Epigenetic regulation of papillary thyroid carcinoma by long non-coding RNAs.

Thyroid cancer is the most common primary endocrine malignancy with papillary thyroid carcinoma (PTC) its most common subtype. The jump in diagnoses over last many years has prompted re-assessment of molecularly targeted therapies and the discovery of novel targets. Long non-coding RNAs (lncRNAs) are increasingly being assessed for their expression in various PTC models. Interestingly, in addition to cell line models, a large proportion of the reported studies have evaluated lncRNA levels in PTC patient samples providing an immediate clinical relevance of their findings. While most lncRNAs either promote or suppress PTC pathogenesis, data on individual lncRNAs is not very clear. As expected, lncRNAs function in PTC through sponging of microRNAs as well as modulation of several signaling pathways. The process of epithelial-mesenchymal transition and the PI3K/Akt and wnt signaling pathways have emerged as the primary targets of lncRNAs in PTC. This comprehensive review discusses all the information that is available on lncRNAs in PTC, ranging from in vitro and in vivo findings to the possible role of lncRNAs as diagnostic and/or prognostic biomarkers.

LncRNA SNHG14 Sponges miR-206 to Affect Proliferation, Apoptosis, and Metastasis of Hepatocellular Carcinoma Cells by Regulating SOX9.

OBJECTIVE: To explore how lncRNA SNHG14 modulates the biological features of hepatocellular carcinoma (HCC) cells by regulating SOX9 via mediating miR-206. METHODS: HCC tissues were collected to perform the quantitative reverse transcriptase polymerase chain reaction to determine the expressions of SNHG14, miR-206, and SOX9. HCC cell line SMCC7721 was selected for co-transfection by si-SNHG14/miR-206 inhibitor/si-SOX9, followed by the measurement of cell proliferation using Cell Count Kit-8 (CCK-8) assay and clone formation assay. The migration and invasion were evaluated by wound healing test and Transwell assay. The apoptotic rate was determined by flow cytometry. Levels of the apoptosis-related proteins were measured through Western blotting. RESULTS: SNHG14 and SOX9 were up-regulated in HCC tumor tissues compared with adjacent normal tissues, with decreased miR-206 expression. Moreover, SNHG14 expression was significantly associated with the TNM stage, lymphatic metastasis, and histological differentiation of HCC patients. Besides, inverse correlations between SNHG14 and miR-206, as well as between miR-206 and SOX9, were noted. The dual luciferase reporter gene assay, RIP, and RNA pull-down experiments also revealed the targeting relationship between SNHG14 and miR-206 or between miR-206 and SOX9. Silencing SNHG14 and SOX9 inhibited the proliferation, invasion, and migration of HCC cells, with increased apoptosis, which was all abolished by silencing miR-206. CONCLUSION: Inhibition of SNHG14 suppresses SOX9 by up-regulating miR-206, to further inhibit the proliferation, migration, and invasion of HCC cells with the promoted apoptosis, which is a novel target for the treatment of HCC.

Mefloquine targets ß-catenin pathway and thus can play a role in the treatment of liver cancer.

The current study was designed and performed to investigate the effect of mefloquine on the proliferation and tumor formation potential of liver cancer stem cells. CD133 + HepG2 cells were identified using MACS and showed markedly higher tumor formation potential compared to the parental cells. The secondary tumors formed by CD133 + cells were markedly large in size and more in number compared to the parental cells. Mefloquine treatment of CD133 + HepG2 cells inhibited the proliferation selectively in concentration based manner. The rate of proliferation was inhibited to 82 and 12% in parental and CD133 + sphere forming cells, respectively on treatment with 10 µM concentration of mefloquine. The number of secondary tumors formed by primary tumors was decreased significantly on treatment with 10 µM mefloquine concentration. Treatment of the liver cancer stem cells with mefloquine markedly decreased the potential to undergo self-renewal at 10 µM concentration after 48 h. The results from western blot analysis showed significantly higher expression of cancer stem cell molecules ß-catenin and cyclin D1 in LCSCs. Treatment of the LCSCs with various concentrations of mefloquine reduced the expression levels of ß-catenin and cyclin D1. Administration of the CD133 + cell tumor xenografts in the mice led to the formation of large sized tumors in the control group. However, the tumor growth was inhibited significantly in the mice on treatment with 10 mg/kg doses of mefloquine after day 21. The tumor weight was significantly lower in the animals of mefloquine treatment group compared to the control group. Thus, mefloquine treatment inhibits self-renewal and proliferation potential of cells through targeting ß-catenin pathway.

Overexpression of microRNA-205-5p exerts suppressive effects on stem cell drug resistance in gallbladder cancer by down-regulating PRKCE.

Some microRNAs (miRs or miRNAs) have been reported to function as tumor suppressors in gallbladder cancer (GBC). However, the specific effect of miR-205-5p on GBC remains unclear. The objective of the present study was to unravel the effects of miR-205-5p on the drug resistance in GBC. For this purpose, the expression of miR-205-5p and protein kinase C ϵ (PRKCE) was quantified in the peripheral blood sample harvested from GBC patients and healthy volunteers. Then the relationship between miR-205-5p and PRKCE was validated. After isolating the GBC stem cells, ectopic expression and depletion experiments were conducted to analyze the effect of miR-205-5p and PRKCE on cell proliferation, drug resistance, apoptosis, and colony formation rate as well as the expression of apoptotic factors (Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and cleaved caspase 3). Finally, the mouse xenograft model of GBC was established to verify the function of miR-205-5p in vivo. Intriguingly, our results manifested that miR-205-5p was down-regulated, while PRKCE was up-regulated in peripheral blood samples and stem cells of patients with GBC. Moreover, miR-205-5p targeted PRKCE and negatively regulated its expression. The overexpression of miR-205-5p or silencing of PRKCE inhibited the drug resistance, proliferation, and colony formation rate while promoting apoptosis of GBC stem cells. Additionally, the overexpression of miR-205-5p attenuated drug resistance to gemcitabine but promoted the gemcitabine-induced cell apoptosis by inhibiting the PRKCE in vivo. Overall, an intimate correlation between miR-205-5p and PRKCE is a key determinant of drug resistance of GBC stem cells, thus, suggesting a novel miR-205-5p-based clinical intervention target for GBC patients.

Wnt/ß-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/ß-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of ß-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of ß-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/ß-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3ß, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/ß-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/ß-catenin along with its relation with other signaling pathways in the induction and progression of CCA.

Microarray Analysis of lncRNA and mRNA Reveals Enhanced Lipolysis Along With Metabolic Remodeling in Mice Infected With Larval Echinococcus granulosus.

Parasitic infection improves metabolic homeostasis in "western diet"-induced obesity through the regulation of adipogenesis. However, the underlying mechanism is not yet fully understood. Using microarray analysis, this study investigated the long non-coding RNA (lncRNA) and messenger RNA (mRNA) profiles of subcutaneous adipose tissues from mice infected with Echinococcus granulosus protoscoleces. A total of 1052 mRNA (541 upregulated, 511 downregulated) and 220 lncRNA (126 upregulated, 94 downregulated) transcripts were differentially expressed (fold change ≥2, P < 0.05) in the infected subcutaneous adipose tissues. When compared with the control group, the infected mice showed a decrease in adipose tissue mass and a reduction in adipocyte size. Indirect calorimetry revealed the change in the energy metabolism after infection, characterized by a lower CO2 production and O2 consumption, a sharp decline in carbohydrate oxidation, and a slight increase in fat oxidation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the parasitic infection reprogrammed a complex metabolic network. Notably, "lipoxygenase" and "arginine and proline metabolism" pathways were significantly upregulated while "glycolysis," "tricarboxylic acid cycle," "de novo lipogenesis," and "lipid droplet" pathways were dramatically downregulated. In addition, several key lncRNAs were associated with insulin resistance and adipocyte differentiation. Overall, the present study suggested that E. granulosus infection could enhance lipolysis. Thus, our findings provide novel insights into parasite-mediated metabolic homeostasis, and into the mechanism of hypertrophic adipocytes in obesity.