The up-regulation and nuclear relocation of epithelial-mesenchymal transition (EMT) regulator Twist1 have been implicated in the tumor invasion and metastasis of human hepatocellular carcinoma (HCC). The term vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. However, the relationship between Twist1 and VM formation is not clear. In this study, we explored HCC as a VM and EMT model in order to investigate the role of Twist1 in VM formation. We first examined the expression of Twist1 in human HCC samples and cell lines and found that Twist1 was frequently overexpressed in the nuclear relocation occurring in VM-positive HCCs (13/18 [72%]). Twist1 nuclear expression was likewise significantly associated with VM formation. Clinicopathological analysis revealed that both VM and Twist1 nuclear expressions present shorter survival durations than those without expression. We consistently demonstrated that an overexpression of Twist1 significantly enhanced cell motility, invasiveness, and VM formation in an HepG2 cell. Conversely, a knockdown of Twist1 by the short hairpin RNA approach remarkably reduced Bel7402 cell migration, invasion, and VM formation. Using chromatin immunoprecipitation, we also showed that Twist1 binds to the vascular endothelial (VE)-cadherin promoter and enhances its activity in a transactivation assay. Conclusion: The results of this study indicate that Twist1 induces HCC cell plasticity in VM cells more through the suppression of E-cadherin expression and the induction of VE-cadherin up-regulation than through the VM pattern in vivo and in a three-dimensional in vitro system. Our findings also demonstrate a novel cogitation in cancer stem-like cell differentiation and that related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis. (HEPATOLOGY 2010;51:545-556.)
Heterostructured Cu2S-In2S3 nanocrystals with various shapes and compositions were synthesized by a high-temperature precursor-injection method using the semiconductor nanocrystal Cu1.94S as a catalyst. The intrinsic cationic deficiencies formed at high temperature by Cu ions made the Cu1.94S nanocrystal a good candidate for catalyzing the nucleation and subsequent growth of In 2S3 nanocrystals, eventually leading to the formation of heterostructured Cu2S-In2S3 nanocrystals. Gelification of the reaction systems, which were composed of different types of nanocrystal precursors and solvent, was found to be a very effective measure for controlling the growth kinetics of the heterostructured particles. Consequently, matchsticklike Cu2S3-In2S3 heterostructured nanorods, teardroplike quasi-core/shell Cu2S@In2S3 nanocrystals, and pencil-like In2S3 nanorods were successfully obtained by manipulating the gelification of the reaction system; this formed a solid experimental basis for further discussion of the growth mechanisms for differently shaped and structured nanocrystals. By reaction with 1,10-phenanthroline, a reagent that strongly and selectively binds to Cu(+), a compositional transformation from binary matchsticklike Cu2S-In2S3 nanorods to pure In2S3 nanorods was successfully achieved.
Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. In the study we demonstrated that CD133 expression was the highest in triple-negative (TN) breast cancer specimens. Importantly, VM showed statistical correlation with CD133(+) expression. The presence of the close relationship between VM and CD133(+) expression might be central for TN tumor relapse and progression. The TN breast cancer cell line, MDA-MB-231 cells developed a range of colony morphologies paralleling the holoclone, meroclone and paraclone morphologies produced by normal keratinocytes and other epithelial cancer cell lines when plated at clonal densities. Holoclone cells were capable of forming more colonies on soft agar than meroclone cells and paraclone cells, suggesting that holoclone cells had higher self-renew potential and might harbors cancer stem cells (CSCs) subpopulation. Strikingly, it was holoclone that displayed CD133(+) phenotype and formed VM. In addition, holoclone acquired endothelial cell marker vascular endothelial-cadherin expression and upregulated VM mediators matrix metalloproteinase (MMP)-2 and MMP-9 expression. The subpopulation with holoclone morphology, CD133(+) phenotype and CSCs characteristics might have the capacity of transdifferentiation and contributed to VM in TN breast cancer. The related molecular pathways may be used as novel therapeutic targets for the inhibition of angiogenesis and metastasis in TN breast carcinoma.
The antiapoptotic protein Bcl-2 plays multiple roles in apoptosis, immunity, and autophagy. Its expression in tumors correlates with tumor grade and malignancy. The recapitulation of the normal developmental process of epithelial-mesenchymal transition (EMT) contributes to tumor cell plasticity. This process is also a characteristic of metastatic cells and vasculogenic mimicry. In the present study we report functional and structural interactions between Bcl-2 and the EMT-regulating transcription factor Twist1 and the relationship with metastasis and vascular mimicry. Bcl-2 and Twist1 are coexpressed under hypoxia conditions. The Bcl-2 can bind to Twist1 in vivo and in vitro. This interaction involves basic helix-loop-helix DNA binding domain within Twist1 and through two separate domains within Bcl-2 protein. Formation of the Bcl-2/Twist1 complex facilitates the nuclear transport of Twist1 and leads to transcriptional activation of wide ranges of genes that can increase the tumor cell plasticity, metastasis, and vasculogenic mimicry. Finally, nuclear expression of Bcl-2 and Twist1 is correlated with poor survival of these patients in a cohort of 97 cases of human hepatocellular carcinoma. Conclusion: The results describe a novel function of Bcl-2 in EMT induction, provide insight into tumor progression, and implicate the Bcl-2/Twist1 complex as a potential target for developing chemotherapeutics.
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