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Here we showed that hepatocellular carcinoma (HCC) cell lines with high metastatic potential had low levels of NDRG2. The iron chelator Dp44mT up-regulated NDRG2, suppressed epithelial-mesenchymal transition (EMT) and inhibited tumor metastasis in HCC having high metastatic potential. Also Dp44mT attenuated the TGF-β1-induced EMT in HCC having low metastatic potential. In agreement, silencing endogenous NDRG2 with shNDRG2 in HCC cells attenuated the effect of Dp44mT. We showed that the NDRG2/gp130/STAT3 pathway can mediate Dp44mT effects. In agreement, we found that a combination of NDRG2 expression and p-STAT3 levels is a strong predictor of prognosis in HCC patients. We suggest that up-regulation of NDRG2 by Dp44mT is a promising therapeutic approach in HCC.

// Kathleen M. Capaccione 1,2 , Xuehui Hong 2,3 , Katherine M. Morgan 1,2 , Wenyu Liu 2 , J. Michael Bishop 4 , LianXin Liu 3 , Elke Markert 2,5 , Malik Deen 6 , Christine Minerowicz 6 , Joseph R. Bertino 5 , Thaddeus Allen 4 , and Sharon R. Pine 1,2,5 1 Department of Pharmacology, Rutgers Graduate School of Biomedical Science, Piscataway, New Jersey 2 Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 3 Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 4 G.W. Hooper Research Foundation, University of California, San Francisco, CA 5 Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey 6 Department of Pathology, Robert Wood Johnson Medical School, New Brunswick, New Jersey Correspondence: Sharon R. Pine, email: // Keywords : Sox9, Notch1, TGF-β, lung cancer, EMT Received : May 01, 2014 Accepted : May 19, 2014 Published : May 19, 2014 Abstract Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1 , and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-β pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1- Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-β , Sox9 also acts downstream of NF-κB , BMP , EGFR, and Wnt /β-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.

// Juan Liu 1,4 , Cen Zhang 1,4 , Meihua Lin 1 , Wei Zhu 1,2 , Yingjian Liang 1 , Xuehui Hong 1,2 ,Yuhan Zhao 1,2 , Ken H. Young 3 , Wenwei Hu 1,2 , Zhaohui Feng 1 1 Department of Radiation Oncology, 2 Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA 3 Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston , TX , USA 4 These two authors contributed equally to this work Correspondence: Wenwei Hu, email: // Zhaohui Feng, email: // Keywords :p53; GLS2; tumor suppression; PI3K/AKT; Hepatocellular carcinoma Received : February 15, 2014 Accepted : March 24, 2014 Published : March 26, 2014 Abstract The tumor suppressor p53 and its signaling pathway play a critical role in tumor prevention. As a direct p53 target gene, the role of glutaminase 2 (GLS2) in tumorigenesis is unclear. In this study, we found that GLS2 expression is significantly decreased in majority of human hepatocellular carcinoma (HCC). Restoration of GLS2 expression in HCC cells inhibits the anchorage-independent growth of cells and reduces the growth of HCC xenograft tumors. Interestingly, we found that GLS2 negatively regulates the PI3K/AKT signaling, which is frequently activated in HCC. Blocking the PI3K/AKT signaling in HCC cells largely abolishes the inhibitory effect of GLS2 on the anchorage-independent cell growth and xenograft tumor growth. The GLS2 promoter is hypermethylated in majority of HCC samples. CpG methylation of GLS2 promoter inhibits GLS2 transcription, whereas reducing the methylation of GLS2 promoter induces GLS2 expression. Taken together, our results demonstrate that GLS2 plays an important role in tumor suppression in HCC, and the negative regulation of PI3K/AKT signaling contributes greatly to this function of GLS2. Furthermore, hypermethylation of GLS2 promoter is an important mechanism contributing to the decreased GLS2 expression in HCC.

MicroRNAs are critical in various human cancers, including gastric cancer (GC). However, the mechanism underlying the GC development remains elusive. In this study, we demonstrate that miR-448 is increased in GC samples and cell lines. Overexpression of miR-448 facilitated the proliferation of GC cells by stimulating glycolysis. Mechanistically, we identified KDM2B, a reader for methylated CpGs, as the target of miR-448 that represses glycolysis and promotes oxidative phosphorylation. Overexpression of miR-448 reduced both the mRNA and protein levels of KDM2B, whereas KDM2B re-expression abrogated the miR-448-mediated glycolytic activities. Furthermore, we discovered Myc as a key target of KDM2B that controls metabolic switch in GC. Importantly, a cohort of 81 GC tissues revealed that miR-448 level closely associated with a battery of glycolytic genes, in which KDM2B showed the strongest anti-correlation coefficient. In addition, enhanced miR-448 level was significantly associated with poor clinical outcomes of GC patients. Hence, we identified a previously unappreciated mechanism by which miR-448 orchestrate epigenetic, transcriptional and metabolic networks to promote GC progression, suggesting the possibility of therapeutic intervention against cancer metabolic pathways.