• 생명과학회지
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• 제21권12호
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• pp.1795-1803
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• 2011

현대인의 고지방 식습관과 당뇨와 비만인구 증가로 인한 비 알코올성 지방간(nonalcoholic fatty liver)의 유병률(prevalence rate)은 나날이 증가하고 있는 추세이며, 특히 남성과 폐경기 여성에게서 두드러진다. 이런 성 특이적(sex-specific) 간질환의 차이는 여성 호르몬인 에스트로겐(estrogen)의 보호 역할 때문일 것으로 추정되고 있으나, 에스트로겐의 보호 기작을 포함한 지방간의 만성 간질환으로의 진행 메커니즘이 규명되어 있지 않기 때문에 간질환의 효과적인 예방 및 치료책이 없는 실정이다. 그런데 최근에 간 섬유화(fibrosis)를 포함한 만성 간질환의 진행에서 헤지호그(hedgehog) 신호전달계가 주요한 역할을 함이 보고되면서 손상된 간의 회복과 간질환 진행메커니즘 조절을 위한 연구대상으로서 주목 받고 있다. 헤지호그는 발생 및 분화를 조절하는 모포젠(morphogen)으로 성인의 건강한 간에서는 발현되지 않으나, 손상된 간에서 손상 정도에 비례하게 재 발현되며, 섬유화 유발세포인 근섬유아세포(myofibroblasts) 및 간 줄기세포(hepatic progenitor cells)의 활성 및 증식인자로 작용하여 지나친 간 섬유화를 일으킨다. 이에 반해, 에스트로겐은 간 성상세포(hepatic stellate cells)가 근섬유아세포로 활성화되는 것을 억제함으로써 간 섬유화를 막는 것으로 보고되고 있다. 간 섬유화에 대한 헤지호그와 에스트로겐의 상반된 역할 사이의 관련성은 아직 밝혀지지 않고 있으나, 간 섬유화 유발 물질인 오스테오폰틴(osteopontin) 발현에 대한 에스트로겐의 억제효과와 헤지호그에 의한 오스테오폰틴 발현 유도는 오스테오폰틴에 의해 매개되는 에스트로겐과 헤지호그 신호전달계 사이의 연관성을 시사한다. 따라서, 에스트로겐에 의한 헤지호그 신호전달계 조절 메커니즘을 규명하는 것은 간질환 환자에서의 간 섬유화 및 만성 질환으로의 진행을 억제할 수 있는 치료제 개발에 대한 기초 지식을 제공할 수 있다. 이를 위해 간 섬유화에 대한 헤지호그와 에스트로겐의 역할을 확실하게 이해하고, 상호 관련성 및 조절 기작을 밝히는 연구가 선행되어야 할 것이다.

• 대한의사협회지
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• 제61권11호
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• pp.655-661
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• 2018

Incidence of basal and squamous cell carcinoma is increasing among Korean. With increasing this incidence we need to attend the management and prevention of these cutaneous malignancies. Basal cell carcinoma (BCC) is the most common skin malignancy. Sun exposure is the most important environmental cause of BCC. Daily sun protection especially avoiding sun exposure between 10 a.m. and 4 p.m. provides most effective prevention against chronic ultraviolet-induced skin damage. Hedgehog pathway inhibitors are used locally advanced and metastatic BCC lesions in Korea. Until recently, there are no reports whether it developed resistance of Hedgehog pathway inhibitors with advanced BCC in Korean patients. Among malignant skin tumors, 19.1% were squamous cell carcinoma (SCC). The incidence of SCC was rapidly increased over the past years. However, the incidence rate of SCC in Japan has not been changed from the period 1976-1980 to 1986-1990. Sentinel lymph node biopsy for SCC did not provide diagnostic value. Bowen's disease and Erythroplasia of Queyrat are considered as carcinoma in situ of the skin. Erythroplasia of Queyrat have worse prognosis with a higher rate of malignant degeneration. Dermoscopy may helpful tool in assisting the noninvasive diagnosis of carcinoma in situ of the skin.

• Asian Pacific Journal of Cancer Prevention
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• 제16권2호
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• pp.437-442
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• 2015

Aim: To establish a pancreatic cancer stem cell model using human pancreatic cancer cells in nude mice to provide a platform for pancreatic cancer stem cell research. Materials and Methods: To establish pancreatic cancer xenografts using human pancreatic cancer cell line SW1990, nude mice were randomly divided into control and gemcitabine groups. When the tumor grew to a volume of $125mm^3$, they treated with gemcitabine at a dose of 50mg/kg by intraperitoneal injection of 0.2ml in the gemcitabine group, while the mice in control group were treated with the same volume of normal saline. Gemcitabine was given 2 times a week for 3 times. When the model was established, the proliferation of pancreatic cancer stem cells was observed by clone formation assay, and the protein and/or mRNA expression of pancreatic stem cell surface markers including CD24, CD44, CD133, ALDH, transcription factors containing Oct-4, Sox-2, Nanog and Gli, the key nuclear transcription factor in Sonic Hedgehog signaling pathway was detected by Western blot and/or RT-PCR to verify the reliability of this model. Results: This model is feasible and safe. During the establishment, no mice died and the weight of nude mice maintained above 16.5g. The clone forming ability in gemcitabine group was stronger than that of the control group (p<0.01). In gemcitabine group, the protein expression of pancreatic cancer stem cell surface markers including CD44, and ALDH was up-regulated, the protein and mRNA expression of nuclear transcription factor including Oct-4, Sox-2 and Nanog was also significantly increased (P<0.01). In addition, the protein expression of key nuclear transcription factor in Sonic Hedgehog signaling pathway, Gli-1, was significantly enhanced (p<0.01). Conclusions: The pancreatic cancer stem cell model was successfully established using human pancreatic cancer cell line SW1990 in nude mice. Gemcitabine could enrich pancreatic cancer stem cells, simultaneously accompanied by the activation of Sonic Hedgehog signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제15권22호
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• pp.9791-9795
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• 2014

To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-${\beta}$ signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

• Molecules and Cells
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• 제43권2호
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• pp.168-175
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• 2020

Runx2 is an essential transcription factor for skeletal development. It is expressed in multipotent mesenchymal cells, osteoblast-lineage cells, and chondrocytes. Runx2 plays a major role in chondrocyte maturation, and Runx3 is partly involved. Runx2 regulates chondrocyte proliferation by directly regulating Ihh expression. It also determines whether chondrocytes become those that form transient cartilage or permanent cartilage, and functions in the pathogenesis of osteoarthritis. Runx2 is essential for osteoblast differentiation and is required for the proliferation of osteoprogenitors. Ihh is required for Runx2 expression in osteoprogenitors, and hedgehog signaling and Runx2 induce the differentiation of osteoprogenitors to preosteoblasts in endochondral bone. Runx2 induces Sp7 expression, and Runx2, Sp7, and canonical Wnt signaling are required for the differentiation of preosteoblasts to immature osteoblasts. It also induces the proliferation of osteoprogenitors by directly regulating the expression of Fgfr2 and Fgfr3. Furthermore, Runx2 induces the proliferation of mesenchymal cells and their commitment into osteoblast-lineage cells through the induction of hedgehog (Gli1, Ptch1, Ihh), Fgf (Fgfr2, Fgfr3), Wnt (Tcf7, Wnt10b), and Pthlh (Pth1r) signaling pathway gene expression in calvaria, and more than a half-dosage of Runx2 is required for their expression. This is a major cause of cleidocranial dysplasia, which is caused by heterozygous mutation of RUNX2. Cbfb, which is a co-transcription factor that forms a heterodimer with Runx2, enhances DNA binding of Runx2 and stabilizes Runx2 protein by inhibiting its ubiquitination. Thus, Runx2/Cbfb regulates the proliferation and differentiation of chondrocytes and osteoblast-lineage cells by activating multiple signaling pathways and via their reciprocal regulation.

• International Journal of Industrial Entomology and Biomaterials
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• 제34권1호
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• pp.1-5
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• 2017

Bone morphogenetic protein 2 (BMP2) plays an important role in the development of bone and cartilage. It is involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine receptor interaction. It is involved also in cardiac cell differentiation and epithelial to mesenchymal transition. In this study, We expressed human BMP2 (hBMP2) recombinant protein using Baculovirus Expression Vector System (BEVS) in Sf9 insect cells. The hBMP2 cDNA was cloned into baculovirus transfer vector, pBacgus-4x-1 and recombinant baculovirus was screened out through X-gal and GUS-fusions assay. Western blot analysis shown that molecular weight of hBMP2 recombinant protein was about 44.71 kDa.

• Molecules and Cells
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• 제41권3호
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• pp.224-233
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• 2018

Primary cilia are solitary, non-motile, axonemal microtubule-based antenna-like organelles that project from the plasma membrane of most mammalian cells and are implicated in transducing hedgehog signals during development. It was recently proposed that aberrant SHH signaling may be implicated in the progression of idiopathic pulmonary fibrosis (IPF). However, the distribution and role of primary cilia in IPF remains unclear. Here, we clearly observed the primary cilia in alveolar epithelial cells, fibroblasts, and endothelial cells of human normal lung tissue. Then, we investigated the distribution of primary cilia in human IPF tissue samples using immunofluorescence. Tissues from six IPF cases showed an increase in the number of primary cilia in alveolar cells and fibroblasts. In addition, we observed an increase in ciliogenesis related genes such as IFT20 and IFT88 in IPF. Since major components of the SHH signaling pathway are known to be localized in primary cilia, we quantified the mRNA expression of the SHH signaling components using qRT-PCR in both IPF and control lung. mRNA levels of SHH, the coreceptor SMO, and the transcription factors GLI1 and GLI2 were upregulated in IPF compared with control. Furthermore, the nuclear localization of GLI1 was observed mainly in alveolar epithelia and fibroblasts. In addition, we showed that defective KIF3A-mediated ciliary loss in human type II alveolar epithelial cell lines leads to disruption of SHH signaling. These results indicate that a significant increase in the number of primary cilia in IPF contributes to the upregulation of SHH signals.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4607-4611
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• 2012

Objective: Endometrial cancer (EC) is the most common gynecologic malignancy. Identification of potential biomarkers of EC would be helpful for the detection and monitoring of malignancy, improving clinical outcomes. Methods: The Weighted Gene Co-expression Network Analysis method was used to identify prognostic markers for EC in this study. Moreover, underlying molecular mechanisms were characterized by KEGG pathway enrichment and transcriptional regulation analyses. Results: Seven gene co-expression modules were obtained, but only the turquoise module was positively related with EC stage. Among the genes in the turquoise module, COL5A2 (collagen, type V, alpha 2) could be regulated by PBX (pre-B-cell leukemia homeobox 1)1/2 and HOXB1(homeobox B1) transcription factors to be involved in the focal adhesion pathway; CENP-E (centromere protein E, 312kDa) by E2F4 (E2F transcription factor 4, p107/p130-binding); MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) by PAX5 (paired box 5); and BCL-2 (B-cell CLL/lymphoma 2) and IGFBP-6 (insulin-like growth factor binding protein 6) by GLI1. They were predicted to be associated with EC progression via Hedgehog signaling and other cancer related-pathways. Conclusions: These data on transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of EC.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제37권2호
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• pp.97-108
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• 2011

Cancer stem cells have stem cell-like features, such as the ability for self-renewal and differentiation but show unlimited growth because they have the lost normal regulation of cell growth. Cancer stem cells and normal stem cells have similar features. They show high motility, diversity of progeny, robust proliferative potential, association with blood vessels, immature expression profiles, nestin expression, epidermal growth factor (EGF)-receptor expression, phosphatase and tensin homolog (PTEN) expression, hedgehog pathway activity, telomerase activity, and Wnt pathway activity. On the other hand, with cancer cells, some of these signaling pathways are abnormally modified. In 1875, Cohnheim suggested the concept of cancer stem cells. Recently, evidence for the existence of cancer stem cells was identified. In 1994, the cancer stem cells' specific cell surface marker for leukemia was identified. Since then, other specific cell surface markers for cancer stem cells in solid tumors (e.g. breast and colon cancer) have been identified. In oral cancer, studies on cancer stem cells have been performed mainly with squamous cell carcinomas. Oral cancer specific cell surface markers, which are genes strongly expressed in oral cancer and cancer stem cell specific side populations, have been identified. Cancer stem cells are resistant to radiotherapy and chemotherapy. Therefore, to eliminate malignant tumors efficiently and reduce the recurrence rate, therapy targeting cancer stem cells needs to be performed. Currently, studies targeting the cancer stem cells' specific signaling pathways, telomerase and tumor vasculatures are being done.

• BMB Reports
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• 제45권8호
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• pp.427-432
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• 2012

Primary cilia, single hair-like appendage on the surface of the most mammalian cells, were once considered to be vestigial cellular organelles for a past century because of their tiny structure and unknown function. Although they lack ancestral motility function of cilia or flagella, they share common ground with multiciliated motile cilia and flagella on internal structure such as microtubule based nine outer doublets nucleated from the base of mother centrioles called basal body. Making cilia, ciliogenesis, in cells depends on the cell cycle stage due to reuse of centrioles for cell division forming mitotic spindle pole (M phase) and assembling cilia from basal body (starting G1 phase and maintaining most of interphase). Ciliary assembly required two conflicting processes such as assembly and disassembly and balance between these two processes determines the length of cilia. Both process required highly conserved transport system to supply needed substance to grow tip of cilia and bring ciliary turnover product back to the base of cilia using motor protein, kinesin and dynein, and transport protein complex, IFT particles. Disruption of ciliary structure or function causes multiple human disorder called ciliopathies affecting disease of diverse ciliated tissues ranging from eye, kidney, respiratory tract and brain. Recent explosion of research on the primary cilia and their involvement on animal development and disease attracts scientific interest on how extensively the function of cilia related to specific cell physiology and signaling pathway. In this review, I introduce general features of primary cilia and recent progress in understanding of the ciliary length control and signaling pathways transduced through primary cilia in vertebrates.