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Growth and Invasion of Sporadic Colorectal Adenocarcinomas in Terms of Genetic Change
노선애,최은영,조동형,장세진,김선영,김용성,김진천 대한의학회 2010 Journal of Korean medical science Vol.25 No.3
Integrative genetic changes were examined in relation to tumor growth and progression of sporadic colorectal cancers. Ninety-two sporadic colorectal cancer patients and 12 human colorectal cancer cell lines were evaluated. Genetic changes in representative steps of colorectal tumorigenesis were determined. Biological characteristics,i.e., clinicopathologic parameters, expression of invasion-associated molecules,and in vitro invasion and migration, in association with these changes were further analyzed. Adenomatous polyposis coli (APC) and/or Wnt-activated alterations occurred in 66% patients, whereas mismatch repair (MMR) defects and/or RAFmediated alterations were identified in 47% patients. The crossover rate between these two alterations was 26%. Differential mRNA expression of ARK5 was closely associated with that of MMP2, MMP9, and S100A4 (P≤0.044-0.001). Additionally,enhanced ARK5 mRNA expression was more frequent in tumors displaying RAF-mediated alterations and crossover pathways (P=0.01 and 0.03, respectively). Upregulation of CEA mRNA was more common in the advanced stages (P=0.034), while VEGF expression was greater in poorly differentiated or mucinous tumors (P=0.042). The high expressions of MMP2 and MMP9 were closely associated with invasion and migration of colorectal tumors and cell lines. Our results conclusively show that specific pathways of colorectal tumorigenesis are closely associated with characteristic tumor growth and invasion.
산발성 위암에서 Microsatellite Instability 빈도와 hMLH1 촉진자부위 메칠화
김희철,노선애,육정환,오성태,김병식,유창식,김진천,Kim Hee Cheol,Roh Sun Ae,Yook Jeong Hwan,Oh Sung Tae,Kim Byung Sik,Yu Chang Sik,Kim Jin Cheon 대한위암학회 2003 대한위암학회지 Vol.3 No.1
Background: An aberrant function of the mismatch repair system has been reported to underlie carcinogenesis in several tumors, including colorectal and gastric carcinomas, and to induce the typical genotype of microsatellite instability (MSI). Purpose: We aimed to determine the frequency of MSI in early-onset sporadic gastric carcinoma and elucidate the role of promoter methylation in hMLH1 as the mechanism of MSI. Materials and Methods: Thirty-six early-onset sporadic gastric carcinomas were analyzed to determine the status of MSI and the frequency of methylation of the promoter region in hMLH1. MSI was determined using five markers recommended by NCI: MSI-H (high), MSI-L (low), and MSS (Microsatellite stable). Methylation specific PCR (MSP) and direct automated genomic sequencing analysis with DNA modified by sodium bisulfite have been performed to confirm promoter region methylation. All the data were analyzed regarding characteristics of molecular changes, and clinicopathologic variables. Results: The microsatellite status was determined as MSI-H in five cases ($13.8\%$), MSI-L in 13 cases ($36.1\%$), and MSS in 18 cases ($50.0\%$). hMLH1 was methylated in seven cases ($19.4\%$). In all cases of MSI-H, promoter of hMLH1 was methylated, and in two of the 13 cases of MSI-L, hMLH1 promoter methylation was identified. Methylation was not found in any cases of MSS. Promoter methylation in hMLH1 was significantly correlated with MSI status (P<0.001). We could not find any relationship between MSI and clinicopathologic parameters. Conclusion: These results suggest that an abnormal function of the mismatch repair system may be associated with gastric carcinogenesis in more than $10\%$ of early-onset gastric carcinomas and MSI appeared to be closely related to the promoter methylation in hMLH1.
대장암 세포주의 개별 항암화학요법에 대한 침습성과 약제감수성
이유미,윤용식,노선애,조동형,김진천 대한대장항문학회 2010 Annals of Coloproctolgy Vol.26 No.2
Purpose: Colorectal cancer (CRC) is one of the leading causes of cancer death in South Korea. Angiogenesis has been associated with invasion and metastasis of tumors and with the secretion of various growth factors. Bevacizumab is a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor (VEGF) and that targets integrin aVb3and matrix metalloproteinases (MMPs) as angiogensis inhibitors. The aims of this study were identification of the mechanism of target molecules related to angiogenesis and demonstration of identifiable invasion by using chemotherapeutic regimens in vitro. Methods: The five colorectal cancer cell lines were treated with bevacizumab using standard or combined regimens. The expression of integrin aVb3 was detected and the investigation of apoptosis was done by using flow cytometry. The activations of MMP-2 and MMP-9 were measured by using gelatin zymography. Results: The apoptotic cell death was significantly increased for the combined regimens, especially for FOLFOX (5-FU,leucovorin, and oxaliplatin) with bevacizumab. Bevacizumab inhibited the expression of integrin aVb3 in the HT29 (59%),LoVo (67%), and SW480 (17%) cell lines, but did not in the AMC5 and the RKO cell lines. The activations of MMP-2 and MMP-9 were significantly reduced by treatment with bevacizumab in the HT29 and the LoVo cell lines. In the HT29 and the LoVo cell lines, thus, bevacizumab inhibited invasion and metastasis activity through down-regulation of integrin aVb3 and MMPs. Conclusion: Our results provide biological evidence of potent angiogenic activity and indicate that angiogenesis is a complex process that involves multiple factors, including VEGF, integrin aVb3, and MMPs.