• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2173-2179
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• 2013

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37, also called UCHL5), a member of the deubiquitinating enzymes, can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. It has been proved that UCH37 can be activated by proteasome ubiqutin chain receptor Rpn13 and incorporation into the 19S complex. UCH37, which has been reported to assist in the mental development of mice, may play an important role in oncogenesis, tumor invasion and migration. Further studies will allow a better understanding of roles in cell physiology and pathology, embryonic development and tumor formation, hopefully providing support for the idea that UCH37 may constitute a new interesting target for the development of anticancer drugs.

• BMB Reports
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• v.48 no.1
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• pp.30-35
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• 2015

This study was to investigate the role of Fas in the development of Cisplatin-resistant ovarian cancer. On the cellular level, Fas expression was significantly reduced in Cisplatin resistant A2780 (A2780/CP) cells compared with A2780 cells. Fas silence with siRNA would promote tumor cell lines proliferation, facilitate tumor cell cycle transition of G1/S, prevent cell apoptosis, and promote cell migration. Expression of drug resistance gene was negatively correlated to Fas. In nude mice metastasis model of human ovarian carcinoma by subcutaneous transplantation, after Ad-Fas injected intratumorly, we found that upregulation of Fas could inhibit transplantation tumor tissue growth and reduce the expression of drug resistance gene. Our results indicated that upregulation of Fas in epithelial ovarian cancer reversed the development of resistance to Cisplatin. In conclusion, our findings suggested that Fas might act as a promising therapeutic target for improvement of the sensibility to Cisplatin in ovarian cancer.

• BMB Reports
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• v.45 no.11
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• pp.623-628
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• 2012

Tissue inhibitor of metalloproteinases (TIMPs; TIMP-1, -2, -3 and -4) are endogenous inhibitor for matrix metalloproteinases (MMPs) that are responsible for remodeling the extracellular matrix (ECM) and involved in migration, invasion and metastasis of tumor cells. Unlike under normal conditions, the imbalance between MMPs and TIMPs is associated with various diseased states. Among TIMPs, TIMP-1, a 184-residue protein, is the only N-linked glycoprotein with glycosylation sites at N30 and N78. The structural analysis of the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1 suggests new possibilities of the role of TIMP-1 glycan moieties as a tuner for the proteolytic activities by MMPs. Because the TIMP-1 glycosylation participate in the interaction, aberrant glycosylation of TIMP-1 presumably affects the interaction, thereby leading to pathogenic dysfunction in cancer cells. TIMP-1 has not only the cell proliferation activities but also anti-oncogenic properties. Cancer cells appear to utilize these bilateral aspects of TIMP-1 for cancer progression; an elevated TIMP-1 level exerts to cancer development via MMP-independent pathway during the early phase of tumor formation, whereas it is the aberrant glycosylation of TIMP-1 that overcome the high anti-proteolytic burden. The aberrant glycosylation of TIMP-1 can thus be used as staging and/or prognostic biomarker in colon cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4537-4542
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• 2015

OK-432, a Streptococcus-derived anticancer immunotherapeutic agent, has been applied in clinic for many years and achieved great progress in various cancers. In the present study, we investigated its anticancer effect on bladder cancer through tumor associated macrophages (TAMs). MTS assay validated OK-432 could inhibit proliferation in both T24 and EJ bladder cell lines. OK-432 also induced apoptosis of bladder cancer cells in vitro. Consequently, we demonstrated that OK-432 could suppress the bladder cancer cells migration and invasion by altering the EMT-related factors. Furthermore, using SD rat model, we revealed that OK-432 inhibited tumor growth, suppressed PCNA expression and inhibited metastasis in vivo. Taken together, these findings strongly suggest that OK-432 inhibits cell proliferation and metastasis through inducing macrophages to secret cytokines in bladder cancer.

• BMB Reports
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• v.57 no.4
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• pp.194-199
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• 2024

Overexpression of mitofusin-2 (MFN2), a mitochondrial fusion protein, is frequently associated with poor prognosis in cervical cancer patients. Here, I aimed to investigate the involvement of MFN2 in cervical cancer progression and determine the effect of MFN2 on prognosis in cervical cancer patients. After generating MFN2-knockdown SiHa cells derived from squamous cell carcinoma, I investigated the effect of MFN2 on SiHa cell proliferation using the Cell Counting Kit-8 assay and determined the mRNA levels of proliferation markers. Colony-forming ability and tumorigenesis were evaluated using a colony-formation assay and tumor xenograft mouse models. The migratory and invasive abilities associated with MFN2 were measured using wound-healing and invasion assays. Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT) markers related to MFN2 were assessed through quantitative RT-PCR. MFN2-knockdown SiHa cells exhibited reduced proliferation, colony formation, migration, invasion, and tumor formation in vivo. The motility of SiHa cells with MFN2 knockdown was reduced through Wnt/β-catenin-mediated EMT inhibition. MFN2 promoted cancer progression and tumorigenesis in SiHa cells. Overall, MFN2 could serve as a therapeutic target and a novel biomarker for cervical cancer.

• BMB Reports
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• v.57 no.6
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• pp.273-280
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• 2024

Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different morphological states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a theory derived from tissue biopsy, which explains the acquisition of EMT transcription factors (TFs) that convey mesenchymal features during cancer migration and invasion. On the other hand, adherent-to-suspension transition (AST) is an emerging theory derived from liquid biopsy, which describes the acquisition of hematopoietic features by AST-TFs that reprograms anchorage dependency during the dissemination of circulating tumor cells (CTCs). The induction and plasticity of EMT and AST dynamically reprogram cell-cell interaction and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions.

• Clinical Endoscopy
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• v.56 no.2
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• pp.143-154
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• 2023

Advanced malignant hilar biliary obstruction (MHBO) with inaccessible papilla poses a significant challenge to endoscopists, as drainage of multiple liver segments may be warranted. Transpapillary drainage may not be feasible in patients with surgically altered anatomy, duodenal stenosis, prior duodenal self-expanding metal stent, and after initial transpapillary drainage, but require re-intervention for draining separated liver segments. Endoscopic ultrasound-guided biliary drainage (EUS-BD) and percutaneous trans-hepatic biliary drainage are the feasible options in this scenario. The major advantages of EUS-BD over percutaneous trans-hepatic biliary drainage include a reduction in patient discomfort and internal drainage away from the tumor, thus reducing the possibility of tissue or tumor ingrowth. With innovations, EUS-BD is helpful not only for bilateral communicating MHBO but also for non-communicating systems with bridging hilar stents or isolated right intra-hepatic duct drainage by hepatico-duodenostomy. EUS-guided multi-stent drainage with specially designed cannulas and guidewires has become a reality. A combined approach with endoscopic retrograde cholangiopancreatography for re-intervention, interventional radiology, and intraductal tumor ablative therapies has been reported. Stent migration and bile leakage can be minimized with proper stent selection and technique, and stent blocks can be managed with EUS-guided interventions in a majority of cases. Future comparative studies are required to establish the role of EUS-guided interventions in MHBO as rescue or primary therapy.

• Biomolecules & Therapeutics
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• v.17 no.3
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• pp.288-292
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• 2009

Interactions between tumor cells and the extracellular matrix (ECM) strongly influence tumor development, affecting cell survival, proliferation and migration. Fibronectin, a major component of ECM, has been shown to interact with integrins especially the ${\alpha}5{\beta}1$ integrin. Cell invasion and metastasis are often associated with matrix metalloproteinases (MMPs) which are capable of digesting the different components of the ECM and basement membrane. MMP-2 is produced as a latent pro-MMP-2 (72 kDa) to be activated, resulting the 62 kDa active MMP-2. In this study, we investigated the effect of fibronectin on activation of pro-MMP-2 and the cellular invasiveness in H-Ras-transformed MCF10A human breast epithelial cells. Here we show that fibronectin induces activation of pro-MMP-2 and up-regulation of MT1-MMP and TIMP-2 in H-Ras MCF10A cells. These results demonstrate that H-Ras MCF10A cells secrete high levels of active MMP-2 when cultured with fibronectin, suggesting a possible interaction between the ECM network and H-Ras MCF10A cells to generate active MMP-2 which is important for proteolysis and ECM remodeling. Invasive and migratory abilities of H-Ras MCF10A cells were enhanced by fibronectin. Fibronectin up-regulated the expression of ${\beta}1$ integrin which may play a role in cellular responses exerted by fibronectin. Since acquisition of pro-MMP-2 activation can be associated with increased malignant progression, this study provides a mechanism for the cell surface-matrix degrading effect of fibronectin which will be crucial to breast cell invasion and migration.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.211-217
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• 2011

Panax ginseng CA Meyer, a herb from the Araliaceae, has traditionally been used as a medicinal plant in Asian countries. Ginseng extract fermented by ginsenoside-${\beta}$-glucosidase treatment is enriched in ginsenosides such as Rh2 and Rg3. Here we show that a fermented ginseng extract, BST204, has anti-proliferative and anti-invasive effects on HT-29 human colon cancer cells. Treatment of HT-29 cells with BST204 induced cell cycle arrest at $G_1$ phase without progression to apoptosis. This cell cycle arrest was accompanied by up-regulation of tumor suppressor proteins, p53 and p21$^{WAF1/Cip1}$, down-regulation of the cyclin-dependent kinase/cyclins, Cdk2, cyclin E, and cyclin D1 involved in $G_1$ or $G_1/S$ transition, and decrease in the phosphorylated form of retinoblastoma protein. In addition, BST204 suppressed the migration of HT-29 cells induced by 12-O-tetradecanoylphorbol-13-acetate, which correlated with the inhibition of metalloproteinase-9 activity and extracellular signal-regulated kinase activity. The effects of BST204 on the proliferation and the invasiveness of HT-29 cells were similar to those of Rh2. Taken together, the results suggest that fermentation of ginseng extract with ginsenoside-${\beta}$-glucosidase enhanced the anti-proliferative and the anti-invasive activity against human colon cancer cells and these anti-tumor effects of BST204 might be mediated in part by enriched Rh2.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3507-3511
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• 2012

Objective: The aim of this study was to investigate possible mechanisms of LOX gene effects on invasion and metastasis of breast cancer cells by RNA interference. Methods: LOX-RNAi-LV was designed, synthesized, and then transfected into a breast cancer cell line (MDA-MB-231). Expression of LOX, MMP-2 and MMP-9 was determined by real-time PCR, and protein expression of LOX by Western blotting. Cell migration and invasiveness were assessed with Transwell chambers. A total of 111 cases of breast cancer tissues, cancer-adjacent normal breast tissues, and 20 cases of benign lesion tissues were assessed by immunohistochemistry. Results: Expression of LOX mRNA and protein was suppressed, and the expression of MMP-2 and MMP-9 was significantly lower in the RNAi group than the control group (P<0.05), after LOX-RNAi-LV was transfection into MDA-MB-231 cells. Migration and invasion abilities were obviously inhibited. The expression of LOX protein in breast cancer, cancer-adjacent normal breast tissues and benign breast tumor were 48.6% (54/111), 26.1% (29/111), 20.0% (4/20), respectively, associations being noted with clinical stage, lymph node metastasis, tumor size and ER, PR, HER2, but not age. LOX protein was positively correlated with MMP-2 and MMP-9. Conclusion: LOX displayed an important role in invasion and metastasis of breast cancer by regulating MMP-2 and MMP-9 expression which probably exerted synergistic effects on the extracellular matrix (ECM).