Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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BackgroundMany studies support that chemokine (C-X-C motif) ligand 1 (CXCL1) regulate tumor epithelial-stromal interactions involving in tumor growth and invasion. However, limited studies have been conducted on the expression and function of the CXCL1 gene in hepatocellular carcinoma (HCC).MethodsThe mRNA and protein level expression of CXCL1 was examined in HCC tissues and cell lines. The expression of CXCL1 was correlated with clinicopathological features and follow-up data. Overexpression approaches were used to evaluate the biological functions of CXCL1 by MTT and matrigel invasion assays. Protein expression levels of CXCL1 and P65 were determined by western blot analysis.ResultsIn this study, we found that CXCL1 expression was markedly upregulated in HCC tissues. Ectopic expression of CXCL1 significantly promoted HCC cells proliferation and invasion. Furthermore, CXCL1 promote cell invasion through NF-kB-dependent pathway. CXCL1 expression in HCC associated with clinical stage (P = 0.034) and distant metastasis (P = 0.028). Moreover, Patients with high CXCL1 expression level had poorer overall survival (OS;P = 0.027) than those with low CXCL1 expression.ConclusionsThese data indicated that the CXCL1 upregulation may contribute to both the development and progression of HCC and this effect may be associated with increased proliferation and invasiveness mainly via regulating P65 expression.

Pancreatic cancer remains the fourth deathliest cancer worldwide with a 5-year survival rate of only 4%. The present study tested the hypothesis that dysregulated microRNA (miRNA) expression by pancreatic cancer endothelial cells (CECs) may regulate angiogenesis. Primary EC cultures were established from the pancreatic tumor and adjacent normal tissues of three pancreatic cancer patients. A miRNA microarray was used to identify miRNAs that were differentially expressed. The expression patterns of four highly expressed miRNAs in CECs were confirmed by qPCR analysis. The effects of dysregulated miRNA expression on CEC proliferation, migration and tube formation were determined after transfection with specific miRNA inhibitors. The expression of 14 miRNAs was increased by >20-fold in the the CECs of all three pancreatic patients; the increased expression of miR-200c and miR-139 in CECs was confirmed. miR-1, mir-139 and miR-200c inhibitors significantly reduced CEC migration (all P<0.05), yet not proliferation. The average tube length and total loop number were also significantly decreased upon miR-139 and miR-200c inhibition in all three CEC cultures (all P<0.05). Upregulation of miR-139 and miR-200c expression may increase CEC migration and tube formation, which suggests that these miRNAs may regulate pancreatic tumor angiogenesis.