CASC15 promotes epithelial to mesenchymal transition and facilitates malignancy of hepatocellular carcinoma cells by increasing TWIST1 gene expression via miR-33a-5p sponging.

Long noncoding RNA cancer susceptibility candidate 15 (CASC15) facilitates progression of hepatocellular carcinoma (HCC) cells, but the molecular mechanisms remain unknown. CASC15 co-expressing genes were explored in the Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset. Putative co-expressing genes were analyzed by Gene Ontology and biological pathway enrichment analysis. CASC15 overexpression or knockdown and TWIST1 overexpression or knockdown in HCC cells was achieved by lentiviral transduction or plasmid transfection. Interaction between CASC15 and microRNA-33a-5p (miR-33a-5p) was verified by argonaute 2-RNA Immunoprecipitation (AGO2-RIP) and luciferase reporter assays. HCC cell malignancy was determined by cell proliferation, apoptosis, migration and invasion assays. Tumorigenicity was evaluated by xenograft assay. Epithelial-to-mesenchymal transition (EMT) of HCC cells was assessed by Western blot. TWIST1, sex-determining region Y-related high-mobility group box 4 (Sox4) and Versican were found as putative CASC15 co-expressing genes. CASC15 positively regulated TWIST1 gene expression as well as protein level of Sox4 and Versican in HCC cells. Positive correlation in expression between CASC15 and TWIST1 mRNA was verified in 42 pairs of HCC pathologic and adjacent tissue specimens. CASC15 upregulated TWIST1 gene expression in HCC cells by sponging miR-33a-5p. CASC15 promoted EMT in HCC cells by increasing N-cadherin and Vimentin protein level while decreasing that of E-cadherin through TWIST1. CASC15 facilitated HCC cell proliferation, migration and invasion while reducing cell apoptosis through TWIST1. CASC15 facilitated the tumorigenicity of HCC cells in vivo. a CASC15 could promote EMT and facilitate malignancy of HCC cells by increasing TWIST1 gene expression via miR-33a-5p sponging.

TUG1 confers cisplatin resistance in esophageal squamous cell carcinoma by epigenetically suppressing PDCD4 expression via EZH2.

BACKGROUND: Increasing evidence has suggested the involvement of long non-coding RNA taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in esophageal squamous cell carcinoma (ESCC) chemoresistance are still not well elucidated. In the present study, we investigate the functional role of TUG1 in cisplatin (DDP) resistance of ESCC and discover the underlying molecular mechanism. RESULTS: Our study revealed that TUG1 was up-regulated in DDP-resistant ESCC tissues and cells. High TUG1 expression was correlated with poor prognosis of ESCC patients. TUG1 knockdown improved the sensitivity of ECA109/DDP and EC9706/DDP cells to DDP. Moreover, TUG1 could epigenetically suppress PDCD4 expression via recruiting enhancer of zeste homolog 2. PDCD4 overexpression could mimic the functional role of down-regulated TUG1 in DDP resistance. PDCD4 knockdown counteracted the inductive effect of TUG1 inhibition on DDP sensitivity of ECA109/DDP and EC9706/DDP cells. Furthermore, TUG1 knockdown facilitated DDP sensitivity of DDP-resistant ESCC cells in vivo. CONCLUSION: TUG1 knockdown overcame DDP resistance of ESCC by epigenetically silencing PDCD4, providing a novel therapeutic target for ESCC.

Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway.

Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor-derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients.