MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib

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.

The biological functions of target genes in pan-cancers and cell lines were predicted by miR-375 microarray data from GEO database and bioinformatics

“…MiR-375 can directly target the matrix metalloproteinase 13 (MMP13), insulin-like growth factor-1 receptor (IGF-1R), zinc finger protein 36 ring finger protein 2 (ZFP36L2), Y box binding protein 1 (YBX1), and inositol-trisphosphate 3-kinase B (ITPKB) to inhibit SCC cell proliferation and migration [ 1 – 3 , 33 , 50 ]. In thyroid medullary carcinoma, miR-375 was also down-regulated and associated with metastasis possibly by targeting SEC23A [ 51 ]. MiR-375 was down-regulated in colorectal cancer (CRC) by inhibiting Bcl-2 pathway control of CRC tumor cells [ 52 ].…”

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition

“…Expression of target structures might serve as markers for the integration of TKI such as Vandetanib into standard treatment regimes of medulloblastoma. However, in other cancers microRNA expression patters are discussed as promising indicators of eligibility for patient treatment with Vandetanib [ 51 ].…”

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms

“…On the contrary, miRNA expression profiles in medullary thyroid carcinoma (MTC) have been evaluated in few studies (Nikiforova et al 2008, Abraham et al 2011, Mian et al 2012, Hudson et al 2013, Santarpia et al 2013, Gundara et al 2014, Pennelli et al 2015, Lassalle et al 2016, out of which only three evaluated the prognostic role of miRNAs in MTC. Abraham and coworkers 24:6 (Abraham et al 2011) evaluated the expression of four miRNAs (miR-183, miR 375, miR 9 and miR 9*) selected on the basis of their reported significance in other cancers.…”