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Epigenetic Regulation and Oncogenic Potential of the Cancer/Testis Antigen CAGE
Jeoung, Doo-Il,Lee, Hansoo 이화여자대학교 세포신호전달연구센터 2009 고사리 세포신호전달 심포지움 Vol. No.11
We previously identified a novel cancer/testis antigen gene, CAGE, which is expressed in various histological types of tumors, but not in normal tissues, with the exception of the testis. In our expression analysis, we found that some cancer cell lines did not express CAGE. The expression of CAGE could be restored in these cell lines by treatment with 5'-aza-2'-deoxycytidine, suggesting that the expression of CAGE is mainly suppressed by hypermethylation. Bisulfite sequencing analysis of the 16 CpG sites of the CAGE promoter in various cancer cell lines and tissues revealed a close relationship between the methylation status of the CAGE promoter and the expression of CAGE. A methylation-specific PCR analysis revealed that hypomethylation of the CAGE promoter was present at frequencies of more than 60% in breast, gastric, and lung cancers, and hepatocellular carcinomas, and at frequencies of less than 40% in prostate, uterine cervical, and laryngeal cancers, but absent in normal prostate, normal colon, or chronic hepatitis. These results suggest that the methylation status of the CpG sites of CAGE determines its expression and the hypomethylation of CAGE precedes the development of gastric cancer and hepatocellular carcinoma. Meanwhile, ectopic-expression of CAGE in fibroblast cells resulted in foci formation, suggesting its cell transforming ability. Using stable HeLa transfectant clones with tetracycline-inducible CAGE gene, we found that CAGE overexpression stimulates both anchorage-dependent and -independent cell growth in vitro and promotes tumor growth in a mouse xenograft model. Cell cycle analysis showed that overexpressed CAGE accelerates G₁-S phase transition and activates CDK4/2 by increasing the levels of cyclin D1 and E. Moreover, CAGE-induced expression of the cyclin D1 and E was observed even at arrested-state, indicating direct involvement of CAGE in the regulation of this G₁ cyclin genes expression. The role of CAGE in the transcriptional regulation of cyclin D1 and E genes were found to be mediated by AP-1 and E2F-1 transcription factors and, among AP-1 family members, c-Jun and JunB playa central role in up-regulating cyclin D1 expression. CAGE overexpression also enhanced Rb phosphorylation and subsequent E2F nuclear translocation. These results suggest that the cancer/testis antigen CAGE promotes cell cycle progression by stimulating AP-1- and E2F-dependent expression of cyclin D1 and E.
Epidemiological Observation on Recent Outbreaks of Canine Distemper in Korea
Doo Kim,Son-il Pak,Ji-young Park,So-jeo Ahn,Seok-young Jeoung 한국임상수의학회 2004 한국임상수의학회지 Vol.21 No.3
To characterize the recent outbreaks of canine distemper (CD) in Korea, we carried out epidemiologicalinvestigations by clinical observations, serum neutralizing (SN) antibody titer determination and RT-PCR on the 315 dogswere infected with CDV. Breed or gender did not sem to have effects on the prevalence of CD. The major part ofdogs were in young age from 6 weeks to 18 weeks of age, and were not vaccinated or incompletely vaccinated. Clinicalsigns of dogs with CD were multisystemic and extremely variable. Dogs died from CD had significantly more ocularsigns and neurologic signs than those of dogs survived (p<0.05). The SN titers against CDV of 157 (96.9%) dogs wereunder 1:16, which is less than protective level. One possible explanation for recent outbreaks of CD in Korea mightbe low antibody titers against CDV because of vacination failure. Therefore, to reduce the impact of virulent infectionin the dog population, dogs should be vacinated adequately and prophylactic measures should include isolation of youngdogs from the dog population until vaccination can be expected to provide protection. 본 연구에서는 최근 국내에서 발병하는 개 디스템퍼(CD)의 역학적 조사를 위하여 2002년 2월부터 2002년 10월까지 강원도, 경기도와 서울특별시의 10개 동물병원 수의사에 의하여 CD에 감염된 것으로 잠정진단된 315마리의 개를 대상으로 하였다. 개체의 신상자료와 임상증상을 조사하였으며 CD를 확진하기 위하여 혈액의 단핵구나 결막 상피세포에서 CDV의 NP gene을 RT-PCR로 증폭하였다. CD로 의심되는 총 315마리 중 162마리가 CD 양성으로 진단 되었으며 성별과 종에 따른 발병율에는 차이가 없었다. 나이별 분포는 백신을 접종해야 하는 기간인 6-18주에 가장 높은 분포를 보였으며 1세 이상에서도 소수 발병하였다. CD 환축은 호흡기 증상, 위장관 증상, 눈의 증상 등 다양한 증상이 나타나 임상증상에 근거하여 CD를 진단하기에 어려움이 있었다. CD 양성의 개 중 84.6%가 백신을 한번도 맞지 않았거나 예방접종을 제대로 실시되지 않은 상태였으며 CDV에 대한 혈청 중화 항체가는 96.9%의 개가 방어수준 이하인 1:16 이하를 나타내었다. CD 양성 162마리와 CD음성으로 진단 된 153마리의 혈청 중화 항체가 사이에는 통계적인 유의차가 인정되었으며 (P< 0.05), CD 양성 개 중에 생존 한 개들은 폐사한 개들보다 중화 항체가 높은 경향을 보였다. 눈의 증상과 신경증상을 보인 개체들은 다른 개체들에 비해 생존율이 유의하게 낮은 것으로 나타났다 (P< 0.05). 본 연구의 결과 현재 국내에서 발병하고 있는 개 디스템퍼는 예방접종의 실패에 따라 개들의 항체 수준이 전반적으로 낮은 것에 기인하는 것으로 판단되므로 예방접종에 대한 전반적인 검토가 필요하며 예방을 위하여 감염에 취약한 시기에는 감염원에 접촉을 최소화하는 것이 중요할 것으로 판단되었다.
Epidemiological Observation on Recent Outbreaks of Canine Parvoviral Enteritis in Korea
Seok-Young Jeoung,Doo Kim,So-Jeo Ahn,Son-Il Pak 한국임상수의학회 2006 한국임상수의학회지 Vol.23 No.3
ontrolled successfully by the use of low-passage hightiter modified live CPV vaccines. However, outbreaks of CPV enteritis have been continued in Korea. In this study,we carried out epidemiological investigation on the recent outbreaks of CPV enteritis of dogs and determined thepotential prognostic factors affecting the survival of dogs. The total of 140 dogs diagnosed for CPV enteritis werestatistically analysed. The majority of dogs were from 6 to 18 weeks of age and were not vaccinated or incompletelyvacinated. There were significant difference in the survival rate between male and female dogs with CPV enteritisand among the age groups (PHI titer <80 group and HI titer 160 group (P<0.05). The majority of dogs had a history of diarrhea, vomiting, lethargyand dehydration. It was considered that recent outbreak of CPV enteritis in Korea caused by the failure of vaccinationand/or by the inadequate antibody responses to CPV vaccines. Prophylactic measures should include isolation of youngdogs from the dog population until the vaccination can be expected to provide protection.