Abstract
In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.
Highlights
Thyroid carcinomas are the most common cancer of the endocrine system [1]
The microRNA expression profiles were first determined for 40 medullary thyroid carcinoma (MTC), corresponding to 14 HMTC with germinal RET mutations, and 26 SMTC with (11 cases) or without (15 cases) somatic RET mutations
We found that the miR-375 expression gradually increased with disease progression (Figure 1C), even after an adjustment for the percentage weight based on the estimation of the C-cell content by calcitonin and haematoxylin staining
Summary
Thyroid carcinomas are the most common cancer of the endocrine system [1] Among these tumors, medullary thyroid carcinoma (MTC) is a rare calcitonin-producing tumor, which arises from thyroid gland parafollicular C cells and accounts for 3-8% of all thyroid carcinomas [2]. Most cases of MTC are sporadic (SMTC), whereas the remaining cases are due to hereditary forms (HMTC), caused by germline activating mutations of the RET protooncogene [3]. Surgery is the treatment of choice for MTC, consisting in total thyroidectomy and lymph node dissection. Despite surgery, 50% of patients with MTC relapse [6]. Vandetanib has been recently approved for treatment of patients with recurrent or metastatic unresectable MTC [9, 10]
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