CircNEK6 promoted the progression of thyroid cancer through up-regulating FZD8 and activating Wnt signaling pathway by targeting miR-370-3p.

Considering the resistance of papillary thyroid cancer (PTC) 131 I therapy, this study was designed to find a solution at molecular respect. By probing into lncRNA-NEAT1/miR-101-3p/FN1 axis and PI3K/AKT signaling pathway, this study provided a potential target for PTC therapy. 131 I-resistant cell lines were established by continuous treatment with median-lethal 131 I. Bioinformatic analysis was applied to filtrate possible lncRNA/miRNA/mRNA and related signaling pathway. Luciferase reporter assay was employed in the verification of the targeting relationship between lncRNA and miRNA as well as miRNA and mRNA. MTT assay and flow cytometry assay were performed to observe the impact of NEAT1/miR-101-3p/FN1 on cell viability and apoptosis in radioactivity iodine (RAI)-resistant PTC cell lines, respectively. Western blot and qRT-PCR were conducted to measure the expression of proteins and mRNAs in RAI-resistant PTC tissues and cells. Meanwhile, endogenous PTC mice model were constructed, in order to verify the relation between NEAT1 and RAI-resistance in vivo. NEAT1 was over-expressed in RAI-resistant PTC tissues and cell lines and could resist RAI by accelerating proliferation accompanied by suppressing apoptosis. It indicated that overexpressed NEAT1 restrained the damage of RAI to tumor in both macroscopic and microcosmic. Besides, NEAT1/miR-101-3p exhibited a negative correlation by directly targeting each other. The expression of FN1, an overexpressed downstream protein in RAI-resistance PTC tissues, could be tuned down by miR-101-3p, while the decrease could be restored by NEAT1. In conclusion, both in vitro and in vivo, NEAT1 suppression could inhibit 131 I resistance of PTC by upregulating miR-101-3p/FN1 expression and inactivated PI3K/AKT signaling pathway both in vitro and in vivo.

A vast amount of evidence indicates that long non-coding RNAs (lncRNAs) are involved in cancer. Previous studies have indicated that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) is aberrantly expressed in lung cancer, pancreatic ductal adenocarcinoma and hepatocellular carcinoma. However, the role of DGCR5 in papillary thyroid carcinoma (PTC) has remained elusive. In the present study, it was revealed that DGCR5 was significantly downregulated in PTC tissues compared with that in adjacent normal tissues. Through functional experiments, it was demonstrated that ectopic overexpression of DGCR5 markedly suppressed PTC cell growth and invasion. A bioinformatics analysis suggested that DGCR5 binds to microRNA (miR)-2861. A total of 5 putative binding sites for miR-2861 were identified in DGCR5, and a luciferase reporter assay confirmed the direct interaction between DGCR5 and miR-2861. Furthermore, reverse transcription-quantitative polymerase chain reaction analysis indicated that ectopic overexpression of DGCR5 led to a decreased expression of miR-2861 in PTC cells and miR-2861 mimic transfection caused a downregulation of DGCR5. miR-2861 level was upregulated in PTC tissues compared with adjacent tissues and negatively correlated with DGCR5 level. In addition, rescue experiments indicated that ectopic expression of miR-2861 reversed the effects of DGCR5 overexpression on PTC cell proliferation and invasion. Taken together, the present results demonstrated that DGCR5 inhibits PTC progression via sponging miR-2861, indicating DGCR5 may serve as a therapeutic target.

BackgroundThyroid carcinoma (TC) has been a global issue for its rapid increasing incidence worldwide. Although most TC was not so aggressive with a good prognosis, treatment against anaplastic TC was relatively limited and the mechanisms are not well elucidated yet.MethodsTC cell lines (IHH4 and TPC‐1) were used. Flow cytometry was used to identify the surface marker of M2‐like tumor‐associated macrophages (TAMs) from cell culture. Quantitative real‐time polymerase chain reaction, western blot analysis, immunostaining, and immunohistochemistry were used to detect the expression of Wnt1, Wnt3a, components of Wnt/β‐catenin pathway, and proliferation/epithelial–mesenchymal transition (EMT)‐related proteins. Alkaline phosphatase activity assay, colony formation assay, and transwell assay were used to examine the roles of Wnt1, Wnt3a, and β‐catenin pathway in cell dedifferentiation, proliferation, migration, and invasion of TC cells, respectively. Subcutaneous tumor growth was monitored in nude mice.ResultsCoculture with M2‐like TAMs facilitated dedifferentiation, proliferation, migration, and invasion in TC cells. EMT and proliferation‐related proteins were also promoted in cocultured TC cells. The level of Wnt1 and Wnt3a was increased in the coculture system. Block of Wnt1 or Wnt3a suppressed malignant behaviors in cocultured tumor cells. Furthermore, Wnt1 or Wnt3a knockdown inhibited Wnt/β‐catenin signaling pathway, and suppressed EMT and proliferation‐related signals in cocultured tumor cells. Knockdown of Wnt1 or Wnt3a inhibited tumor growth in xenograft model.ConclusionM2‐like TAMs promoted dedifferentiation, proliferation, and metastasis of TC by Wnt1 and Wnt3a secretion and ensuing β‐catenin activation.

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Thyroid carcinoma is primarily treated by surgery combined with radioactive 131iodine (131I) treatment; however, certain patients exhibit resistance to 131I treatment. Previous research indicated that nuclear factor-κB (NF-κB) was associated with resistance to 131I in cancer cells. The present study aimed to investigate the effects of NF-κB on 131I uptake and apoptosis in thyroid carcinoma cells. TPC-1 and BCPAP cell lines were employed as research models in the present study, and the expression of NF-κB was inhibited by RNA interference (RNAi). The ability of TPC-1 and BCPAP cells to uptake 131I was measured and the cell viability was detected by an MTT assay. Finally, the expression of the apoptosis-associated proteins X-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and caspase-3 in TCP-1 and BCPAP cells was determined by western blotting. Western blotting results demonstrated that the expression levels of NF-κB in TPC-1 and BCPAP cells were successfully downregulated by RNAi (P<0.05), while analysis of 131I uptake revealed no significant alterations in the 131I uptake ability of cells following RNAi (P>0.05). MTT experiments demonstrated that the inhibition of NF-κB expression in combination with radiation (131I treatment) led to a marked reduction in cell viability (P<0.05). Furthermore, western blot analysis revealed that the inhibition of NF-κB expression downregulated the expression levels of XIAP and cIAP1 (P<0.05), while the expression levels of caspase-3 were upregulated, indicating that the observed reduction in cell viability following NF-κB inhibition may be due to an increased level of apoptosis. Although NF-κB inhibition did not affect the 131I uptake of thyroid cancer cells, this inhibition may increase the apoptotic effects of radioactive 131I.

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