• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.265-273
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• 2024

This study aims to explore possible effect of RNA polymerase I subunit D (POLR1D) on proliferation and angiogenesis ability of colorectal cancer (CRC) cells and mechanism herein. The correlation of POLR1D and Yin Yang 1 (YY1) expressions with prognosis of CRC patients in TCGA database was analyzed. Quantitative realtime polymerase chain reaction (qRT-PCR) and Western blot were applied to detect expression levels of POLR1D and YY1 in CRC cell lines and CRC tissues. SW480 and HT-29 cells were transfected with si-POLR1D or pcDNA3.1-POLR1D to achieve POLR1D suppression or overexpression before cell migration, angiogenesis of human umbilical vein endothelial cells were assessed. Western blot was used to detect expressions of p38 MAPK signal pathway related proteins and interaction of YY1 with POLR1D was confirmed by dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). TCGA data showed that both POLR1D and YY1 expressions were up-regulated in CRC patients. High expression of POLR1D was associated with poor prognosis of CRC patients. The results showed that POLR1D and YY1 were highly expressed in CRC cell lines. Inhibition or overexpression of POLR1D can respectively suppress or enhance proliferation and angiogenesis of CRC cells. YY1 inhibition can suppress CRC progression and deactivate p38 MAPK signal pathway, which can be counteracted by POLR1D overexpression. JASPAR predicted YY1 can bind with POLR1D promoter, which was confirmed by dual luciferase reporter gene assay and ChIP. YY1 transcription can up-regulate POLR1D expression to activate p38 MAPK signal pathway, thus promoting proliferation and angiogenesis ability of CRC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.63-68
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• 2013

Background: Tumor angiogenesis correlates with recurrence and appears to be a prognostic factor for both breast and prostate cancers. In the present study, we aimed to investigate the correlation of microvessel density (MVD), a measure of angiogenesis, with nuclear pleomorphism, mitotic count, and vascular invasion in breast and prostate cancers at preclinical and clinical levels. Methods: Samples from xenograft tumors of luminal B breast cancer and prostate adenocarcinoma, established by BT-474 and PC-3 cell lines, respectively, and commensurate human paraffin-embedded blocks were obtained. To determine MVD, specimens were immunostained for CD-34. Nuclear pleomorphism, mitotic count, and vascular invasion were determined using hematoxylin and eosin (H&E)-stained slides. Results: MVD showed significant correlations with nuclear pleomorphism (r=0.68, P=0.03) and vascular invasion (r=0.77, P=0.009) in breast cancer. In prostate cancer, MVD was significantly correlated with nuclear pleomorphism (r=0.75, P=0.013) and mitotic count (r=0.75, P=0.012). In the breast cancer xenograft model, a significant correlation was observed between MVD and vascular invasion (r=0.87, P=0.011). In the prostate cancer xenograft model, MVD was significantly correlated with all three parameters (nuclear pleomorphism, r=0.95, P=0.001; mitotic count, r=0.91, P=0.001; and vascular invasion, r=0.79, P=0.017; respectively). Conclusions: Our results demonstrate that MVD is correlated with nuclear pleomorphism, mitotic count, and vascular invasion at both preclinical and clinical levels. This study therefore supports the predictive value of MVD in breast and prostate cancers.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4549-4553
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• 2015

Background: Colorectal carcinoma (CRC) is one of the major causes of cancer death worldwide. Data from the literature indicate differences between the proliferation rate of endothelial cells relative to the morphology growth type, possibly due to origin of specimens (autopsy material, surgery fragments) or quantification methods. Vascular endothelial growth factor (VEGF) is a factor that stimulates the proliferation of endothelial cells. It is expressed in more than 90% of cases of metastatic CRC. Aim: The aim of this study was to evaluate the endothelial cell proliferation and VEGF expression in primary tumors and corresponding liver metastases. Materials and Methods: Our study included 24 recent biopsies of primary tumors and corresponding liver metastases of CRC cases. CD34/Ki67 double immunostaining and RNA scope assay for VEGF were performed. Results: In the primary tumors analysis of VEGFmRNA expression indicated no significant correlation with differentiation grade, proliferative and non-proliferative vessels in the intratumoral and peritumoral areas. In contrast, in the corresponding liver metastases, VEGFmRNA expression significantly correlated with the total number of non-proliferative vessels and total number of vessels. CD34/Ki67 double immunostaining in the cases with poorly differentiated carcinoma indicated a high number of proliferating endothelial cells in the peritumoral area and a low number in the intratumoral area for the primary tumor. Moderately differentiated carcinomas of colon showed no proliferating endothelial cells in the intratumoral area in half of the cases included in the study, for both, primary tumor and liver metastasis. In well differentiated CRCs, in primary tumors, a high proliferation rate of endothelial cells in the intratumoral area and a lower proliferation rate in the peritumoral area were found. A low value was found in corresponding liver metastasis. Conclusions: The absence of proliferative endothelial cells in half of the cases for the primary tumors and liver metastases in moderately differentiated carcinoma suggest a vascular mimicry phenomenon. The mismatch between the total number of vessels and endothelial proliferation in primary tumors indicate that a functional vascular network is already formed or the existence of some mechanisms influenced by other angiogenic factors.

• THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
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• v.7 no.1
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• pp.61-75
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• 2001

The purpose of this study is to prove the angiogenesis effects of WhaYoungJiTongTang (hereinafter referred to as the 'WYJTT'). For the study, by utilizing liver cancer cell line; SK-HEP-1, lung cancer cell line: A549, stomach cancer cell line: AGS and bovine capillary endothelial cell: BCE, the effects of the WYJTT on toxicity and proliferation ability of cells and the effects on anti-angiogenesis of bovine capillary endothelial cell and of mice's aorta were studied. 1. Cell viability assay In comparison with the control group, when $100{\mu}g/ml$ of WYJTT was injected, the viability was reduced in SK-Hep-1, $400{\mu}g/ml$ in A549 and $200{\mu}g/ml$ in AGS. 2. Cell proliferation assay In comparison with the control group, when $600{\mu}g/ml$ of WYITT was injected, DNA synthesis was reduced to 35.1% in the SK-Hep-1, 56.0% in A549, and 25.8% in BCE (bovine capillary endothelial cell); and when $400{\mu}g/ml$ was injected, DNA synthesis was reduced to 12.1 in AGS. 3. Tube formation assay In the event that BCE is injected with WYJTT in each of its content gradient, the anti-angiogenesis was effective in amounts of $400{\mu}g/ml$ with 6 hours of the treatment. 4. Aortic ring assay In comparison with the control group, the angiogenesis was restricted to the remarkable degree in amount of $200{\mu}g/ml$: 10% in $400{\mu}g/ml$; and fully inhibited in each of $800{\mu}g/ml$ and $1600{\mu}g/ml$. As a result of the experiments mentioned above, WYJTT showed its anti-angiogenesis effects against cancer cell line.

• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.4
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• pp.969-979
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• 2003

Gamisoamsan is a prescription originated in Soamsan which is known as an anti-cancer remedy in the traditional Korean Medicine. To enhance the synergic effects of anti-cancer activity of Soamsan, this study reconstituted the original components of Soamsan with a slight modification and produced a novel herbal remedy, namely Gamisoamsan. To investigate the effects of Gamisoamsan on anti-cancer reaction, I studied the effects of Gamisoamsan on angiogenesis via chorioallantoic membrane (CAM) assay, corneal neovascularization assay and the effects on expression of growth factor which are VEGF, TGF-β, bFGF and IMUP-1. Anti-cancer effects of Gamisoamsan was also abserved through hematological parameters, tumor volume and survival rate in mice. Gamisoamsan inhibited embryonic angiogenesis of blood vessels in CAM assay and inhibited neovascularization of ral cornea. Gamisoamsan reduced cell proliferation in HT1080 cells and IC50 was 2.18 ㎎/㎖ Gamisoamsan reduced the expression of VEGF, TGF-β, bFGF and IMUP-1 which was known as vascular growth factor and this effects of Gamisoamsan was predominant than VP-16. The treatment of Gamisoamsan decreased the CT-26 cell inoculated-tumor volume in mice colon adenocarcinoma and increased mice survival which was inoculated CT-26 cells. The results of the present study suggest that Gamisoamsan extracts has a potential anti-tumor activity and may be an useful remedy to prevent and/or treat cancer.

• Journal of Life Science
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• v.24 no.5
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• pp.573-587
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• 2014

Angiogenesis, the formation of new capillary blood vessels, is a tightly regulated process. Under normal physiological conditions, angiogenesis only takes place during embryonic development, wound healing, and female menstruation. Dysregulation of angiogenesis is associated with many diseases, such as cancer, rheumatoid arthritis, psoriasis, and proliferative retinopathy. The growth and expansion of adipose tissue require the formation of new blood vessels. Adipose tissue is probably the most highly vascularized tissue in the body, as each adipocyte is surrounded by capillaries, and the angiogenic vessels supply nutrients and oxygen to adipocytes. Accumulating evidence shows that capillary endothelial cells communicate with adipocytes via paracrine signaling pathways, extracellular components, and direct cell-cell interactions. Activated adipocytes produce multiple angiogenic factors, including VEGF, FGF-2, leptin, and HGF, which either alone or cooperatively stimulate the expansion and metabolism of adipose tissue by increasing adipose tissue vasculature. Recently, it was demonstrated that antiangiogenic herbal Ob-X extracts and Korean red ginseng extracts reduce adipose tissue mass and suppress obesity by inhibiting angiogenesis in obese mice. Thus, angiogenesis inhibitors provide a promising therapeutic approach for controlling human obesity and related disorders.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.45 no.4
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• pp.303-306
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• 2012

Anti-angiogenesis therapy is one of the most promising strategies for the treatment of cancer. We investigated the anti-angiogenesis activity of an extract from the ark shell Scapharca subcrenata and attempted to purify the active compounds. The crude extract of the ark shell inhibited the proliferation of human vein endothelial cells (HUVEC-1) and tube formation by human dermal microvascular endothelial cells (HMEC-1). The methanol extract of the viscera of the ark shell showed activity. The ark shell extract acts as an angiogenesis inhibitor and could be developed further as a health substance, functional food, and anticancer agent.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2277-2281
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• 2015

Objectives: To explore the expression of astrocyte elevated gene-1 (AEG-1) in cervical cancer and analyze its correlation with microvascular density (MVD), nuclear factor kappaB (NF-kB p65) and vascular endothelial growth factor (VEGF). Materials and Methods: Immunohistochemical MaxVision method was adopted to detect the expression level of AEG-1, NF-kB p65 and VEGF in 45 samples of invading cervical cancer and 12 samples of cervicitis from The First Affiliated Hospital of Wenzhou Medical University. Tumor microvascular endothelial marker CD34 combined with Weidner was used to determine the MVD in cervical cancer tissue. The positive expression and staining conditions of AEG-1, NF-kB p65 and VEGF in cervical cancer tissues were observed under a light microscope. Correlations between expression of AEG-1 protein and those of NF-Kb p65 and VEGF, as well as MVD, were analyzed using Pearson correlation. Results: The expression levels of AEG-1 were $0.186{\pm}0.043$ in cervical cancer and $0.051{\pm}0.002$ in chronic cervicitis (p<0.01). Moreover, expression of AEG-1 was related to vascular invasion and lymphatic metastasis of cervical cancer (p<0.01), but not with age of the patients, differentiation degree, tumour size, pathological type and parametrial infiltration (p>0.05). Pearson correlation analysis showed that the expression of AEG-1 was linked with NF-kB p65 (r=0.501, p=0.000), VEGF (r=0.718, p=0.000) as well as MVD in cervical cancer tissue (r=0.815, p=0.000). Conclusions: AEG-1 is highly expressed in cervical cancer and promotes angiogenesis, which might be related to the fact that AEG-1 activating the signal pathway of NF-kB could up-regulate the level of VEGF expression.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7785-7792
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• 2014

Background: Valproic acid (VPA) is a potent anticancer and antiangiogenic agent. However, design and synthesis of chemical derivatives with improved antiangiogenic and anticancer activities are still necessary. In this study a library of novel derivatives of VPA was synthesized and tested. Methods: A human liver cancer cell line (HepG2) and a human normal embryonic kidney cell line (HEK 293) were exposed to various concentrations of VPA derivatives for 24 hours and cell viability was checked by MTT colorimetric assay. Anti-angiogenic properties were evaluated in transgenic zebrafish embryos. Results: N-valproylglycine derivatives suppressed survival almost 70% (p value 0.001) in HepG2 cells but only 10-12% in HEK 293 cells (p value 0.133). They also suppressed angiogenic blood vessel formation by 80% when used between $2-20{\mu}M$ in zebrafish embryos. Valproic acid hydrazides showed moderate level of anticancer activity by affecting 30-50% (p value 0.001) of cell viability in HepG2 cells and 8-10% in HEK293 cells (p value 0.034). Conclusion: The majority of compounds in this study showed potent and stronger antiangiogenic and anticancer activity than VPA. They proved selectively toxic to cancer cells and safer for normal cells. Moreover, these compounds inhibited developmental angiogenesis in zebrafish embryos. Based on the fact that liver is a highly vascularized organ, in case of liver carcinoma these compounds have the potential to target the pathological angiogenesis and could be an effective strategy to treat hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3219-3222
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• 2012

A comparative study between 17 Japanese and 19 Indian patients with oral squamous cell carcinomas (OSCCs) revealed that the tumour prognostic indicator mean vessel density (MVD) count for angiogenesis was relatively high at 57.1 in Indian as compared to 39.3 in Japanese (P=0.001) cases, whereas the lymph-vessel density (LVD) count for lymphangiogenesis was lower (12.8 vs 48.0, P=0.002). Both male and female Indians had higher MVD counts, but LVD counts were only slightly lower in females. MVD count was relatively high among the cases below 65 years old in both the countries (P=0.4). Japanese cases with Tongue cancer had higher MVD count, but the Indian cases had lower LVD counts. Size-wise, T2 and T3 had higher counts of MVD both in Indian and Japanese cases. MVD and LVD count was higher in grades II and III both in Japanese and Indian cases. There was insignificant difference of the MVD counts among smokers, but the tobacco chewers in Indian cases had higher counts of MVD and LVD (P value by Bartlett test 0.35, 0.57 respectively). The hot-spots of tumour sites had variable rates of lymphocyte infiltration showed higher MVD counts in all the cases. Although the clinical characteristics and demographic variables usually relate to MVD and LVD counts, the tendency of higher values, especially among tobacco chewers, identified as the highest risk group for occurrence of oral cancer needs to be investigated further.