Competing Endogenous RNA of Snail and Zeb1 UTR in Therapeutic Resistance of Colorectal Cancer

The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance.ope

Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition

Protein O-phosphorylation often occurs reciprocally with O-GlcNAc modification and represents a regulatory principle for proteins. O-phosphorylation of serine by glycogen synthase kinase-3β on Snail1, a transcriptional repressor of E-cadherin and a key regulator of the epithelial-mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O-phosphorylation-mediated degradation, O-GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E-cadherin mRNA expression. Hyperglycaemic condition enhances O-GlcNAc modification and initiates EMT by transcriptional suppression of E-cadherin through Snail1. Thus, dynamic reciprocal O-phosphorylation and O-GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT.ope

Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, alpha-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.ope

Snail augments fatty acid oxidation by suppression of mitochondrial ACC2 during cancer progression

Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial-mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial-mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.ope

Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction

The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified. In this study, we show that niclosamide directly targets Axin-GSK3 interaction, at least in part, resulting in suppression of Wnt/Snail-mediated EMT. In vitro and in vivo, disruption of Axin-GSK3 complex by niclosamide induces mesenchymal to epithelial reversion at nM concentrations, accompanied with suppression of the tumorigenic potential of colon cancer. Niclosamide treatment successfully attenuates Snail abundance while increasing E-cadherin abundance in xenograft tumor. Notably, oral administration of niclosamide significantly suppressed adenoma formation in an APC-MIN mice model, indicating that niclosamide is an effective therapeutic for familial adenomatosis polyposis (FAP) patients. In this study, we identified a novel target to control the canonical Wnt pathway and Snail-mediated EMT program, and discovered a repositioned therapeutics for FAP patients.ope

p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells

p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5′ and 3′ UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer.ope

Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of phosphofructokinase, platelet (PFKP), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.ope

전통공간의 구성원리에 의한 환경디자인 모형사례 연구

모든 문화활동은 공간과 시간의 여건과 그 연관관계에 영향을 받아서 발전하며, 한 나라의 건축문화는 그 나라의 역사와 문화활동의 프로세스를 반영하게 된다. 문화의 전파현상은 각 나라 상호 간에 영향을 주고받게 되며, 전파된 외래문화요소들은 취사선택의 여과 과정을 거쳐서 그 나라의 문화요소가 된다. 그러나 격동의 근대사를 보내면서 우리는 이러한 과정을 제대로 밟지 못하였고, 그 결과 무분별한 외래문화의 도입으로 문화적 혼동 속에서 우리의 정체성을 확립하지 못하게 되었다. 현재 우리는 우리문화의 정체성도 확립하지 못하였고 도시는 산업사회의 구조적 모순들로 인하여 인간과 자연이 유리되어있는 획일적이고 몰개성한 환경을 이루고 있다. 이는 우리가 우리문화의 정체성을 확립하지 못한 점도 있으나 근대의 기계론적 세계관으로 인하여 인류 전체가 인간의 소외, 자연환경의 오염과 생태계의 파괴와 같은 심각한 문제점과 문화적 혼란의 위기에 처하게 된 것과도 맥락을 같이 한다고 볼 수 있다. 그리하여 이 시대는 새로운 패러다임을 필요로 하게 되었는데, 새 패러다임은 단절된 인간과 자연의 관계를 회복하여 인간과 환경이 유기적으로 통합된 하나의 시스템을 이루는 것으로서, 자연에 순응하면서 인간과 구축환경이 유기적으로 작용하는 전통건축은 새 패러다임 시대에 적합하다고 할 수 있다. 그래서 전통공간의 개념을 현대적으로 해석하여 건축에 적용하는 것은 이 시대가 요구하는 새로운 패러다임에도 적합하며, 우리 문화의 정체성을 확립하고, 또 현재 근대적 세계관의 가치기준에 의해 급속한 도시화와 인구의 과밀화로 혼잡해져서 인간과 자연이 유리되어있는 획일적이고 몰개성한 도시의 문제점을 해결할 수 있는 디자인으로서 가치가 있다. 21세기를 맞이하여 사람들은 가치관과 생활양식의 변화로 예전처럼 직장이나 일의 성취도를 우선적으로 생각하기보다는 가족과 건강, 여가문화에 많은 관심을 기울이게 되었다. 그러나 도시화가 진행되면서 사람들을 배려하는 공간의 비율이 점점 낮아지고 있으며 신도시의 경우는 문화적 욕구를 충족하기가 더욱 어려운 실정이다. 그러므로 시민의 휴식과 정서생활 함양에 기여할 수 있고, 이용객의 여가행태를 고려한 공간을 조성함으로써 질적으로 높아진 여가수요에 부응해야한다. 이에 본 연구는 전통공간 형성의 기저를 이루는 개념들을 고찰하여 전통공간의 특성과 공간구성의 원리를 이해하고 그 원리를 적용시킨 모형사례를 제시함으로써, 그 가능성을 검증하였으며 이러한 연구의 과정을 통하여 다음과 같은 사실을 확인할 수 있었다. 첫째, 근대의 기계론적 세계관의 붕괴와, 동양의 사상과 맥락을 같이하는 부분이 있는 전일적인 새 패러다임의 출현으로 식민지 시대의 왜곡된 경험과 서구사조의 무비판적인 수용으로 평가절하가 되었던 우리문화의 가치를 재발견하게 되었다. 둘째, 전통건축의 공간구성의 원리를 디자인 언어로 도출하는 것은 전 시대의 문화능력의 한계를 뛰어넘어 새로운 문화로 발전할 수 있게끔 보다 적극적인 방향을 제시하는 것이라는 것을 알 수 있었다. 셋째, 도시를 관찰함으로써 도시는 많은 복합적인 기능들을 제공하고 있으며, 환경디자인을 할 때에는 사용자의 공간에 대한 요구도를 파악하고 그것을 구체적 실체로서 계획에 적용할 수 있어야 함을 알게 되었다. 넷째, 전통공간 구성의 원리에 의한 환경디자인 연구가 우리 문화의 정체성을 확립하고 현재 도시의 문제점을 해결할 수 있는 디자인 방안으로 제시될 수 있음을 알 수 있었다. 이상의 연구결과, 한국 전통공간의 특성과 구성원리를 적용한 환경디자인의 모형사례를 제시함으로써, 도시화로 삭막해지는 현재의 도시공간에서 인간과 자연의 관계를 회복시키고 여가를 보람있게 보낼 수 있도록 도시주민의 삶의 질을 높일 수 있는 디자인의 대안을 제시하는데 의의를 두고자 한다. ; All cultural activities progress as they are effected by space and time and the correlation of the two. Moreover, architectural culture of a nation reflects its history and process of its cultural activities. Propagation of culture mutually effects the nations and foreign elements of propagated culture become genuine elements of one s culture through the process of selection and filtration. However, Korea s failure to go through the proper process of selection and indiscreet acceptance of foreign culture due to its upheavals of modern history resulted failure to its own cultural identities. Therefore, cities are full of structural contradictions where human race is totally isolated from Mother Nature and create inharmonious, dull and eyesore atmosphere. This unpleasant atmosphere of city is not only proof of our failure to establish cultural identity but also remaining vestiges of modern age mechanistic worldview. The modern age mechanistic worldview has led to human isolation, cultural confusion, environmental pollution and ecological destruction which became major crisis to human race. As a result, modern age became to be in need of so called New Paradigm , a whole, organic system which restores relationship between human and the Mother Nature. In light of this view, Korean traditional architecture meets the requirements of New Paradigm Era because it has been in harmony with the nature. Therefore, interpreting traditional spatial concept to modernistic view and its application will establish our unique cultural identity and solve problems of cities such as plain looks due to rapid urbanization and over population. On the threshold of 21st century, people value family, health and leisure rather than job and/or personal achievement more than ever. However, urbanization led to decrease in spatial ratio and cultural dissatisfaction of people. Contributing and promoting appropriate leisure and the space for people is therefore, urgently needed than ever. This research is based on concepts of traditional space, characteristics of traditional space & principles of spatial structure, application of the above by presenting examples of models and verification of possibilities. In completion of the study, the researcher was able to confirm the following: First, rediscovery of our cultural value which was devalued by distorted historical experience of colonial period and indiscriminate acceptance of western ideology. Second, classification of design language in accordance with characteristics of spatial design is a more constructive way of presenting new culture, exceeding limits of previous era of culture. Third, demands of complex functions of cities and actual plans to fulfil and implement the demands. Fourth, environmental design research of traditional spatial principles will establish identity of Korean culture and solve problems of cities. Designs based on structural principles of traditional spatial design will pave a way to restore humanity and nature and improve the life quality of urban citizens.논문개요 1. 서론 = 1 1.1. 연구의 배경 및 목적 = 1 1.2. 연구의 범위 및 방법 = 2 2. 한국 전통공간 특성에 관한 이론적 배경 = 3 2.1. 건축에서의 전통의 개념 = 4 2.2. 전통공간형성의 배경 = 5 2.2.1 자연환경 = 6 2.2.2. 문화 및 사상적 배경 = 10 3. 한국 전통공간의 구성적 원리 = 18 3.1. 전통공간의 구성적 원리 = 18 3.1.1. 자연과의 조화 = 18 3.1.2. 배치의 불규칙적인 질서 = 20 3.1.3. 연속적 공간체계와 위계성 = 27 3.1.4. 유기적인 공간체계 = 34 3.1.5. 내부공간적 외부공간 = 36 3.2. 전통공간의 패턴언어 = 37 4. 모형사례 디자인 연구를 위한 기본 계획 = 45 4.1. 도시환경의 문제점 = 45 4.2. 미술관에 대한 일반적 고찰 = 54 4.2.1. 미술관의 사회적 기능과 역할 = 54 4.2.2. 지역사회문화와 미술관 = 55 5. 디자인 과정 = 59 5.1. 디자인 전제 = 59 5.1.1. 디자인 개요 및 목표 = 60 5.1.2. 디자인 진행과정 = 61 5.2. 디자인 프로그래밍 = 62 5.2.1. 대상지 선정 및 분석 = 62 5.2.2. 대상공간 프로그래밍 = 73 5.2.3. 공간구성의 디자인 개념 = 80 5.3. 디자인 단계 = 88 5.3.1. 공간 계획 = 88 5.3.2. 디자인 = 97 5.4. 디자인 적용 단계 = 109 5.4.1. 각 공간의 디자인 해결방안 = 109 5.4.2. 최종 디자인 = 115 5.6. 종합 및 평가 = 125 6. 결론 = 128 참고문헌 = 130 Abstract = 13

a study on creating a substructure of korean heritage portal by implementing cidoc CRM

학위논문(석사) - 한국과학기술원 : 문화기술대학원, 2010.08, [ v, 64 p. ]This paper attempts to build basic conditions for Korean cultural heritage ontology structure using CIDOC CRM (ICOMs International Committee for Documentation Conceptual Reference Model). Issues are derived from the situations in other countries such as Finland, Netherlands, and United Kingdom. Also, heritage information structures on the web in Korea are studied. The existing heterogeneous heritage database is a basis for current heritage web in Korea. In this study, we define the obstacles for Korean heritage portals to operate semantically. In addition, these obstacles are classified into three categories. Lastly, a test is followed in order to verify the efficiency of the proposed solutions. Through this study, the heritage information in Korea could find a way to be semantically interlinked. Consequently, users could acquire knowledge related to heritage more easily and meaningfully.한국과학기술원 : 문화기술대학원

Breadth-First 검색에 기반한 HEVC 인트라 코딩 유닛 모드 결정

학위논문(석사) - 한국과학기술원 : 전기및전자공학과, 2014.8, [ iv, 28 p. ]This research proposed a fast CU mode decision algorithm for intra coding in HEVC. The main idea is simple, but effective early termination on quadtree decision process inspired by the breadth-first search algorithm. RDO process is entailed to ensure the visual quality of encoded video sequences. However, the number of calculation of the RD cost is significantly increased in HEVC standard due to quadtree structure, increase in intra modes, and variable size of CTUs. This phenomena lead to increase in computational complexity in HEVC intra coding. In order to reduce this complexity, we proposed an algorithm for fast CU mode decision for HEVC intra coding based on breadth-first search. By observing the RD cost improvement of the coding tree structure, a new algorithm is proposed and tested. The proposed technique reduced the encoding time alone at the cost of slight increase in bit rate and negligible PSNR loss. There is a complexity reduction about 66.93% at very less loss in performance with high complexity reduction. The average loss in PSNR is only 0.42dB in comparison with HEVC standard.한국과학기술원 : 전기및전자공학과