• BMB Reports
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• 제36권1호
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• pp.43-48
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• 2003

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multi-mechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.

• Journal of Gastric Cancer
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• 제20권2호
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• pp.212-224
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• 2020

Purpose: miR-205 is a tumor suppressor and plays an important role in tumor invasiveness. However, the role of miR-205 in human gastric cancer (GC) epithelial-mesenchymal transition (EMT) remains unclear. The aim of this study was to investigate the molecular mechanism of miR-205 in the regulation of EMT in GC invasion. Materials and Methods: Quantitative polymerase chain reaction (qPCR) was used to detect the expression of miR-205 in GC. Further, the correlation between the pathological parameters and prognosis of GC was statistically analyzed. A transwell model was used to evaluate the effect of miR-205-3p on the invasion and migration of GC cells. qPCR, western blotting, and luciferase assay were performed to analyze the relationship and target effects between miR-205-3p and the expression of zinc finger electron box binding homologous box 1 (ZEB1) and 2 (ZEB2). Results: We found that the levels of miR-205-3p were significantly lower (P<0.05) in GC tissues than in matched normal tissues. Additionally, the expression of miR-205-3p was related to the tumor invasion depth, lymph node metastasis, lymph node invasion, and tumor, node, metastasis stage. Patients with lower miR-205-3p expression levels in the tumors had a poorer prognosis. The in vitro assays indicated that miR-205-3p could affect the invasion ability and EMT of GC cells by targeting the expression of both ZEB1 and ZEB2. Conclusions: miR-205-3p promotes GC progression and affects the prognosis of patients by targeting both ZEB1 and ZEB2 to directly influence EMT.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제27권2호
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• pp.142-149
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• 2001

To investigate the correlation between the clinical features and the expression of p53, PCNA, and Ki-67 of the head neck squamous cell carcinoma, immunohistochemicalstaining of p53, PCNA, and Ki-67 on the paraffin embedded tissue blocks of 116 surgically removed specimens were done. The staining intensity was divided as grade 1 to grade 3 and the results were statistically analysed. 1. The positive reation rates of cell proliferation markers (PCNA and Ki-67) were higher than that of p53. There was significant correlations of the PCNA and Ki-67 expression but there was no significant correlations between p53 and PCNA or p53 and Ki-67. 2. There were no significant correlation between the expression of p53, PCNA and Ki-67 and tumor site or tumor size. 3. There was no significant differences in the positive response according to the nodal status. The node metastasis groups revealed that higher proportion of grade 3 staining of PCNA and Ki-67 than node negative group. From the above results it is concluded that p53 and cell proliferation markers PCNA and Ki-67 might have their unique mechanism involving in the growing and progression of tumor. Overexpression of p53 does not appear to represent an independent prognostic marker in head neck squamous cell carcinoma.

• 생명과학회지
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• 제29권1호
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• pp.9-17
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• 2019

암조직의 내부에서 hypoxia와 glucose depletion 등의 microenvironmental stress를 받게 되면 necrosis가 유도되고, 실제로 암 조직 내부에서 necrotic core 형성이 관찰된다. Necrotic cells은 high mobility group box 1(HMGB1)를 extracellular space로 방출하는 것으로 알려져 있다. 방출된 HMGB1은 tumor-promoting cytokine으로 작용함으로써 tumor development 시 inflammation, metabolism 및 metastasis에 기여한다. 본 연구에서 non-invasive breast cancer cells MCF-7이 solid tumor의 in vitro model인 multicellular tumor spheroid (MTS) 배양을 통해 완전한 구형의 MTS를 형성하며 MTS가 성장함에 따라 inner region에 necrosis가 유도됨을 밝혔다. 또한 MCF-7 세포의 MTS 배양은 Snail 의존적으로 epithelial-mesenchymal transition (EMT)를 유도함을 관찰하였다. HMGB1의 cell surface receptors인 RAGE, TLR2, TLR4 발현이 MTS 배양에 의해 증가됨을 발견하였다. RAGE, TLR2, TLR4 를 knockdown한 결과 MTS 성장을 억제할 뿐만 아니라 MTS에 의해 증가되는 Snail 발현을 억제함을 밝혔다. 이는 MTS-induced Snail 발현이 RAGE/TLR2/TLR4의존적으로 조절되며 RAGE/TLR2/TLR4-Snail이 MTS 성장에 관여하는 것으로 보인다. 또한 Snail, RAGE, TLR2, TLR4 shRNA는 MTS 배양에 의해 유도되는 EMT를 억제함을 밝혔다. 실제 인간 암조직에서 정상조직에 비해 RAGE, TLR2, TLR4 유전자의 발현이 높음을 관찰하였다. 따라서 HMGB1이 RAGE/TLR2/4-Snail axis를 통해 MTS 배양에 따른 성장 및 EMT에 중요하게 작용할 것으로 예상된다.

• 대한골관절종양학회지
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• 제11권1호
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• pp.46-53
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• 2005

목적: Bisphosphonate(BPs)는 endogenous pyrophosphates의 유사체로 Paget's disease, 골다공증, 종양 유발성 골용해와 같은 골격계 질환의 치료에 쓰이고 있으며, 유방암의 골파괴성 전이에 대한 치료제로 사용되어 지고 있다. 골전이의 양상이 골흡수성 및 골생성이 혼합되어 나타나는 전립선암의 전이에서도 치료제의 하나로 이용되고 있다. BPs는 파골세포성 골흡수가 과하게 일어난 질환에 대해서는 비교적 널리 알려져 있지만, 골종양 세포에 대한 직접적인 효과에 대해서는 아직 밝혀져 있지 않다. 가장 강력한 질소 함유(nitrogen-containing) BPs인 Zoledronic acid(ZOL)로서 골육종이 발현된 nude mouse model을 이용하여 ZOL의 종양 억제능을 생체내 실험으로 확인하고자 하였다. 대상 및 방법: 인간 골육종 세포주로는 MG-63과 HOS 골육종 세포주를 이용하였고, 종양의 크기 변화를 육안으로 확인하기 위하여 GFP 유전자가 형질 전환된 MG-63-GFP, HOSGFP 세포를 6주령된 수컷 마우스 10마리에 각각 피하주사하여 종양의 조각이 $3{\times}3{\times}3$ mm이 될 때까지 사육한 후, ZOL을 120 ug/kg의 농도로 일주일에 2번 피하에 주사하였다. 종양의 크기를 일주일에 두 번씩 측정하고, 형광조명을 이용하여 촬영하였다. 결과: HOS 골육종 세포주를 이용한 생체실험에서 대조군의 종양의 평균 크기는 2,520 $mm^3$이며 ZOL 투여군은 131 $mm^3$로서 94%의 감소를 보이며, MG-63 골육종 세포주를 이용한 생체실험에서는 대조군의 종양의 평균 크기는 2,866 $mm^3$이며 실험군은 209 $mm^3$로서 72%의 감소를 보였다(P<0.05). 결론: Nude mouse를 이용한 생체실험에서 ZOL은 골육종의 세포사멸에 직접적인 영향을 미치며 이것은 앞으로 골육종 치료의 약제중 하나로 선택되어 질수 있다고 판단되며, 종양세포주에 따라 ZOL의 영향이 다를 수 있으므로 ZOL에 감수성 있는 종양세포를 찾아 적용하는 것이 좋을 것으로 사료된다.

• 대한두경부종양학회지
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• 제21권1호
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• pp.3-9
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• 2005

Purpose: In oral tongue cancer, the degree of tumor invasion has a significant effect on the prognosis. We hypothesized that the destruction of extracelluar matrix and neovascularization are related to tumor infiltration mechanism. By studying the the tissues of early stage oral tongue cancer patients, we are intend to clarify the invasion related factors in oral tongue cancer. Material and Methods: To demonstrate the invasion process in early T-stage oral tongue cancer, the expressions of extracellular matrix destruction related molecules(MMP2, MMP9) and neovascularization related molecule(VEGF) were observed by immunohistochemical study. Also, immunohistochemical staining of CD31 was done for quantification of neovascularization. With the experiment showed above, we analyzed relationship between expression of each substances and tumor invasion depth, tumor free survival rates and cervical lymph node metastasis rate in early T-stage oral tongue cancer. Results: The expression rates of MMP2, MMP9, VEGF in 38 early oral cancer patients were 52.6%, 78.9% 52.6%, respectively. Significant correlation was found between the VEGF expression and microvessel density showed by CD31 immunohistochemical staining(p<0.001). VEGF expressions were significantly related with tumor invasion depth(p=0.002). The tumor free survival rate of those patients with VEGF-positive tumors was significantly poorer than in those with VEGF-negative tumors(p=0.019). Conclusion: This results indicate that VEGF is a useful marker for predicting the tumor invasion in patients with early tongue cancer and could be used as a beneficial factors in defining operative field and prognosis.

• Journal of Gastric Cancer
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• 제1권2호
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• pp.92-99
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• 2001

Purpose: E-cadherin is an adhesion molecule essential for tight connection between cells, forming the cadherin/catenin complex. Truncated $\beta$-catenin disrupts the interaction between E-cadherin and $\alpha$-catenin, leading to the loss of intercellular adhesion. Met protein, the hepatocyte growth factor receptor, plays important roles in signal transduction. We investigated the relationships between the expressions of E-cadherin, $\beta$-catenin, and c-met protein and the clinicopathological and prognostic parameters in gastric adenocarcinomas. Materials and Methods: The patterns of E-cadherin, $\beta$-catenin, and c-met protein expression were studied using immunohistochemistry in formalin-fixed, paraffin-embedded archival tissues from 76 surgically resected gastric adenocarcinomas. Results: Increased expressions of E-cadherin, $\beta$-catenin, and c-met were more significantly correlated in early gastric cancers (EGC) than in advanced gastric cancers (AGC) (P=0.002, P=0.003 and P=0.026). The positive immunoreactivities of all three markers were markedly lower in signet ring-cell type and poorly differentiated type lesions than in intestinal-type lesions. Decreased expression of the $\beta$-catenin protein correlated well with increased tumor invasion depth (P=0.039), and increased lymph node metastasis correlated well with reduced expression of c-met (P=0.046). Conclusion: In gastric cancers, reduced expressions of the E-cadherin, $\beta$-catenin, and c-met proteins may play some role in poorer tumor differentiation, deeper tumor invasion, and increased lymph node metastasis. Also, the c-met gene is thought to play a specific role in the mechanism of the yet unknown catenin action.

• 한국임상수의학회지
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• 제25권4호
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• pp.249-256
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• 2008

This experiment was conducted to investigate antitumor and immunomodulatory effects of Artemisia capillaris extracts against Hepa-lc1c7 and Sarcoma 180 cancer cells. In in vivo experimental tests using 210 ICR mice, on the $28^{th}$ day and the $42^{nd}$ day, all animals in vehicle controled HP (Hepa-lclc7 tumor cell inoculated vehicle control) and SP (Sarcoma 180 tumor cell inoculated vehicle control) showed tumor cells in the liver and spleen based on the histopathology. However, the incidences and the percentages of regions occupied by tumor cells were dramatically and dose-dependently decreased by mACH (Artemisia capillaris methanol extracts) treatment on the histomorphometry. Although the exact mechanism of inhibition of the incidences of tumor cells in the parenchyma whether inhibition of metastasis or proliferation is unclear, mACH dramatically reduce the percentages of regions occupied by tumor cells in the liver and spleen apart from the inoculation sites of Hepa-lclc7 and Sarcoma 180. In addition, they also effectively inhibit the abnormal changes on the kidney detected in the present study. The results suggest that Artemisia capillaris methanol extracts have prominent antitumor effects on the cancer cell lines Hepa-lclc7 and Sarcoma 180 m mice.

• 대한약침학회지
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• 제19권3호
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• pp.259-263
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• 2016

Lung cancer has a high mortality rate and is often diagnosed at the metastatic stage. Gefitinib is a targeted molecular therapeutic drug used to treat patients with non-small-cell lung cancer (NSCLC). Korean herbal medicines may also have therapeutic efficacy against lung cancer, reduce the side effects associated with chemotherapy, and improve patient quality of life (QOL). This case report describes the effects of a Korean herbal medicine regimen combined with gefitinib in a patient with NSCLC and bone metastasis. The Korean herbal medicine regimen included woohwanggeosa-dan, hwanggibujeong-dan and geonchilgyebok-jeong. The computed tomography (CT) findings showed that following combination treatment, the size of the tumor was markedly decreased without serious adverse events. Moreover, the Eastern Cooperative Oncology Group (ECOG) performance status was improved and cancer-related pain was decreased. These results suggest that a combination of Korean herbal medicines and gefitinib may be an effective therapeutic option for patients with advanced NSCLC and bone metastasis. Further studies are needed to examine the mechanism and the clinical efficacy of Korean herbal medicines against NSCLC.

• BMB Reports
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• 제50권12호
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• pp.621-627
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• 2017

We previously reported the involvement of zinc-finger protein 143 (ZNF143) on cancer cell motility in colon cancer cells. Here, ZNF143 was further characterized in breast cancer. Immunohistochemistry was used to determine the expression of ZNF143 in normal tissues and in tissues from metastatic breast cancer at various stages. Notably, ZNF143 was selectively expressed in duct and gland epithelium of normal breast tissues, which decreased when the tissue became malignant. To determine the molecular mechanism how ZNF143 affects breast cancer progression, it was knocked down by infecting benign breast cancer cells with short-hairpin (sh) RNA-lentiviral particles against ZNF143 (MCF7 sh-ZNF143). MCF7 sh-ZNF143 cells showed different cell-cell contacts and actin filament (F-actin) structures when compared with MCF7 sh-Control cells. In migration and invasion assays, ZNF143 knockdown induced increased cellular motility in breast carcinoma cells. This was reduced by the recovery of ZNF143 expression. Taken together, these results suggest that ZNF143 expression contributes to breast cancer progression.