Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14 ARF ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha-fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. Conclusion: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14 ARF and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. (HEPATOLOGY 2015;61:1603-1614 H epatocellular carcinoma (HCC) ranks as the fifth-most common cancer and the third cause of cancer-related mortality worldwide, mainly owing to its high rate of metastasis and recurrence.1 The recent identification of several oncogenes and tumor-suppressor genes has significantly deepened the understanding of the invasion and metastasis of HCC. 2 However, the effects of tumor progressionrelated genes often depend on the level of their protein products as well as their post-translational Abbreviations: 2D-LC-MS/MS, two-dimensional liquid chromatography coupled with tandem mass

Tumor hypoxia and hypoxia-related sorafenib resistance adversely affected the prognosis of HCC patients. Hypoxia-inducible factor (HIF) s are defined as the central transcriptional mediator of hypoxic response. Recent efforts have identified HIF-2α that has been involved in sorafenib resistance. However, the regulatory mechanisms of HIF-2α activity in HCC remain obscure. Here, using both in vitro and in vivo HCC models, we show that the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) axis is a driver of HIF-2α expression and activity, which then promotes HCC growth, metastasis and angiogenesis. We further show that COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment by regulating the HIF-2α level and activity. These observations support further clinical developments of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.Research.

There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human and zebrafish or murine together with in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention. These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma. http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg .

Long noncoding RNAs (lncRNAs) have been implicated in numerous physiological and pathological processes, including cancer development and progression. However, the role and molecular mechanism of lncRNAs in resistance to chemotherapy of colorectal cancer (CRC) remain enigmatic. Here, we found that lncRNA small Cajal body‐specific RNA 2 (SCARNA2) is expressed higher in CRC tissues than in adjacent normal tissues, and a robust expression of SCARNA2 is correlated with a bad prognosis of CRC patients after surgery. SCARNA2 overexpression significantly promoted chemoresistance in CRC cells, and downregulation of SCARNA2 obviously inhibited chemoresistance in vitro. SCARNA2 promotes chemotherapy resistance via competitively binding miR‐342‐3p to facilitate epidermal growth factor receptor (EGFR) and B‐cell lymphoma 2 (BCL2) expression in CRC cells. Together, our results reveal a novel pathway that SCARNA2 regulates CRC chemoresistance through targeting miR‐342‐3p‐EGFR/BCL2 pathway, providing a promising therapeutic target for CRC.

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Background:Our previous study indicates that leptin enhances gastric cancer (GC) invasion. However, the exact effect of leptin on GC metastasis and its underlying mechanism remain unclear. Intercellular adhesion molecule-1 (ICAM-1), a major molecule in stabilising cell–cell and cell–extracellular matrix interactions, is overexpressed and has crucial roles in tumour metastasis.Methods:Here, we investigated leptin and ICAM-1 expression in GC tissues. Furthermore, we characterised the influence of leptin on ICAM-1 expression in GC cells and elucidated the underlying mechanism.Results:Leptin and ICAM-1 were overexpressed in GC tissues, and a strong positive correlation was observed. They were also related with clinical stage or lymph node metastasis. Furthermore, leptin induced GC cell (AGS and MKN-45) migration by upregulating ICAM-1, and knockdown of ICAM-1 by small interference RNA (siRNA) blocked this process. Cell surface ICAM-1, as well as soluble ICAM-1 (sICAM-1), was also enhanced by leptin. Moreover, leptin increased ICAM-1 expression through Rho/ROCK pathway, which was attenuated by pharmacological inhibition of Rho (C3 transferase) or its downstream effector kinase Rho-associated protein kinase (ROCK) (Y-27632).Conclusions:Our findings indicate that leptin enhances GC cell migration by increasing ICAM-1 through Rho/ROCK pathway, which might provide new insight into the significance of leptin in GC.

Aim: Galectin-3 (Gal-3) is a member of the carbohydrate-binding protein family that contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis. The aim of this study is to investigate the role of Gal-3 in human tongue cancer progression. Methods: Human tongue cancer cell lines (SCC-4 and CAL27) were transfected with a small-interfering RNA against Gal-3 (Gal-3-siRNA). The migration and invasion of the cells were examined using a scratch assay and BD BioCoat Matrigel Invasion Chamber, respectively. The mRNA and protein levels of β-catenin, Akt/pAkt, GSK-3β/pGSK-3β, MMP-9 in the cells were measured using RT-PCR and Western blotting, respectively. Results: Transient silencing of Gal-3 gene for 48 h significantly suppressed the migration and invasion of both SCC-4 and CAL27 cells. Silencing of Gal-3 gene significantly decreased the protein level of β-catenin, leaving the mRNA level of β-catenin unaffected. Furthermore, silencing Gal-3 gene significantly decreased the levels of phosphorylated Akt and GSK-3β, and suppressed the mRNA and protein levels of MMP-9 in the cells. Conclusion: Our data suggest that Gal-3 mediates the migration and invasion of tongue cancer cells in vitro via regulating the Wnt/ β-catenin signaling pathway and Akt phosphorylation.