Abstract
Anaplastic thyroid carcinoma (ATC) responds for the majority of death of thyroid carcinoma and often causes chemotherapy resistance. We investigated the influence of circEIF6 (Hsa_circ_0060060) on the cisplatin-sensitivity in papillary thyroid carcinoma (PTC) and ATC cells, and explored its regulation to downstream molecules miR-144-3p and Transforming Growth Factor α (TGF-α). Differentially expressed circRNAs in PTC were analyzed using the GSE93522 data downloaded. Expressions of circEIF6, miR-144-3p, TGF-α, autophagy-related proteins and apoptosis-related proteins were determined using qRT-PCR or western blot. RNA pull-down assay and dual luciferase report assay were applied to reveal the target relationships. Autophagy marker LC3 and cell proliferation marker ki67 were evaluated by immunofluorescence and immunohistochemistry. Cell viability was evaluated with MTT assay and cell apoptosis was assessed by flow cytometric analysis. CircEIF6, could promote autophagy induced by cisplatin, thus inhibiting cell apoptosis and enhancing the resistance of PTC and ATC cells to cisplatin. Has-miR-144-3p was the target of circEIF6 and was regulated by circEIF6. Besides, circEIF6 promoted autophagy by regulating miR-144-3p/TGF-α axis, enhancing the cisplatin-resistance in PTC and ATC cells. CircEIF6 promoted tumor growth by regulating miR-144-3p/TGF-α and circEIF6 knock-down enhanced cisplatin sensitivity in vivo. CircEIF6 could provide a target for therapy of cisplatin-resistance in thyroid carcinoma.
Highlights
Thyroid carcinoma is a common cancer, which can be roughly divided into well-differentiated thyroid carcinoma including papillary and follicular thyroid carcinoma, anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma (MTC) [1]
To further confirm the finding from bioinformatics, the circEIF6 expressions were detected in ATC tissues and both in papillary thyroid carcinoma (PTC) and ATC cells
Result of qRT-PCR proved that circEIF6 was overexpressed in ATC tissues and both in ATC and PTC cells (TPC1 and BHT101 cells) compared with para-carcinoma tissues and normal thyroid cells (HTori3), respectively (Figure 2A and 2B, P < 0.05)
Summary
Thyroid carcinoma is a common cancer, which can be roughly divided into well-differentiated thyroid carcinoma including papillary and follicular thyroid carcinoma, anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma (MTC) [1]. ATC is an orphan disease with high fatality rate and the effective treatment is not available at present. These cancers are treated with surgery, radiotherapy, chemotherapy, target therapy, or multimodal therapy [2]. Due to the undifferentiated phenotype and its aggressive nature of ATC, resistance to conventional treatments such as radiotherapy and chemotherapy, was often observed in the patients with ATC [6], including cisplatin-resistance [7]. The patients with ATC have a very poor prognosis
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