CDCA8 Contributes to the Development and Progression of Thyroid Cancer through Regulating CDK1.

Background: This study aims to reveal regulatory role of cell division cycle associated 8 (CDCA8) in thyroid cancer progression and metastasis. Methods: A series of experiments in vivo and in vitro were performed to explore the function of CDCA8 in thyroid cancer. Results: Immunohistochemical analysis showed that CDCA8 expression levels were upregulated in thyroid cancer tissues compared with normal tissues, and were statistically correlated with tumor stage. Results of in vitro loss-of-function assay showed that downregulation of endogenous expression of CDCA8 could significantly inhibit cell proliferation, colony formation, cell migration, and promote apoptosis. Thyroid cancer cells lacking CDCA8 expression also had reduced tumorigenicity in vivo. Further, results of preliminary mechanistic exploration showed that CDK1 may be a potential downstream molecule of CDCA8 in regulating thyroid cancer progression. We subsequently confirmed that CDK1 itself exerted a significant regulatory function in thyroid cancer by loss- and gain-of-function experiments. Moreover, overexpression of CDK1 could weaken the tumor suppressive effect caused by CDCA8 knockdown. Conclusions: CDCA8 functions as an oncogene in thyroid cancer, and CDCA8 knockdown suppresses cancer development in vitro and in vivo. Additionally, CDK1 was further identified as a potential target of CDCA8 in thyroid cancer.

F12 as a reliable diagnostic and prognostic biomarker associated with immune infiltration in papillary thyroid cancer.

OBJECTIVE: To explore the function of coagulation factor XII (F12) in papillary thyroid cancer (PTC). MATERIALS AND METHODS: We assessed F12 expression and its relationship with overall survival (OS) in various cancers using TIMER and TISIDB databases. Further, we evaluated the mRNA and protein expression levels of F12 in PTC via different bioinformatics tools. The receiver operating characteristic (ROC) curve was applied to determine the diagnostic value of F12 in PTC. Then, the Kaplan-Meier plotter and Cox regression analyses were performed to examine the prognostic significance of F12. The possible mechanism of F12 in PTC was investigated through enrichment analyses. Finally, the correlation between F12 expression and immune cell infiltration was analyzed using TCGA data. RESULTS: This study revealed the clinical significance of F12 in various cancers. Higher mRNA (P <0.001) and protein expressions of F12 were observed in PTC compared with normal tissues. Besides, F12 expression exhibited high diagnostic performance in PTC and its overexpression served as an independent predictor for the poor OS (P <0.05). Enrichment analyses results showed that F12 was mainly involved in metabolism-associated pathways. Additionally, F12 expression was significantly linked to immune cell infiltration levels, especially macrophage infiltration. CONCLUSIONS: F12 might be a reliable diagnostic and prognostic biomarker for PTC. Moreover, F12 expression might affect the OS of PTC patients via regulating metabolic pathways.

Trivalent methylated arsenic metabolites induce apoptosis in human myeloid leukemic HL-60 cells through generation of reactive oxygen species.

Arsenic trioxide (As2O3) has remarkable therapeutic efficacy against leukemia. However, after As2O3 biotransformation, the role of arsenic metabolites in the clinical efficacy against leukemia still needs to be elucidated. Therefore, to explore the contribution of trivalent methylated arsenicals in the therapeutic effects, we investigated and compared the effects of arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on HL-60 cells. Methylated arsenic species MMA(III) and DMA(III) showed potentially reduced cell survival with IC50 values of 3 and 2 µM, respectively. We found that methylated metabolites caused apoptosis through oxidative stress and loss of mitochondrial membrane potential. Furthermore, we found that the caspase-9 and -3 were markedly activated by exposure to methylated metabolites, with cleavage of poly-ADP ribose polymerase (PARP). Conversely, cellular apoptosis, generation of ROS, activation of caspase-3, -9 as well as PARP cleavage were significantly attenuated by pretreatment with an antioxidant, N-acetylcysteine (NAC). DNA damage was also markedly observed in HL-60 cells exposed to either MMA(III) or DMA(III), while iAs(III) did not show any relevant effects in HL-60 cells. Likewise, phosphorylation of the histone H2A variant (γ-H2AX), a biomarker of DNA damage, significantly occurred in cellular nuclei following exposure to two methylated species, which was reduced in the presence of NAC, suggesting that the induction of DNA damage was predominantly caused by the two metabolites via oxidative stress. In conclusion, we suggest that arsenic intermediate metabolites; MMA(III) and DMA(III) might prove to be of clinical relevance in future as such approaches may help in the treatment of leukemia and other types of cancers.