et al 2015, Riesco-Eizaguirre et al 2015.…”