sphingosine-kinase and Carcinoma--Papillary

Accumulating evidences have emphasized the essential roles of differentially expressed miRNAs in papillary thyroid cancer (PTC) and follicular thyroid carcinoma (FTC) progression. MiR-128 has been reported to be down-regulated in multiple cancers to restrain tumor growth. However, the role of miR-128 in the development of PTC and FTC and the underlying mechanism remain to be unclear. In this present study, the results indicated that miR-128 expression was markedly down-regulated in PTC and FTC tissues and various thyroid carcinoma cell lines. Functional analysis indicated that over-expression of miR-128 suppressed PTC and FTC cancer cell growth, induced apoptosis and cell cycle arrest in G0/G1 phase. In addition, miR-128 over-expression markedly inhibited cancer cell migration and invasion. However, the processes above were reversed by silencing miR-128 expressions in thyroid tumor cells. Following, we characterized sphingosine kinase-1 (SPHK1) as a direct target of miR-128 that interacted with the 3'-untranslated region (UTR) of SPHK1, and the results were confirmed by using luciferase-reporter assay. We also observed that SPHK1 expression was decreased and negatively correlated with miR-128 expression in PTC and FTC tissues clinically. Importantly, ectopic expression of SPHK1 significantly abrogated the tumor-suppressive effect induced by miR-128, as supported by the reduced apoptosis, while the enhanced proliferation and metastasis. Finally, over-expressing miR-128 apparently reduced the tumor growth rate and tumor weight in vivo using xenograft tumor model, accompanied with a remarkable decrease of SPHK1. Thus, our study illustrated that miR-128 might be a tumor suppressor microRNA that played an essential role in thyroid carcinoma progression.

Topics: 3' Untranslated Regions; Animals; Apoptosis; Carcinoma, Papillary; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Phosphotransferases (Alcohol Group Acceptor); Thyroid Gland; Thyroid Neoplasms

Sphingolipid metabolites are emerging as key signaling molecules in cancer. Sphingosine kinase 1 is up-regulated in many different types of human malignancies and plays a crucial role in cancer development and progression. The utility of sphingosine kinase 1 to act as a predictive biomarker in thyroid cancer remains unclear.. Sphingosine kinase 1 expression was evaluated using immunohistochemical staining in 110 formalin-fixed, paraffin-embedded papillary thyroid carcinoma tissue samples.. Sphingosine kinase 1 expression in papillary thyroid carcinoma tissue was significantly higher than in nodular goiter (p<0.001) or normal thyroid (p<0.001) tissue. Sphingosine kinase 1 was observed in the cytoplasm of tumor cells. Thirty-four (30.9%) of 110 papillary thyroid carcinomas exhibited high sphingosine kinase 1 expression, that was significantly associated with tumor multiplicity (p=0.004), extrathyroidal extension (p=0.013), presence of lymph node metastasis (p<0.001), and number of metastatic lymph nodes (p=0.042). In addition, high sphingosine kinase 1 expression was the only independent predictor of lymph node metastasis (p<0.001).. Sphingosine kinase 1 is involved in papillary thyroid carcinoma development and progression and can serve as a potential biomarker predictive of lymph node metastasis.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Disease Progression; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Phosphotransferases (Alcohol Group Acceptor); Predictive Value of Tests; Prognosis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tissue Array Analysis; Up-Regulation; Young Adult

The oncogenic roles of sphingosine kinase 1 (SphK1) in various cancers, including thyroid cancer, have been well demonstrated. However, the microRNAs (miRNAs) associated with the oncogenic roles of SphK1 remain largely unknown.. Global gene and miRNA expression in TPC1-Vector and TPC1-SphK1 cells was analyzed using digital gene expression (DGE) analysis and small RNA-seq, respectively. miRNA-mRNA interactions were explored by microT-CDS, and the predicted networks were visualized using CytoScape. In this study, we found that overexpression of SphK1 differentially regulates the expression of 46 miRNAs and 506 mRNAs in papillary thyroid cancer (PTC) TPC1 cells. Combining bioinformatics predictions of mRNA targets with DGE data on mRNA expression allowed us to identify the mRNA targets of deregulated miRNAs. The direct interaction between miR-144-3p and FN1, which mediates the pro-invasive role of SphK1 in PTC cells, was experimentally validated.. Our results demonstrated that SphK1 overexpression drives a regulatory network governing miRNA and mRNA expression in PTC cells. We also demonstrated the roles played by miR-144-3p and FN1 in mediating the oncogenic function of SphK1, which enhanced the understanding of the etiology of PTC.

Topics: Carcinoma; Carcinoma, Papillary; Gene Expression Profiling; Humans; MicroRNAs; Oncogenes; Phosphotransferases (Alcohol Group Acceptor); Thyroid Cancer, Papillary; Thyroid Neoplasms