Reduction of malignant phenotype of HEPG2 cell is associated with the expression of connexin 26 but not connexin 32

Yano, Tomohiro; Hernandez-Blazquez, Francisco-Javier; Omori, Yasufumi; Yamasaki, Hiroshi

doi:10.1093/carcin/22.10.1593

Cited by 81 publications

(62 citation statements)

References 43 publications

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“…The loss of E-cadherin-mediated adhesion led to the increased motility of tumor cells (31). Since E-cadherin expression can be induced by Cxs (32,33), our study cannot fully exclude the possibility that E-cadherin may be involved in the Cx32-related increase in cell adhesion.…”

Section: Discussionmentioning

confidence: 80%

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

et al. 2011

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Abstract. The effects of connexin (Cx) and its derived homotypic gap junctional intercellular communication (GJIC) between tumor cells on the invasion of metastatic cancers and the underlying mechanisms remain unclear. In this study, we investigated the influence of Cx32 and the homotypic GJIC mediated by this Cx on the migration, invasion and intercellular adhesion of transfected HeLa cells. The expression of Cx32 significantly increased cell adhesion and inhibited migration and invasion. The inhibition of GJIC by oleamide, a widely used GJIC inhibitor, reduced the enhanced adhesion and partly reversed the decreased migration and invasion that had been induced by Cx32 expression. Blockage of the p38 and extracellular signal-regulated kinase 1 and 2 mitogenactivated protein kinase (ERK1/2 MAPKs) pathways using their specific inhibitors attenuated the effects of Cx32, but not those of GJIC, on cell adhesion, migration and invasion. These results indicate that the homotypic GJIC mediated by Cx32, as well as the Cx itself, inhibit cell migration and invasion, most likely through the elevation of intercellular adhesion. The suppressive effect of Cx32 on the migration and invasion of cancer cells, but not that of its derived homotypic GJIC, partly depends on the activation of the p38 and the ERK1/2 MAPKs pathways.

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Section: Discussionmentioning

confidence: 80%

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

et al. 2011

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“…Among c-myc transgenic mice that developed HCC, more than 70% showed reduced E-cadherin, and in some cases, this was associated with hypermethylation of the E-cadherin promoter (Calvisi et al, 2004). Restoration of E-cadherin expression in HepG2 cells resulted in reduced cell growth in culture, and reduced clonability in soft agar (Masuda et al, 2000;Yano et al, 2001), suggesting that E-cadherin also acts as a negative growth regulatory protein in HCC.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

et al. 2005

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Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, Ecadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAgpositive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of b-catenin in the cytoplasm and/ or nuclei in tissues and cell lines, which is characteristic of activated b-catenin. Additional work showed that HBxAg-activated b-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of b-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.

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“…Among tumor suppressor genes contributing to tissue homeostasis, connexin (Cx) genes, a member of gap junction (GJ), are frequently down-regulated at an early stage of the carcinogenic process. Furthermore, the Cx gene preferentially exerts a tumorsuppressive effect on the tumor from normal cells in which the Cx gene is naturally expressed (5,6). Thus, if we could determine the Cx gene specifically expressed in the progenitor cell of each tumor and clarify the tissue-specific tumor suppressive effect of the gene, we could use it to establish a new therapy against the cancer.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Src activity enhances the tumor-suppressive effect of the connexin 32 gene in Caki-1 renal cancer cells

Fujimoto

Sato²,

Shirai³

et al. 2006

Oncol Rep

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Abstract. Connexin (Cx) genes exert negative growth effects on tumor cells with certain cell specificity. We have recently reported that Cx32 acts as a tumor suppressor gene in a metastatic renal cancer cell line (Caki-1) due to the inactivation of Src. In line with the previous study, here we investigated if an Src family inhibitor (PP1) could enhance the tumor-suppressive effect of Cx32 in Caki-1 cells from human metastatic renal cell carcinoma. We examined the difference in the cytotoxic effect of PP1 on two cell clones, Cx32-transfected Caki-1 cells (Caki-1T) and mock-transfected Caki-1 cells (Caki-1W), in vitro as well as in vivo. PP1 showed more cytotoxic effect on Caki-1T than on Caki-1W at lower doses. This reinforcement was also observed in a xenograft model of nude mice. The in vitro reinforcement of the cytotoxic effect depended not only on control of cell-cycle transition but also on the induction of apoptosis, and the occurrence of the event was mostly caused by potential inhibition of Src activity in Caki-1T. Also, under a hypoxic condition, which is a typical environment of tumor tissue, Cx32 suppressed hypoxia-induced Src activation, and PP1 enhanced cytotoxicity in Caki-1T. These results suggest that, in addition to the Cx32-dependent tumor-suppressive effect, the concomitant inhibition of Src by PP1 is an effective procedure to induce a cytotoxic effect in Caki-1 cells.

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Reduction of malignant phenotype of HEPG2 cell is associated with the expression of connexin 26 but not connexin 32

Cited by 81 publications

References 43 publications

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

Inhibition of Src activity enhances the tumor-suppressive effect of the connexin 32 gene in Caki-1 renal cancer cells

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