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ABSTRACT: Metastatic hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. However, the cell population responsible for its metastasis remains largely unknown. Here, we reported that CD133(+)CD44(+/high) defined a subgroup of tumor cells that was responsible for hematogenous metastasis of liver cancers. Immunohistochemical investigation of human HCC specimens revealed that the number of CD133(+) and CD44(+) HCC cells was increased and was associated with portal vein invasion. Purified CD133(+) or CD44(high) HCC cells were superior in clonogenic growth and vascular invasion, respectively. Thus, the combination of CD133 and CD44 was used to define a novel HCC sub-population. CD133(+)CD44(high), but not CD133(+)CD44(low/-), CD133(-)CD44(high) or CD133(-)CD44(low/-) xenografts, produced intrahepatic or lung metastasis in nude mice. Further analysis of human HCC samples by flow cytometry showed that the number of CD133(+)CD44(+) tumor cells was associated with portal vein metastasis. The cDNA microarray analysis of CD133(+)CD44(+) and CD133(+)CD44(-) tumor cells isolated from metastatic HCC patients revealed that these cells comprised of two different populations possessing distinct gene expression profiles. Our results suggest that CD133(+)CD44(+) tumor cells are a particular population responsible for hematogenous metastasis in liver cancers and that these cells might be targets for treatment of HCC metastasis.
Cell Research 08/2011; 22(1):259-72. · 8.19 Impact Factor
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ABSTRACT: Intracellular Ca(2+) signaling plays critical roles in VEGF-mediated angiogenesis. Transient receptor potential canonical (TRPC) channel 6, a Ca(2+)-permeable non-selective cation channel, can be activated by VEGF. Here, we report that TRPC6 is important for VEGF-mediated angiogenesis. Inhibition of TRPC6 in human umbilical vein endothelial cells (HUVECs) by pharmacological or genetic approaches arrested HUVECs at G2/M phase and suppressed VEGF-induced HUVEC proliferation and tube formation. Furthermore, inhibition of TRPCs abolished VEGF-, but not FGF-induced angiogenesis in the chick embryo chorioallantoic membrane. These results suggest that TRPC6 plays an important role in VEGF-mediated angiogenesis.
Cancer letters 05/2009; 283(1):43-51. · 4.86 Impact Factor
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ABSTRACT: We recently reported that the level of ZNF23, a KRAB-containing zinc finger protein, is reduced in human cancers and it inhibits cell growth by inducing cell cycle arrest. Here we showed that ZNF23 also induces apoptosis in ovarian cancer cells. The protein level of ZNF23 in ovarian cancers was greatly down-regulated compared with that in the normal ovaries. Introduction of ZNF23 into ovarian cancer cells led to apoptosis as demonstrated by activation of caspase-3, nuclear condensation and formation of a sub-G1 peak. This apoptotic process was correlated with loss in mitochondrial membrane potential, cytochrome c release and caspase-9 activation. Furthermore, ZNF23 induced apoptosis partially via down-regulation of Bcl-XL. Thus, our results suggest that ZNF23 may also induce apoptosis to suppress tumor cell growth and points to the possibility that its down-regulation might facilitate ovarian cancer cell survival.
Cancer Letters 09/2008; 266(2):135-43. · 4.24 Impact Factor
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ABSTRACT: The Krupple-associated box-containing zinc-finger proteins (KRAB-ZFPs) make up one of the largest family of transcription factors. Several members of the KRAB-ZFPs modulate cell growth, survival and are implicated in malignant disorders. However, most members are not well characterized and their functions are largely unknown. Here we report that ZNF23, a member of KRAB-ZFPs, inhibits cell cycle progression. ZNF23 protein localized to the nucleus and was ubiquitously expressed in all tested normal tissues. However, the expression levels of ZNF23 protein were lost or greatly reduced in human cancer. Ectopic expression of ZNF23 led to enhancement of p27(kip-1) expression, growth inhibition and cell cycle arrest in G(1) phase. Downregulation of p27(kip-1) by siRNA against p27(kip-1) reversed growth inhibition induced by ZNF23. Furthermore, the growth-inhibitory effect of ZNF23 was p53-independent. Deletion analysis revealed that the effect of ZNF23 did not rely on its KRAB domain, but on the C-terminal zinc fingers. Thus, we have identified a new member of KRAB-ZNF superfamily with growth-inhibitory ability and its downregulation may contribute to carcinogenesis.
Experimental Cell Research 02/2007; 313(2):254-63. · 3.58 Impact Factor
