Beyond X-Chromosome Inactivation: The Oncogenic Facet of XIST in Human Cancers

Long-non coding RNAs (LncRNAs) constitute a wide and extremely diverse family of RNA transcripts that are greater than 200 base pairs in length and are not translated into proteins. X-inactive specific transcript (XIST) was the first long non-coding RNA to be discovered, back in 1991. Its function in X-chromosome inactivation has been extensively studied for three decades, though other functional roles of XIST that involve a variety of fascinating mechanisms remain to be elucidated. Here, we review the emerging oncogenic role of XIST in various human cancers.ope

조직유형에 따른 조절효과를 중심으로

학위논문(석사) -- 서울대학교대학원 : 행정대학원 공기업정책학과, 2022. 8. 박정훈.This study analyzed the effect of the introduction of the 52-hour workweek system on workers' organizational commitment and workers' satisfaction, and whether there is a difference in the policy effect of the 52-hour workweek system depending on the type of organization, that is, the difference between public and private organization. The 52-hour workweek system was revised by the government to improve the long-term working culture and to promote balance workers' work and life in 2018. The law was implemented step by step, starting with the public sector and large companies. Unlike the existing labor policy that limits legal working hours, it is a policy that limits the actual maximum working hours to 52 hours per week. So, it is necessary to study how the policy effect of the new 52-hour workweek system will appear. This study used data based on the results of the three-year (2016, 2017, 2018) survey conducted by the Korean Labor and Income Panel Study(KLIPS). To analyze the policy effect of the 52-hour workweek system according to the type of organization, it was analyzed through DID(Double Difference, Difference in difference) model and DDD(Triple Difference, Difference in difference in difference) model. Independent variables were set the policy groups and the policy time. Policy time is before and after policy implementation. Dependent variables were worker’s organizational commitment, worker’s job satisfaction, and worker’s life satisfaction. The factors that there were gender, age, education level, marital experience, health status, wage or income, and total working hours were used as control variables, and public organizations and private organizations were used as moderator variables to determine their impact. As a result of the analysis, the 52-hour workweek system was found to have a negative effect on workers' organizational commitment, The workers' job satisfaction and workers' life satisfaction were not statistically significant. In addition, organizational commitment of workers according to the organizational type was not statistically significant. In job satisfaction and life satisfaction, statistically, it was significant in the negative (-) direction. In other words, it was confirmed that the 52-hour workweek system effect on job satisfaction and life satisfaction was greater in public organizations than in private organizations. Through these analysis results, the following policy implications were presented. First, in order to maximize the policy effect of the 52-hour workweek system, the government and companies should supplement and implement policies according to the type of organization and the nature of the company. It can be seen that many consultations are needed through labor unions for each other's benefit. Second, since the simple reduction of working hours does not affect the employee's organizational commitment, job satisfaction, and life satisfaction, it is necessary to prepare various working systems to suit individual optimal working hours and working environment. Third, unlike public organizations, private organizations that pursue efficiency should consider the direction of establishing a 52-hour workweek system by reducing working hours and giving appropriate incentives to individuals to increase their motivation to work. This study is significant in that it restricts overtime and empirically analyzes the policy effects of the 52-hour workweek system by type of organization. However, the limitations of this study are that it was not a questionnaire whose main purpose was to investigate the reduction of working hours, that it used only some personal data and did not reflect the characteristics of individual companies, and that it was not possible to perform a detailed analysis including various control variables. Therefore, it is necessary to analyze the above-mentioned limitations in subsequent studies.본 연구는 주 52시간제 도입이 근로자의 조직몰입도와 만족도에 미치는 영향에 대한 분석과 조직유형에 따른 차이 즉, 공공조직과 민간조직의 근로자에 따라 주 52시간 근로제도의 정책효과 차이가 존재하는가에 대한 분석을 다루었다. 주 52시간 근로제도는 장시간 근로문화를 개선하고 근로자의 일과 생활의 균형을 위해 정부가 2018년 근로기준법을 개정하였고 공공부문과 대기업을 시작으로 기업 규모별로 단계적으로 법이 시행되었다. 기존 근로 정책이 법정근로시간을 제한하였다면 개정된 주 52시간제는 주당 실제 최대 근로시간을 주 52시간으로 제한하는 정책이다. 이에 차별성을 구분하여 개정된 주 52시간제 정책도입 효과에 대해 분석해 볼 필요가 있다. 본 연구는 국내 유일의 노동 자료인 한국노동패널 자료 중 정책 시행 전후 3개년을 활용하였고 조직유형에 따른 주 52시간 근로제도의 정책효과 분석을 위해 이중차분모형과 삼중차분모형을 활용해 분석하였다. 독립변수는 정책적용 그룹, 정책 전후로 정하고, 종속변수는 조직몰입도, 직무만족도, 삶의 만족도로 하였다. 성별, 연령, 교육수준, 결혼경험유무, 건강상태, 임금 또는 소득, 총근로시간 요소를 통제변수로 하고, 공공조직과 민간조직을 조절변수로 하여 그 영향을 파악하고자 하였다. 분석결과 주 52시간 근로제도는 근로자의 조직몰입도에 부정적인 영향을 미치는 것으로 나타났으며 근로자의 직무만족도, 삶의 만족도는 통계적으로 유의미하지 않았다. 그리고 조직유형에 따른 근로자의 조직몰입도는 통계적으로 유의미하지 않게 나타났으며 직무만족도 및 삶의 만족도에서는 통계적으로 음(-)의 방향으로 유의하게 나왔다. 즉, 민간조직보다 공공조직에서 직무만족도, 삶의 만족도에 대한 주 52시간제 정책효과가 크게 나타난다는 것을 확인하였다. 이러한 분석결과를 통하여 다음과 같은 정책적 시사점을 제시하였다. 첫째, 정부와 기업은 주 52시간 근로제도의 정책효과를 극대화하기 위해 조직유형, 기업의 성격 등에 맞게 정책을 보완해서 시행해야 하며 기업과 근로자 간 서로의 편익을 위해 노동조합을 통해 사전에 많은 협의와 조정이 필요함을 알 수 있다. 둘째, 단순 근로시간 단축은 근로자의 조직몰입도, 직무만족도, 삶의 만족도에 영향을 끼치지 않으므로 개인의 최적 근로시간, 근무환경 등에 맞게 다양한 근로제도가 마련되어야 할 필요성이 있다. 셋째, 공공조직과 달리 효율성을 추구하는 민간조직은 근로시간 단축과 더불어 개인에게 적절한 인센티브를 부여하여 근로 의욕을 높이는 방법으로 주 52시간 정책을 정착해 나가는 방향도 고려해야 한다. 본 연구는 초과근로를 제한하고 조직유형별로 주 52시간 근로제도의 정책효과를 실증적으로 분석하였다는 점에서 의의가 있다. 그러나 근로시간 단축 조사가 주요 목적인 설문지가 아니었던 점, 일부 개인용 자료만 활용하고 개별 기업 특성을 반영 못했던 점, 다양한 통제변수를 포함시켜 정밀한 분석을 하지 못했던 점이 본 연구의 한계이다. 이에 후속 연구에서는 앞서 언급한 한계점을 반영하여 분석할 필요성이 있다.제 1 장 서 론 1 제 2 장 이론적 배경과 선행연구 검토 3 제 1 절 주 52시간제 3 1. 주 52시간제 도입배경 3 2. 주 52시간제 선행연구 7 제 2 절 조직몰입도 15 1. 조직몰입 개념과 이론 15 2. 조직몰입 관련 선행연구 16 제 3 절 직무만족도 18 1. 직무만족 개념과 이론 18 2. 직무만족 관련 선행연구 20 제 4 절 삶의 만족도 22 1. 삶의 만족 개념과 이론 22 2. 삶의 만족 관련 선행연구 23 제 5 절 조직유형 25 1. 조직유형 이론 25 2. 조직유형 관련 선행연구 26 제 6 절 선행연구와의 차별성 28 제 3 장 연구 방법 29 제 1 절 연구의 분석틀 29 1. 연구모형 29 2. 연구문제 및 가설의 설정 30 제 2 절 변수의 조작적 정의 32 1. 독립변수 32 2. 종속변수 32 3. 조절변수 35 4. 통제변수 35 5. 변수의 조작적 정의 36 제 3 절 자료수집 및 분석방법 37 1. 자료수집 37 2. 분석방법 : 이중차분법과 삼중차분법 39 제 4 장 분석결과 40 제 1 절 기초통계량 40 1. 요인분석 및 신뢰도 분석 41 2. 빈도분석 43 3. 기술통계분석 45 4. 독립표본 T검정 47 5. 상관관계 분석 48 제 2 절 다중회귀 분석 50 1. 다중회귀 분석 50 2. 주 52시간제 정책효과 분석 52 3. 조직유형에 따른 주 52시간제 정책효과 분석 61 4. 가설검증 결과 64 제 5 장 결론 65 제 1 절 연구의 요약 65 제 2 절 정책의 시사점 67 제 3 절 연구의 한계 69 참고문헌 71 부 록 75 Abstract 90석

Depletion of CTCF disrupts PSG gene expression in the human trophoblast cell line Swan 71

Pregnancy-specific glycoproteins (PSGs) are fetal proteins secreted by the placenta during pregnancy. The PSG level in maternal serum is an indicator of risk for pregnancy complications. However, little is known about the molecular mechanisms underlying PSG gene expression. Recently, the importance of epigenetic regulation of placental genes has been emphasized in the study of developmental defects and placental disease. In this study, the role of the CCCTC-binding factor (CTCF) in regulation of PSG expression was investigated to better understand the epigenetic regulatory mechanisms of the PSG genes. Inhibition of CTCF expression disturbed transcription of several PSG genes: PSG1, PSG2, PSG4, PSG5, PSG8, and PSG9 were upregulated and PSG6 and PSG11 were downregulated. These transcriptional changes were correlated with decreased CTCF binding and changes in histone modification at the PSG promoters. Our data demonstrate that CTCF is a potential mediator in the regulation of PSG gene expression.ope

FAM188B Expression Is Critical for Cell Growth via FOXM1 Regulation in Lung Cancer

Although family with sequence similarity 188 member B (FAM188B) is known to be a member of a novel putative deubiquitinase family, its biological role has not been fully elucidated. Here, we demonstrate the oncogenic function of FAM188B via regulation of forkhead box M1 (FOXM1), another oncogenic transcription factor, in lung cancer cells. FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1. FAM188B knockdown also resulted in downregulation of Survivin and cell cycle-related proteins, which are direct targets of FOXM1. Interestingly, FOXM1 co-immunoprecipitated with FAM188B, and the levels of FOXM1 ubiquitination increased with FAM188B knockdown but decreased with FAM188B overexpression. In addition, in vivo xenograft of FAM188B siRNA (siFAM188B) RNA-treated cells resulted in the retardation of tumor growth compared with that in the control. Furthermore, protein levels of FAM188B and FOXM1 were elevated in the human lung cancer tissues, and FAM188B expression was negatively correlated with the overall survival of lung cancer patients. These results indicate that FAM188B exerts its oncogenic effects by regulating FOXM1 deubiquitination and thus its stability. Therefore, FAM188B might be a potential therapeutic target to control lung cancer progression.ope

FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD-L1 Expression and Cell Proliferation

Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3+ T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.ope

한국의 생체장기 기증제도에 대한 윤리적 고찰

의료법윤리학과협동과정 의료윤리전공/박사[한글] 1968년 미국 하버드대학의 뇌사 정의 특별위원회((Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death)에서 뇌사를 죽음으로 인정하고 뇌사의 기준을 발표하였다. 이를 계기로 세계적으로 장기이식을 위한 장기 확보방법에 일대 방향전환이 이루어졌다. 이후 서구 여러나라들은 뇌사를 인정하는 법률을 정하고 이식용 장기를 대부분 뇌사자로부터 기증받아오고 있다. 한국의 경우도 늦은 감이 있으나 1999년 뇌사자로부터의 장기적출을 인정하는 법률을 제정하였다. 그러나 이런 법적 인정에도 불구하고 뇌사자 장기기증은 증가하지 않았고 아직도 90% 이상의 장기이식 수술이 생체기증자들에 의존해 이루어지고 있으며, 최근에는 생체부분간이식 수술이 급격히 증가하고 있는 등 생체장기이식을 둘러싼 여러 문제들이 나타나고 있다. 생체장기기증은 이식수술의 한 과정일 뿐 아니라 기증자들의 삶의 한 부분이다. 기증자들은 기증 후에도 온전한 삶을 살아가야 한다. 생체장기기증의 문제점들에 대한 다양한 논의는 기증자들의 기증 후 삶을 위해서는 반드시 필요하다. 그러나 지금까지 생체기증은 아름다운 미담이나 또는 장기매매의 의혹이라는 양분된 시각에서만 논의되고 기증자들을 둘러싼 의학적, 윤리적, 사회적 문제점들에 대해서는 공식적 논의나 연구가 별반 없었던 것이 현실이다. 이제 생체장기기증과 관련하여 진솔하고도 다각적인 논의가 필요한 시점이 된 것 같다. 이에 본 연구는 현재 한국의 장기이식 관련 제도들을 생체장기기증에 초점을 두어 조망해보고 윤리적 문제점들은 없는지 검토해보고자 한다. 본 연구는 생체장기기증과 관련한 윤리적 판단의 기준으로 채택된 생명의료윤리의 네가지 원칙을 알아보고, 현재 한국의 생체장기기증과 관련된 제도 및 현황을 파악하여 이것들이 네원칙에 부합하고 있는지를 검토하여 현재 한국의 생체장기기증제도에 윤리적인 문제점은 없는지를 살펴보고자 하였다. 현재 한국에서는 신장, 간장, 골수 등의 생체기증 만이 가능하다. 1969년 한국에서 최초로 신장이식이 실시된 이후 신장, 간장, 골수 등 생체장기기증을 한 사람들은 약 2만 명에 이르는 것으로 추산된다. 생체장기기증 절차를 살펴보면, 먼저 장기를 기증하고자하는 사람은 장기이식등록기관에 등록을 한다. 이후 기증받을 환자가 정해지면 서류를 제출하여 국립장기이식관리센터의 승인을 받아 장기이식의료기관에서 장기적출수술을 시행받도록 하고 있다. 관련 법률인 ‘장기등이식에관한법률’이 1999년에 제정되고 2000년부터 시행되었다. 법률은 장기매매를 금지하고, 16세 이하에서의 장기적출을 금지하고 있다. 그러나 16세 이상의 미성년자의 경우 부모 등 4촌 이내의 친족에게 부모의 동의 아래 기증이 가능하며, 20세 이상의 성년인 경우에는 기증자가 이식받을 환자를 지정할 수 있도록 하고 있다. 또한 장기이식의료기관이 장기이식등록기관을 겸할 수 있고, 장기이식등록기관이 장기이식을 받기 원하는 환자와 기증자를 모두 등록 받아 관리할 수 있도록 하고 있다. 또한 장기이식 비용을 장기이식을 받는 환자가 모두 부담하는 것이 원칙임을 법에 명시하고 있다. 한국의 생체장기기증 제도를 살펴본 바 장기이식의료기관에서 거의 모든 과정을 독자적으로 진행할 수 있었다. 이는 이식수술과 관련한 정보를 제공하고 설명을 하는 사람들이 이식을 받을 환자를 돌보는 의료진일 수 있어 객관적인 입장에서 기증자에게 적출 수술의 위험성 및 부작용 등에 대하여 충분한 설명하지 못할 가능성이 많다는 것을 의미한다. 또한 미성년자의 장기기증이 부모를 비롯한 친족에게 가능하도록 하고 있어 거절했을 때의 가족 내의 갈등에 대한 부담감 등으로 인하여 자유로운 마음 상태에서 자발적으로 기증동의가 이루어져야 한다는 자율성 존중 원칙이 훼손될 우려가 일부 존재한다. 또한 적절한 기증자 선별을 위한 신체 및 정신적 평가 과정 및 기준 등에 대한 구체적인 안이 없어 기증자의 선별이 정확하지 않을 수 있다. 이는 적절치 못한 기증 결정으로 기증자에게 장기적출이 해가 될 가능성을 증가시킬 수 있다. 그러므로 우리의 생체장기기증 제도는 악행금지 의무를 다하고 있다고 할 수 없을 것이다. 또 한편으로 생체기증자들이 기증 후에 지속적인 관찰 및 건강관리를 받도록 하는 제도가 마련되어 있지 않아 기증자들이 장기 적출 후 건강에 대한 안전보장을 받지 못 할 가능성이 있어 기증자들에 대해 선행 의무를 다하고 있다고 볼 수 없다. 정의 원칙과 관련하여 보면 비지정?비혈연기증(Non-directed unrelated donation)의 경우 수혜자를 시행기관에서 임의의 기준으로 정하고 있어 수혜자 선정에 있어서 공정성이 확보되지 못할 우려가 있으며, 법이 이식받는 환자가 모든 이식비용을 부담하도록 명시하여 비용을 감당할 수 없는 환자를 원칙적으로 이식 대상에서 제외되도록 하고 있어 정의 원칙이 지켜지고 있다고 볼 수 없다. 우리는 흔히 생체장기기증이 타인의 생명을 구하기 위하여 자신의 신체 일부를 떼어주는 숭고한 행위라고 이야기 한다. 이러한 숭고한 행위가 제도의 미비로 본래의 의도와는 다르게 인간을 목적이 아닌 수단으로 전락시켜서는 안 될 것이다. 목적이 선하다고 모든 수단이 정당화 될 수는 없다. 아무리 좋은 결과를 얻는 행위라도 윤리적으로 옳지 않다면 가치 있는 행위라 할 수 없다. 생체장기기증이 참 가치를 가지기 위해서는 그 과정은 윤리적이야 한다. 현재 한국의 생체장기기증 제도는 생명의료윤리의 네원칙 모두에 충실하지 못한 상황이라고 판단되었다. 그러므로 한국에서 생체장기이식이 더욱 폭 넓은 윤리적 정당성을 얻고 참 가치를 얻기 위해서는 관계자들의 생명의료윤리에 충실한 새로운 제도를 만들고자하는 노력이 절실히 필요하다. [영문]In 1968, the Ad-hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death first recognized brain death and announced the criteria for its determination. This has become globally a big turnover in securing organs, and many Western countries enacted the laws to approve brain death and such organs have been donated by people who died of brain death in most cases. In spite of the late enactment of the ''Act on Organ Transplantation Etc.'' to approve the organ in 1999, the organ donation from brain death has not been increased and still more than 90% of organ transplantation is depending on living donors. Recently, a rapid increase in living donor partial liver transplantation have revealed various problems on living organ donation in Korea. Living organ donation is not only a part of transplantation process but also a part of donor''s life, so that they should be able to live on a complete life after donation. Nevertheless, there has been no detailed medico-ethico-social discussions or approaches, but just a dichotomy between beautiful cherished work and organ sales, on living organ transplantation. Therefore, the objective of this study is to take a view of current organ transplant related systems focusing on living organ donation and to review whether there is any ethical problem. Thus, this study examined and applied the ''Four Principles of Biomedical-ethics'' to review whether the Korean organ transplantation system related to the living donor organ transplantation satisfies the ''Four Principles of Biomedical-ethics'', and examined whether any ethical problem may occur in the current Korean living organ donation system. Currently, only kidneys, livers, and bone marrow are approved for living organ donation and since the first kidney transplantation in Korea in 1969, about 20,000 living donors donated their organs. Regarding the living organ donation procedure, the person who wants to donate his organ first register at the organ transplant registration center. Then, when the patient for transplant is determined, his organ would be procured at the organ transplant medical center with the approval of the Korean Network for Organ Sharing (KONOS). According to the ''Act on Organ Transplantation Etc.'', it prohibits organ sales and organ procurement from the children under 16 years old. However, even those under 16 can donate their organs to their parents or near relatives to cousins under the their parent''s consent, and adults over 20 can appoint the patients who would receive the transplant. In addition, an organ transplant medical center can be an organ transplant registration center at the same time, and an organ transplant registration can manage both patients and donors. Also, the act provides that any cost for organ donation is responsible for patients, not donors. First, this shows that almost every process for donation at the organ transplant medical centers or registration centers is independent, which means that the information on risks and side effects of organ procurement might be insufficiently provided to donors in an objective position since the people who provide such information would be those who care the patients. Moreover, since the donation by minors is possible for their parents as well as near relatives, the Principle of Autonomy may be infringed due to the conflicts and burdens for their families. Second, the donor selection may not be accurate since there is no specific process standard on physical and mental evaluation for appropriate donor selection. This inappropriate determination may increase the possibility of more harm to donors. Therefore, our living donor transplantation system dose not satisfy the Principle of Maleficence. On th other hand, since any follow-up system or health management system for living donors are not provided, their health after organ procurement is not secured, which do not meet the Principle of Beneficence. Third, regarding the Principle of Justice, non-directed unrelated donation do not insure the fairness in beneficiary selection due to discretional criteria, and the burden of high transplant cost for patients may exclude those who can not afford, which dose not suit the Principle of Justice. We often say that living organ donation is a sublime work which donates a part of one''s own body to save someone''s life. Such a sublime work should not be degraded to the means, but the objects due to the lack of systems, and also all kinds of means can not be justified even though the objects are good. Even the acts which may produce good results cannot valuable acts if they are not ethical. The procedure should be ethical for living organ donation to be valuable. Currently, it is determined that the Korean living organ donation system is insufficient to satisfy the Four Principles of Biomedical-ethics. Therefore, all the related professionals should put their efforts to establish the new system which fully satisfies the biomedical-ethics to secure ethical justification and value on living organ donation.ope

Rapid Analysis for the Isolation of Novel Genes Encoding Putative Effectors to the Position-specific Regulatory Element of Murine Hoxa-7

Hox genes are known to play a critical role in pattern formation during vertebrate development by being expressed at the specific time and in the specific position along the antero-posterior body axis. In order to understand the regulatory mechanism for the position-specific expression of murine Hoxa-7, yeast one-hybrid system was applied. DNA fragment conferring a position specificity to the Hoxa-7 gene was placed just upstream from the yeast CYC1 promoter and lacZ gene in a reporter. Selection of LacZ positive clones after cotransformation of the reporter and mouse embryonic cDNA library as an effector, which was designed to be expressed as fusion proteins to the GAlA activation domain, allowed us to isolate putative factors interacting with the position-specific regulatory element of murine Hoxa-7. A total of 28 positive clones were screened from 5 x 105 yeast transformants. About 70% of the clones turned out to be novel and most of the candidate clones selected in this study showed a temporally restricted expression pattern during embryonic development, suggesting that this method could provide an efficient way for isolating novel genes whose expressions are temporally regulated during embryogenesis.ope

Molecular genetic analysis of the DiGeorge syndrome among Korean patients with congenital heart disease.

The DiGeorge syndrome (DGS) is a developmental defect of the third and fourth pharyngeal pouches, which is associated with congenital heart defects, hypoparathyroidism, cell-mediated immunodeficiency, velo-pharyngeal insufficiency and craniofacial dysmorphism. The aetiological factor in a great majority of DGS cases is monosomy for the chromosomal region 22q11. To analyze DGS at the molecular level, a new molecular probe (DGCR680) encompassing the ADU balanced translocation breakpoint was prepared. When 13 Korean patients with DGS-type congenital heart disease were analyzed with this probe, 9 turned out to have a deletion at this locus, and all of them except one exhibited a typical facial dysmorphism associated DGS. Though only 9 independent patients were detected to have a deletion at the locus using the commercial probe N25 (D22S75), which maps at about 160 kb from the ADU breakpoint to the telomeric end, results from fluorescence in situ hybridization revealed a deletion in all cases tested at this locus. Two patients who had a deletion at the locus D22S75 but not at DGCR680 did not exhibit any DGS-type facial abnormalities. This result implies that the 680 bp probe covering the ADU translocation breakpoint might be a candidate for a molecular marker that can distinguish a specific phenotype, such as facial features associated with the DiGeorge syndrome. This study also suggested that systematic approaches with several small DNA probes along the DGCR could help to dissect the complex phenotypes associated with the DiGeorge syndrome, such as cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia, etc.ope

Transcriptional activation of EGFR by HOXB5 and its role in breast cancer cell invasion

HOX genes are transcription factors that play important roles in body patterning and many cellular processes during embryonic, fetal, and adult development. Given their important function in normal tissues, it is reasonable to assume that abnormal expression of HOX genes in adults could lead to serious diseases such as cancer. Our previous study reported HOXB5 to be significantly up-regulated in breast cancer, and its expression was found to be associated with tumor cell proliferation and invasion. Furthermore, the epidermal growth factor receptor (EGFR), a cellular tyrosine kinase that plays an important role in breast cancer progression, was found significantly up-regulated by HOXB5 in ER-positive breast cancer cells. In the present study, we demonstrated that HOXB5 regulates EGFR expression at the transcriptional level by directly binding to its promoter region and promotes phosphorylation of EGFR as well as its downstream effectors. Patients with ER-positive breast cancer, having high co-expression of HOXB5 and EGFR, had poor prognosis than those with low expression. Knockdown studies validated a key role played by EGFR in the HOXB5-induced invasion of breast cancer cells. These results suggest that targeting EGFR could be an effective strategy to treat breast cancer in patients with high HOXB5 expression.ope

Effects of Dexamethasone on Embryo Development and Hox Gene Expression Patterns in Mice

During pregnancy, stress induces maternal glucocorticoid secretion, which in turn is known to affect structural malformation, retardation of growth, reduced birth weight of the fetus. As Hox genes are master transcription factors which fulfill critical roles in embryonic development, we aimed to explore the possibility that alterations of the Hox gene expression might be involved in stress-induced malformation. The pregnant mice were injected with dexamethasone at a dose of 1 mg/kg or 10 mg/kg on day 7.5, 8.5 and 9.5 p.c. (post coitum), as well as saline as control. Embryos of E11.5 and E18.5 were obtained by sacrificing pregnant animals. Weight and crown-rump length (CRL) were measured. RT-PCR was performed to examine the Hox gene expression levels. Embryos given dexamethasone at day 7.5~9.5 p.c. had small CRL and weighed less both in E11.5 and E18.5. The percentage of embryos showing abnormalities was high in groups received high dose of dexamethasone. To define the molecular basis for abnormal embryonic development, we analyzed the Hox gene expression pattern and found that many Hox genes display altered expression. Effects of prenatal dexamethasone treatment on embryonic development might be associated with the aberrant Hox gene expression.ope