Publications by authors named "Dawoon E Jung"

15 Publications

  • Page 1 of 1

Identification of Circulating Serum miRNAs as Novel Biomarkers in Pancreatic Cancer Using a Penalized Algorithm.

Int J Mol Sci 2021 Jan 20;22(3). Epub 2021 Jan 20.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Pancreatic cancer (PC) is difficult to detect in the early stages; thus, identifying specific and sensitive biomarkers for PC diagnosis is crucial, especially in the case of early-stage tumors. Circulating microRNAs are promising non-invasive biomarkers. Therefore, we aimed to identify non-invasive miRNA biomarkers and build a model for PC diagnosis. For the training model, blood serum samples from 63 PC patients and 63 control subjects were used. We selected 39 miRNA markers using a smoothly clipped absolute deviation-based penalized support vector machine and built a PC diagnosis model. From the double cross-validation, the average test AUC was 0.98. We validated the diagnosis model using independent samples from 25 PC patients and 81 patients with intrahepatic cholangiocarcinoma (ICC) and compared the results with those obtained from the diagnosis using carbohydrate antigen 19-9. For the markers miR-155-5p, miR-4284, miR-346, miR-7145-5p, miR-5100, miR-661, miR-22-3p, miR-4486, let-7b-5p, and miR-4703-5p, we conducted quantitative reverse transcription PCR using samples from 17 independent PC patients, 8 ICC patients, and 8 healthy individuals. Differential expression was observed in samples from PC patients. The diagnosis model based on the identified markers showed high sensitivity and specificity for PC detection and is potentially useful for early PC diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863930PMC
January 2021

Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression.

Neoplasia 2019 10 23;21(10):1003-1014. Epub 2019 Aug 23.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Iroquois homeobox 1 (IRX1) belongs to the Iroquois homeobox family known to play an important role during embryonic development. Interestingly, however, recent studies have suggested that IRX1 also acts as a tumor suppressor. Here, we use homozygous knockout mutants of zebrafish to demonstrate that the IRX1 gene is a true tumor suppressor gene and mechanism of the tumor suppression is mediated by repressing cell cycle progression. In this study, we found that knockout of zebrafish Irx1 gene induced hyperplasia and tumorigenesis in the multiple organs where the gene was expressed. On the other hands, overexpression of the IRX1 gene in human tumor cell lines showed delayed cell proliferation of the tumor cells. These results suggest that the IRX1 gene is truly involved in tumor suppression. In an attempt to identify the genes regulated by the transcription factor IRX1, we performed microarray assay using the cRNA obtained from the knockout mutants. Our result indicated that the highest fold change of the differential genes fell into the gene category of cell cycle regulation, suggesting that the significant canonical pathway of IRX1 in antitumorigenesis is done by regulating cell cycle. Experiment with cell cycle blockers treated to IRX1 overexpressing tumor cells showed that the IRX1 overexpression actually delayed the cell cycle. Furthermore, Western blot analysis with cyclin antibodies showed that IRX1 overexpression induced decrease of cyclin production in the cancer cells. In conclusion, our in vivo and in vitro studies revealed that IRX1 gene functionally acts as a true tumor suppressor, inhibiting tumor cell growth by regulating cell cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715957PMC
October 2019

Identification of potential biomarkers for diagnosis of pancreatic and biliary tract cancers by sequencing of serum microRNAs.

BMC Med Genomics 2019 05 16;12(1):62. Epub 2019 May 16.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.

Background: Pancreatic and biliary tract cancer (PC and BTC, respectively) are difficult to diagnose because of their clinical characteristics; however, recent studies suggest that serum microRNAs (miRNAs) might be the key to developing more efficient diagnostic methods for these cancers.

Methods: We analysed the genome-wide expression of serum miRNAs in PC and BTC patients to identify novel biomarker candidates using high-throughput sequencing and experimentally validated miRNAs on clinical samples.

Results: Statistical and classification analysis of the serum miRNA-expression profiles of 55 patient samples showed distinguishable patterns between cancer patients and healthy controls; however, we were unable to distinguish the two cancers. We found that three of the highest performing miRNAs were capable of distinguishing cancer patients from controls, with an accuracy of 92.7%. Additionally, dysregulation of these three cancer-specific miRNAs was demonstrated in an independent sample group by quantitative reverse transcription polymerase chain reaction.

Conclusions: These results suggested three candidate serum miRNAs (mir-744-5p, mir-409-3p, and mir-128-3p) as potential biomarkers for PC and BTC diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-019-0521-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524273PMC
May 2019

Novel Gastric Cancer Stem Cell-Related Marker LINGO2 Is Associated with Cancer Cell Phenotype and Patient Outcome.

Int J Mol Sci 2019 Jan 28;20(3). Epub 2019 Jan 28.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson's disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers-N-Cadherin and Vimentin and stemness-associated markers- POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44⁺ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20030555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387145PMC
January 2019

Study of Natural Killer (NK) Cell Cytotoxicity Against Cholangiocarcinoma in a Nude Mouse Model.

In Vivo 2018 Jul-Aug;32(4):771-781

Research Institute of SMT Bio, SMT Bio Co., Ltd., Seoul, Republic of Korea

Background/aim: Natural killer (NK) cells are one of the lymphocytes clinically used for various cancer types. Cytotoxicity of NK cells to cholangiocarcinoma (CC), however, has not yet been studied. Nor NK cell therapy against CC has been clinically applied. In this study, relevance of NK cell therapy for anti-tumor efficacy against CC was pre-clinically investigated.

Materials And Methods: Human HuCCT-1 cells, an intrahepatic CC cell line, were xenografted into nude mice. The HuCCT-1 tumor-bearing nude mice then received multiple infusions of ex vivo-expanded human NK cells (SMT01) and in vivo cytotoxic activity of the NK cells against the CC cells was evaluated.

Results: SMT01 infusion resulted in significant inhibition of the CC tumor growth. Body weight of the mice administrated with chemotherapy was found to be maintained at the lowest level among all treatment groups while all the SMT01 infusion groups well maintained their body weight.

Conclusion: The present in vivo study demonstrates that NK cells contain cytolytic activity against cholangiocarcinoma and show beneficial effect of NK cell therapy in relevance to quality of life. Further investigation of the NK cell-based immunotherapy can be useful to determine cancer therapeutics for the specific tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.11307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117784PMC
October 2018

Combined use of CEMIP and CA 19-9 enhances diagnostic accuracy for pancreatic cancer.

Sci Rep 2018 02 21;8(1):3383. Epub 2018 Feb 21.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5 U/ml (40.8-3342.5) and 0.67 ng/ml (0.40-1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806-0.888) and 0.760 (95% CI: 0.689-0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P < 0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-21823-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821821PMC
February 2018

Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by oncoprotein CagA.

Oncotarget 2017 Oct 27;8(45):78365-78378. Epub 2017 Jun 27.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Injection of the cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with possessing the CagA protein produce more reactive oxygen species (ROS) and show an increased risk of developing gastric cancer. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and mitochondrial SIRT3 is known to be a tumor suppressor via its ability to suppress ROS and hypoxia inducible factor 1α (HIF-1α). However, it is unclear whether increased ROS production by is regulated by SIRT3 followed by HIF-1α regulation and whether intracellular CagA acts as a regulator thereof. In this study, we investigated correlations among SIRT3, ROS, and HIF-1α in -infected gastric epithelial cells. We observed that SIRT3-deficient AGS cells induce HIF-1α protein stabilization and augmented transcriptional activity under hypoxic conditions. In CagA infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA infection also increased HIF-1α activity through the ROS production induced by the downregulated SIRT3 activity, which is similar to the hypoxic condition in gastric epithelial cells. In contrast, overexpression of SIRT3 inhibited the HIF-1α protein stabilization and attenuated the increase in HIF-1α transcriptional activity under hypoxic conditions. Moreover, CagA attenuated HIF-1α stability and decreased transcriptional activity in SIRT3-overexpressing gastric epithelial cells. Taken together, these findings provide valuable insights into the potential role of SIRT3 in CagA -mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667968PMC
October 2017

CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway.

Sci Rep 2017 09 7;7(1):10921. Epub 2017 Sep 7.

Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action. CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-β2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-11094-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589721PMC
September 2017

The DNA aptamer binds stemness-enriched cancer cells in pancreatic cancer.

J Mol Recognit 2017 04 28;30(4). Epub 2016 Nov 28.

Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.

Pancreatic cancer remains one of the most common and lethal cancers. Most patients (80%) present with inoperable advanced pancreatic cancer at initial diagnosis, and their early diagnosis is a significant unmet challenge. Recent studies indicate that cancer, including pancreatic cancer, is initiated and propagated by cancer stem cells (CSCs). CSCs are responsible not only for the pathogenesis of cancer but also for the heterogeneity, malignant degree, anticancer therapy resistance, and recurrence of tumors. Therefore, the identification of CSCs may be a crucial stepping stone for overcoming this disastrous pancreatic cancer. Here, we investigated pancreatic CSC-associated aptamers as a novel tool for diagnosis and therapeutic agents. Aptamers that bind to stemness-enriched cancer cells in pancreatic cancer were developed by modified Cell-SELEX method. Positive selection was performed by the sphere cells generated by pancreatic cancer cell line, HPAC, and then the aptamer pool was negatively selected by pancreatic normal cell line, HPDE. Aptamers 1 and 146 showing high specificity upon the K values with 22.18 and 22.62 nM were selected. These 2 aptamers were validated by binding to HPAC sphere cells and to HPDE cells, and both aptamers showed specificity to HPAC sphere cells only. Aptamer-positive cells showed high expression levels of CSC-associated genes compared with the aptamer-negative cells by FACS analysis. The colocalization of CD44, CD24, ESA, and CD133 was also observed in the aptamer-positive cells by confocal microscopy. In the present study, these 2 pancreatic CSC-associated aptamers may be potential candidates for novel diagnostic markers, CSC-targeting drug delivery, or circulating tumor cell detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmr.2591DOI Listing
April 2017

Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

Neoplasia 2016 08;18(8):468-79

Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2016.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018095PMC
August 2016

Embigin is overexpressed in pancreatic ductal adenocarcinoma and regulates cell motility through epithelial to mesenchymal transition via the TGF-β pathway.

Mol Carcinog 2016 May 14;55(5):633-45. Epub 2015 Mar 14.

Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Embigin is a member of the immunoglobulin superfamily and encodes a transmembrane glycoprotein. There have been reports of Embigin involvement in neuromuscular junction formation and plasticity; however, the molecular functions of Embigin in other organs are unknown. Our aim was to investigate the possible role of Embigin in pancreatic cancer. In pancreatic ductal adenocarcinoma tissues, Embigin expression was higher than that in normal pancreatic tissues. Immunohistochemical analysis revealed expression of Embigin in pancreatic cancer cells, as well as expression of monocarboxylate transporter 2 (MCT2) in cancer tissues. To gain further insight, we transfected BxPC-3 and HPAC pancreatic cancer cells with siRNA or shRNA targeting Embigin and observed reductions in cell proliferation, migration, invasion, wound healing, and reduced levels of matrix metalloproteinases-2 and -9. Silencing of Embigin increased intracellular L-lactate concentration by 1.5-fold and decreased MCT2 levels at the plasma membrane. Furthermore, Embigin silencing led to a reduced expression of PI3K, GSK3-β, and Snail/Slug. Upon treating BxPC-3 cells with transforming growth factor-β (TGF-β), we observed elevated expression of Snail/Slug, Embigin, and Vimentin; meanwhile, when treating cells with SB-216763, a GSK3-β inhibitor, we noted decreases in GSK3-β, Snail/Slug, and Embigin expression, suggesting that the TGF-β signaling cascade, comprising PI3K, GSK3-β, Snail/Slug, and Embigin signals, mediates epithelial to mesenchymal transition (EMT) in pancreatic cancer cells. These findings indicate the involvement of Embigin in EMT in pancreatic cancer progression and suggest Embigin as a putative target for the detection and/or treatment of pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.22309DOI Listing
May 2016

Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish.

Neuro Oncol 2013 Mar 16;15(3):290-304. Epub 2013 Jan 16.

Postgraduate School of National Core Research Center for Nanomedical Technology, Seoul, Korea.

Background: Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma.

Methods: We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1(G12V) (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.

Results: Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas.

Conclusions: The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nos387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578497PMC
March 2013

Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish.

PLoS One 2011 2;6(12):e27941. Epub 2011 Dec 2.

Postgraduate School of National Core Research Center for Nanomedical Technology, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Hedgehog (Hh) signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP) to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1), Smoothened (Smo), and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs), especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1) only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4). Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of MMPs and TGFß1 by Hh signaling expands on the current understanding of how Hh signaling affects fibrosis and tumorigenesis. These transgenic models will be a valuable platform in exploring the mechanism of fibrogenic pancreatic diseases which are induced by Hh signaling activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027941PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229500PMC
July 2012

Differentially expressed microRNAs in pancreatic cancer stem cells.

Pancreas 2011 Nov;40(8):1180-7

Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Objective: The objective of this study was to analyze and identify pancreatic cancer stem cell-specific microRNAs (miRNAs) and messenger RNAs (mRNAs) to investigate their correlations to cancer stem cell biology.

Methods: We used sphere cultivation methods to enrich the stem cell population and analyzed overall miRNA and mRNA expressions using microarray analysis.

Results: Differentially expressed miRNAs including miR-99a, miR-100, miR-125b, miR-192, and miR-429 were detected in pancreatic cancer stem cells. Furthermore, examining both profiles, we obtained 210 miRNAs and 258 stem cell-associated mRNAs that were differentially expressed in the pancreatic cancer stem cells. These miRNAs and mRNAs were further investigated using cross-correlation analysis, which yielded 6 groups of miRNAs and 3 groups of mRNAs. The number of miRNA clusters and mRNA clusters showed high correlation based on microarray result.

Conclusions: Differentially expressed miRNAs in pancreatic cancer stem cells provide insights into possible linkages between clusters of miRNAs and clusters of stem cell-associated mRNAs in cancer stem cells and have broad implications in our understanding of cancer stem cells and cancer stem cell-targeted cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0b013e318221b33eDOI Listing
November 2011

Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel up-regulated secretory protein in pancreatic ductal adenocarcinoma.

Cancer Sci 2009 May 2;100(5):828-36. Epub 2009 Mar 2.

Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

The identification of novel tumor-specific proteins or antigens is of great importance for diagnostic and therapeutic applications in pancreatic cancer. Using oligonucleotide microarrays, we identified a broad spectrum of differentially expressed pancreatic cancer-related genes. Of these, we selected an overexpressed expressed sequence taq and cloned a 721-bp full-length cDNA with an open reading frame of 196 amino acids. This novel gene was localized on the Homo sapiens 16p13.3 chromosomal locus, and its nucleotide sequence matched the Homo sapiens similar to common salivary protein 1 (LOC124220). We named the gene pancreatic adenocarcinoma up-regulated factor. The pancreatic adenocarcinoma up-regulated factor was secreted into the culture medium of pancreatic adenocarcinoma up-regulated factor-overexpressing Chinese hamster ovary cells, had an apparent molecular mass of approximately 25 kDa, and was N-glycosylated. The induction of pancreatic adenocarcinoma up-regulated factor in Chinese hamster ovary cells increased cell proliferation, migration, and invasion ability in vitro. Subcutaneous injection of mice with Chinese hamster ovary/pancreatic adenocarcinoma up-regulated factor cells resulted in 3.8-fold greater tumor sizes compared to Chinese hamster ovary/mock cells. Reverse transcription-polymerase chain reaction and western blotting with antirecombinant human pancreatic adenocarcinoma up-regulated factor antibodies confirmed that pancreatic adenocarcinoma up-regulated factor was highly expressed in six of eight pancreatic cancer cell lines. Immunohistochemical staining of human pancreatic cancer tissues also showed pancreatic adenocarcinoma up-regulated factor overexpression in the cytoplasm of cancer cells. Transfection with pancreatic adenocarcinoma up-regulated factor-specific small-interfering RNA reduced cancer cell migration and invasion in vitro. Treatment with antirecombinant human pancreatic adenocarcinoma up-regulated factor in vitro and in vivo reduced proliferation, migration, invasion, and tumorigenic ability. Collectively, our results suggest that pancreatic adenocarcinoma up-regulated factor is a novel secretory protein involved in pancreatic cancer progression and might be a potential target for the treatment of pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1349-7006.2009.01106.xDOI Listing
May 2009