Publications by authors named "Suhwan Chang"

64 Publications

Localized Photothermal Ablation Therapy of Obstructive Rectal Cancer Using a Nanofunctionalized Stent in a Mouse Model.

ACS Biomater Sci Eng 2021 Dec 24;7(12):5890-5898. Epub 2021 Nov 24.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.

The self-expanding metal stent (SEMS) is a versatile, palliative treatment method for unresectable, malignant, non-vascular strictures. Colorectal cancer (CRC) is one of the candidates for the application of the SEMS, in combination with the photothermal ablation (PTA) technique that enhances its therapeutic efficacy. The objective of this study was to investigate the efficacy of stent-mediated PTA therapy in an endoscopy-guided, orthotopic rectal cancer model. A total of 30 of 40 mice with the tumor size of grade 4 were included and were divided into three groups of 10 mice each. Group A underwent a gold nanoparticle (AuNP)-coated SEMS but no near-infrared (NIR) irradiation, group B received an uncoated control SEMS with NIR irradiation, and group C received a AuNP-coated SEMS and NIR irradiation together. Colonoscopy and imaging, immunohistochemical analysis, and quantitative reverse-transcription polymerase chain reaction of major tumor markers were performed. Stent placement and PTA were technically successful using colonoscopy. The tumor grade reduction after PTA is significant in group C, compared with groups A or B ( < 0.001). Molecular analysis validated this observation with a significantly reduced Mapk1 proliferation marker or increased Jnk expression. Histological analysis confirmed the localized PTA therapy using AuNP-coated SEMS profoundly ablated tumor outgrowth through the stent. Our results indicate that this novel strategy of localized PTA therapy could be a promising option for palliative treatment of CRC and to support prolonged stent patency with a decreased tumor volume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.1c01166DOI Listing
December 2021

Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response.

Cancer Res 2022 Jan 28;82(1):142-154. Epub 2021 Oct 28.

Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning-based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. SIGNIFICANCE: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-21-2023DOI Listing
January 2022

siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model.

Cells 2021 10 13;10(10). Epub 2021 Oct 13.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea.

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 ([email protected]). The [email protected] exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the [email protected] sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34 hematopoeitic stem cells onto NSG mice. The [email protected] significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and [email protected] tumors. However, we found higher Granzyme B expression in the [email protected] tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of [email protected] as an immunotherapeutic agent for pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10102734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534711PMC
October 2021

Metagenomic analysis of gut microbiome reveals a dynamic change in Alistipes onderdonkii in the preclinical model of pancreatic cancer, suppressing its proliferation.

Appl Microbiol Biotechnol 2021 Nov 14;105(21-22):8343-8358. Epub 2021 Oct 14.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.

Pancreatic cancer is a lethal cancer with aggressive and invasive characteristics. By the time it is diagnosed, patients already have tumors extended to other organs and show extremely low survival rates. The gut microbiome is known to be associated with many diseases and its imbalance affects the pathogenesis of pancreatic cancer. In this study, we established an orthotopic, patient-derived xenograft model to identify how the gut microbiome is linked to pancreatic ductal adenocarcinoma (PDAC). Using the 16S rDNA metagenomic sequencing, we revealed that the levels of Alistipes onderdonkii and Roseburia hominis decreased in the gut microbiome of the PDAC model. To explore the crosstalk between the two bacteria and PDAC cells, we collected the supernatant of the bacteria or cancer cell culture medium and treated it in a cross manner. While the cancer cell medium did not affect bacterial growth, we observed that the A. onderdonkii medium suppressed the growth of the pancreatic primary cancer cells. Using the bromodeoxyuridine/7-amino-actinomycin D (BrdU/7-AAD) staining assay, we confirmed that the A. onderdonkii medium inhibited the proliferation of the pancreatic primary cancer cells. Furthermore, RNA-seq analysis revealed that the A. onderdonkii medium induced unique transcriptomic alterations in the PDAC cells, compared to the normal pancreatic cells. Altogether, our data suggest that the reduction in the A. onderdonkii in the gut microbiome provides a proliferation advantage to the pancreatic cancer cells. KEY POINTS: • Metagenome analysis of pancreatic cancer model reveals A. onderdonkii downregulation. • A. onderdonkii culture supernatant suppressed the proliferation of pancreatic cancer cells. • RNA seq data reveals typical gene expression changes induced by A. onderdonkii.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00253-021-11617-zDOI Listing
November 2021

Identification of a Splice Variant (c.5074+3A>C) of by RNA Sequencing and TOPO Cloning.

Genes (Basel) 2021 05 26;12(6). Epub 2021 May 26.

Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Grading the pathogenicity of 1/2 variants has great clinical importance in patient treatment as well as in the prevention and screening of hereditary breast and ovarian cancer (HBOC). For accurate evaluation, confirming the splicing effect of a possible splice site variant is crucial. We report a significant splicing variant (c.5074+3A>C) in in a patient with recurrent ovarian cancer. Next-generation sequencing (NGS) of from patient's peripheral blood identified the variant, which was strongly suspected of being a splicing mutation based on in silico predictions. Direct RNA analysis yielded multiple transcripts, and TOPO cloning of the complementary DNA (cDNA) and Sanger sequencing revealed an aberrant transcript with an insertion of the first 153 bp of intron 17, and another transcript with the 153 bp insertion along with an exon 18 deletion. A premature termination codon was presumed to be formed by the 153 bp partial intron retention common to the two transcripts. Therefore, c.5074+3A>C was classified as a likely pathogenic variant. Our findings show that active use of functional studies of variants suspected of altered splicing are of great help in classifying them.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12060810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229931PMC
May 2021

Generation of Colon Cancer Model Based on Colonoscopy Injection.

Authors:
Suhwan Chang

Methods Mol Biol 2021 ;2224:147-152

Department of Biomedical Sciences, Physiology, College of Medicine, Asan Medical Center, University of Ulsan, Seoul, South Korea.

Colorectal cancer animal model is a very useful tool to explore the tumor initiation and development. In the past year, many methods have been used for building up the mouse model including the subcutaneous injection and cecal wall injection or implantation. But this model cannot reflect the native stromal environment of the colon mucosa. Recently, the in vivo murine endoscopy has been developed allowing high-resolution imaging of the colon. Endoscopy orthotopic injection tumor cell line becomes a low cost, fast tumor growth simple technique. In this chapter, we describe detailed protocols for rapidly and efficiently building up colon cancer tumors model by using the colonoscopy-guided mucosal injection. This model can be used to explore drug testing, gene function assessment, and cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1008-4_11DOI Listing
April 2021

Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155.

J Exp Clin Cancer Res 2021 Jan 25;40(1):43. Epub 2021 Jan 25.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.

Background: Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it's function in prostaglandin metabolism is largely unknown.

Methods: A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production.

Results: We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients' survival.

Conclusions: Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-021-01839-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831268PMC
January 2021

The Establishment of a Fast and Safe Orthotopic Colon Cancer Model Using a Tissue Adhesive Technique.

Cancer Res Treat 2021 Jul 15;53(3):733-743. Epub 2020 Dec 15.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: We aimed to develop a novel method for orthotopic colon cancer model, using tissue adhesive in place of conventional surgical method.

Materials And Methods: RFP HCT 116 cell line were used to establish the colon cancer model. Fresh tumor tissue harvested from a subcutaneous injection was grafted into twenty nude mice, divided into group A (suture method) and group B (tissue adhesive method). For the group A, we fixed the tissue on the serosa layer of proximal colon by 8-0 surgical suture. For the group B, tissue adhesive (10 μL) was used to fix the tumor. The mortality, tumor implantation success, tumor metastasis, primary tumor size, and operation time were compared between the two groups. Dissected tumor tissue was analyzed for the histology and immunohistochemistry. Also, we performed tumor marker analysis.

Results: We observed 30% increase in graft success and 20% decrease in mortality, by using tissue adhesive method, respectively. The median colon tumor size was significantly increased by 4 mm and operation time was shortened by 6.5 minutes. The H&E showed similar tumor structure between the two groups. The immunohistochemistry staining for cancer antigen 19-9, carcinoembryonic antigen, cytokeratin 20, and Ki-67 showed comparable intensities in both groups. Real-time quantitative reverse transcription analysis showed eight out of nine tumor markers are unchanged in the tissue adhesive group. Western blot indicated the tissue adhesive group expressed less p-JNK (apototic marker) and more p-MEK/p-p38 (proliferation marker) levels.

Conclusion: We concluded the tissue adhesive method is a quick and safe way to generate orthotopic, colon cancer model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4143/crt.2020.494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291175PMC
July 2021

Potential of MALDI-TOF-based serum N-glycan analysis for the diagnosis and surveillance of breast cancer.

Sci Rep 2020 11 5;10(1):19136. Epub 2020 Nov 5.

R&D Center, NOSQUEST Inc., 660, Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13494, Republic of Korea.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based serum N-glycan analysis has gained acknowledgment for the diagnosis of breast cancer in recent years. In this study, the possibilities of expanding its application for breast cancer management and surveillance were discovered and evaluated. First, a novel MALDI-TOF platform, IDsys RT, was confirmed to be effective for breast cancer analysis, showing a maximum area under the curve of 0.91. Multiple N-glycan markers were identified and validated using this process, and they were found to be applicable for differentiating recurring breast cancer samples from healthy control or ordinary breast cancer samples. Recurrence samples were especially distinct from non-recurrence samples when N-glycan signatures were sampled in multiple time points and monitored via MALDI-TOF, throughout the therapy. These results suggested the feasibility of MALDI-TOF-based N-glycan analysis for tracking the molecular signatures of breast cancer and predicting recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-76195-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644762PMC
November 2020

Analysis of the serial circulating tumor cell count during neoadjuvant chemotherapy in breast cancer patients.

Sci Rep 2020 10 15;10(1):17466. Epub 2020 Oct 15.

Department of Surgery, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.

We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80-63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26-155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74577-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562710PMC
October 2020

tRNA-Derived Small RNAs: Novel Epigenetic Regulators.

Cancers (Basel) 2020 Sep 27;12(10). Epub 2020 Sep 27.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea.

An epigenetic change is a heritable genetic alteration that does not involve any nucleotide changes. While the methylation of specific DNA regions such as CpG islands or histone modifications, including acetylation or methylation, have been investigated in detail, the role of small RNAs in epigenetic regulation is largely unknown. Among the many types of small RNAs, tRNA-derived small RNAs (tsRNAs) represent a class of noncoding small RNAs with multiple roles in diverse physiological processes, including neovascularization, sperm maturation, immune modulation, and stress response. Regarding these roles, several pioneering studies have revealed that dysregulated tsRNAs are associated with human diseases, such as systemic lupus, neurological disorder, metabolic disorder, and cancer. Moreover, recent findings suggest that tsRNAs regulate the expression of critical genes linked with these diseases by a variety of mechanisms, including epigenetic regulation. In this review, we will describe different classes of tsRNAs based on their biogenesis and will focus on their role in epigenetic regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599909PMC
September 2020

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation.

Int J Mol Sci 2020 Aug 27;21(17). Epub 2020 Aug 27.

Department of Biomedical Sciences, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 05505, Korea.

ADAR (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to generate inosine, through its binding to double-stranded RNA (dsRNA), a phenomenon known as RNA editing. One of the functions of ADAR1 is suppressing the type I interferon (IFN) response, but its mechanism in gastric cancer is not clearly understood. We analyzed changes in RNA editing and IFN signaling in ADAR1-depleted gastric cancer cells, to clarify how ADAR1 regulates IFN signaling. Interestingly, we observed a dramatic increase in the protein level of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 9 (IRF9) upon ADAR1 knockdown, in the absence of type I or type II IFN treatment. However, there were no changes in protein expression or localization of the mitochondrial antiviral signaling protein (MAVS) and interferon alpha and beta-receptor subunit 2 (IFNAR2), the two known mediators of IFN production. Instead, we found that miR-302a-3p binds to the untranslated region (UTR) of IRF9 and regulate its expression. The treatment of ADAR1-depleted AGS cells with an miR-302a mimic successfully restored IRF9 as well as STAT1 protein level. Hence, our results suggest that ADAR1 regulates IFN signaling in gastric cancer through the suppression of STAT1 and IRF9 via miR-302a, which is independent from the RNA editing of known IFN production pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21176195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504523PMC
August 2020

Computational inference of cancer-specific vulnerabilities in clinical samples.

Genome Biol 2020 06 29;21(1):155. Epub 2020 Jun 29.

Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.

Background: Systematic in vitro loss-of-function screens provide valuable resources that can facilitate the discovery of drugs targeting cancer vulnerabilities.

Results: We develop a deep learning-based method to predict tumor-specific vulnerabilities in patient samples by leveraging a wealth of in vitro screening data. Acquired dependencies of tumors are inferred in cases in which one allele is disrupted by inactivating mutations or in association with oncogenic mutations. Nucleocytoplasmic transport by Ran GTPase is identified as a common vulnerability in Her2-positive breast cancers. Vulnerability to loss of Ku70/80 is predicted for tumors that are defective in homologous recombination and rely on nonhomologous end joining for DNA repair. Our experimental validation for Ran, Ku70/80, and a proteasome subunit using patient-derived cells shows that they can be targeted specifically in particular tumors that are predicted to be dependent on them.

Conclusion: This approach can be applied to facilitate the development of precision therapeutic targets for different tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02077-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386251PMC
June 2020

Colocalization of MID1IP1 and c-Myc is Critically Involved in Liver Cancer Growth via Regulation of Ribosomal Protein L5 and L11 and CNOT2.

Cells 2020 04 16;9(4). Epub 2020 Apr 16.

Cancer Molecular Targeted Herbal Research Laboratory, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Though midline1 interacting protein 1 (MID1IP1) was known as one of the glucose-responsive genes regulated by carbohydrate response element binding protein (ChREBP), the underlying mechanisms for its oncogenic role were never explored. Thus, in the present study, the underlying molecular mechanism of MID1P1 was elucidated mainly in HepG2 and Huh7 hepatocellular carcinoma cells (HCCs). MID1IP1 was highly expressed in HepG2, Huh7, SK-Hep1, PLC/PRF5, and immortalized hepatocyte LX-2 cells more than in normal hepatocyte AML-12 cells. MID1IP1 depletion reduced the viability and the number of colonies and also increased sub G1 population and the number of TUNEL-positive cells in HepG2 and Huh7 cells. Consistently, MID1IP1 depletion attenuated pro-poly (ADP-ribose) polymerase (pro-PARP), c-Myc and activated p21, while MID1IP1 overexpression activated c-Myc and reduced p21. Furthermore, MID1IP1 depletion synergistically attenuated c-Myc stability in HepG2 and Huh7 cells. Of note, MID1IP1 depletion upregulated the expression of ribosomal protein L5 or L11, while loss of L5 or L11 rescued c-Myc in MID1IP1 depleted HepG2 and Huh7 cells. Interestingly, tissue array showed that the overexpression of MID1IP1 was colocalized with c-Myc in human HCC tissues, which was verified in HepG2 and Huh7 cells by Immunofluorescence. Notably, depletion of CCR4-NOT2 (CNOT2) with adipogenic activity enhanced the antitumor effect of MID1IP1 depletion to reduce c-Myc, procaspase 3 and pro-PARP in HepG2, Huh7 and HCT116 cells. Overall, these findings provide novel insight that MID1IP1 promotes the growth of liver cancer via colocalization with c-Myc mediated by ribosomal proteins L5 and L11 and CNOT2 as a potent oncogenic molecule.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9040985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227012PMC
April 2020

Breast cancer diagnosis by analysis of serum N-glycans using MALDI-TOF mass spectroscopy.

PLoS One 2020 9;15(4):e0231004. Epub 2020 Apr 9.

R&D Center, NOSQUEST Inc., Seongnam, Gyeonggi, Republic of Korea.

Blood and serum N-glycans can be used as markers for cancer diagnosis, as alterations in protein glycosylation are associated with cancer pathogenesis and progression. We aimed to develop a platform for breast cancer (BrC) diagnosis based on serum N-glycan profiles using MALDI-TOF mass spectroscopy. Serum N-glycans from BrC patients and healthy volunteers were evaluated using NosQuest's software "NosIDsys." BrC-associated "NosID" N-glycan biomarkers were selected based on abundance and NosIDsys analysis, and their diagnostic potential was determined using NosIDsys and receiver operating characteristic curves. Results showed an efficient pattern recognition of invasive ductal carcinoma patients, with very high diagnostic performance [area under the curve (AUC): 0.93 and 95% confidence interval (CI): 0.917-0.947]. We achieved effective stage-specific differentiation of BrC patients from healthy controls with 82.3% specificity, 84.1% sensitivity, and 82.8% accuracy for stage 1 BrC and recognized hormone receptor-2 and lymph node invasion subtypes based on N-glycan profiles. Our novel technique supplements conventional diagnostic strategies for BrC detection and can be developed as an independent platform for BrC screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231004PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144955PMC
July 2020

Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer.

J Hum Genet 2020 Mar 6;65(3):209-220. Epub 2020 Jan 6.

Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.

The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-019-0713-2DOI Listing
March 2020

PLGA Nanoparticles Codelivering siRNAs against Programmed Cell Death Protein-1 and Its Ligand Gene for Suppression of Colon Tumor Growth.

Mol Pharm 2019 12 7;16(12):4940-4953. Epub 2019 Nov 7.

Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea.

Tumor-infiltrating T lymphocytes highly express programmed cell death protein-1 (PD-1) that interacts with its ligand, programmed cell death protein ligand-1 (PD-L1) on tumors. PD-1/PD-L1 interactions cause functional exhaustion of effector T cells and impair antitumor immunity, allowing tumors to escape immune surveillance. In addition to such extrinsic interactions, tumors proliferate by transmitting intrinsic PD-L1 signals via the mTOR pathway. Here, we simultaneously silenced PD-1 and PD-L1 expressions on CTLs and colon tumors using PD-1 siRNA/PD-L1 siRNA-loaded PLGA nanoparticles and investigated functional activation of tumor-specific CTLs. When compared to a single PD-1 silencing on CTLs or a single PD-L1 silencing on tumors, cosilencing of PD-1/PD-L1 on CTLs and tumors more efficiently promoted effector functions of tumor-specific CTLs. Moreover, PD-L1-silenced tumors inhibited mTOR signaling and showed an antiproliferative response independent of the adaptive immune response. Ultimately, systemic administration of PD-1 and PD-L1 siRNA via PLGA nanoparticles restored the effector functions of tumor-specific CTLs in MC38 tumor-bearing mice. Compared with antitumor effects of single silencing of PD-1 or PD-L1 alone, cosilencing of PD-1 and PD-L1 showed more significant tumor growth suppression and long-term tumor inhibition in colon cancer. Thus, this study provides an efficient therapeutic strategy for achieving immunotherapy in colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.9b00826DOI Listing
December 2019

The Role of miRNAs in Immune Cell Development, Immune Cell Activation, and Tumor Immunity: With a Focus on Macrophages and Natural Killer Cells.

Cells 2019 09 24;8(10). Epub 2019 Sep 24.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea.

The tumor microenvironment (TME) is the primary arena where tumor cells and the host immune system interact. Bidirectional communication between tumor cells and the associated stromal cell types within the TME influences disease initiation and progression, as well as tumor immunity. Macrophages and natural killer (NK) cells are crucial components of the stromal compartment and display either pro- or anti-tumor properties, depending on the expression of key regulators. MicroRNAs (miRNAs) are emerging as such regulators. They affect several immune cell functions closely related to tumor evasion of the immune system. This review discusses the role of miRNAs in the differentiation, maturation, and activation of immune cells as well as tumor immunity, focusing particularly on macrophages and NK cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8101140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829453PMC
September 2019

A CRISPR-based base-editing screen for the functional assessment of BRCA1 variants.

Oncogene 2020 01 29;39(1):30-35. Epub 2019 Aug 29.

Department of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Genetic mutations in BRCA1, which is crucial for the process of DNA repair and maintenance of genomic integrity, are known to increase markedly the risk of breast and ovarian cancers. Clinical genetic testing has been used to identify new BRCA1 variants; however, functional assessment and determination of their pathogenicity still poses challenges for clinical management. Here, we describe that CRISPR-mediated cytosine base editor, known as BE3, can be used for the functional analysis of BRCA1 variants. We performed CRISPR-mediated base-editing screening using 745 gRNAs targeting all exons in BRCA1 to identify loss-of-function variants and identified variants whose function has heretofore remained unknown, such as c.-97C>T, c.154C>T, c.3847C>T, c.5056C>T, and c.4986+5G>A. Our results show that CRISPR-mediated base editor is a powerful tool for the reclassification of variants of uncertain significance (VUSs) in BRCA1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0968-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937211PMC
January 2020

A pharmacogenomic analysis using L1000CDS identifies BX-795 as a potential anticancer drug for primary pancreatic ductal adenocarcinoma cells.

Cancer Lett 2019 Nov 9;465:82-93. Epub 2019 Aug 9.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea; Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea. Electronic address:

Pancreatic cancer is one of the leading causes of cancer death, mainly due to the absence of early diagnostic tool and effective therapeutic agents. To identify an effective therapeutic agent for pancreatic ductal adenocarcinoma cells (PDAC), we used 10 Gene Expression Omnibus (GEO) data sets and L1000CDS pharmacogenetic search tool and obtained chemical "perturvants" that were predicted to reverse the abnormal gene expression changes in PDAC. Among 20 initial candidates, we measured IC for six compounds and identified BX-795, PDK1/TBK1 inhibitor, as a therapeutic candidate. We found that BX-795 inhibits primary PDAC cell proliferation more effectively than normal cells. Following molecular analysis revealed that BX-795 down-regulates mTOR-GSK3β pathway and trigger apoptosis. Moreover, we found that BX-795 suppresses primary PDAC cell migration via downregulation of Snail and Slug. Finally, efficacy test in patient-derived xenograft model of PDAC showed BX-795 can inhibit in vivo tumor growth as efficient as gemcitabine and a combination with trametinib further suppresses tumor growth. Collectively, these results demonstrate the BX-795 as an effective therapeutic candidate for PDAC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2019.08.002DOI Listing
November 2019

Cellular context-dependent interaction between cancer and stellate cells in hetero-type multicellular spheroids of pancreatic tumor.

Biochem Biophys Res Commun 2019 07 24;515(1):183-189. Epub 2019 May 24.

Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Heterotypic cell-cell interaction between cancer cells and pancreatic stellate cells (PSCs) within tumor microenvironment is considered as a key mechanism for epithelial-mesenchymal transition (EMT) that triggers disease progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Hence, PSCs should be incorporated into in vitro co-culture models to maximize clinical relevance of data obtained using these models. In this study, we developed hetero-type spheroids of pancreatic cancer cells (ductal carcinoma cells PANC-1 and primacy sarcomatoid adenocarcinoma 36473 cells) and PSCs. Effect of PSC co-culture on the formation and growth of multicellular spheroids was cell-line dependent in that growth stimulation effect appeared in PANC-1/PSC spheroids, but not in 36473/PSC spheroids. Spatial distribution of PSCs within spheroids was also cell-line dependent. It was either confined to the center region (PANC-1) or evenly distributed (36473). Changes in expression levels of E-cadherin and vimentin revealed EMT induction in PANC-1/PSC hetero-type spheroids, but not in 36473/PSC spheroids. Gemcitabine sensitivity was increased partially by PSC co-culture. However, PSCs showed relative resistance to gemcitabine compared to PANC-1 cells in PANC-1/PSC spheroids. Overall, our hetero-type spheroid model can be used to study cancer-stroma interaction and their mechanism and evaluate anticancer drug activity. We demonstrated that stromal effect by PSC co-culture might be cellular context dependent with regard to growth stimulation and EMT induction. Hence, anti-stromal therapy should take these differences into consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.05.101DOI Listing
July 2019

p53-Dependent Apoptotic Effect of Puromycin via Binding of Ribosomal Protein L5 and L11 to MDM2 and its Combination Effect with RITA or Doxorubicin.

Cancers (Basel) 2019 Apr 24;11(4). Epub 2019 Apr 24.

College of Kyung Hee Medicine, Kyung Hee University, Seoul 02447, Korea.

Among ribosomal proteins essential for protein synthesis, the functions of ribosomal protein L5 (RPL5) and RPL11 still remain unclear to date. Here, the roles of RPL5 and RPL11 were investigated in association with p53/p21 signaling in the antitumor effect of puromycin mainly in HCT116 and H1299 cancer cells. Cell proliferation assays using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays and colony formation assays, cell cycle analysis, Reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were performed in cancer cells. Puromycin exerted cytotoxic and anti-proliferative effects in p53 wild-type HCT116 more than in p53 null H1299 cells. Consistently, puromycin increased sub-G1, cleaved Poly (ADP-ribose) polymerase (PARP), activated p53, p21, and Mouse double minute 2 homolog (MDM2), and attenuated expression of c-Myc in HCT116 cells. Notably, puromycin upregulated the expression of RPL5 and RPL11 to directly bind to MDM2 in HCT116 cells. Conversely, deletion of RPL5 and RPL11 blocked the activation of p53, p21, and MDM2 in HCT116 cells. Also, puromycin enhanced the antitumor effect with reactivating p53 and inducing tumor apoptosis (RITA) or doxorubicin in HCT116 cells. These findings suggest that puromycin induces p53-dependent apoptosis via upregulation of RPL5 or RPL11 for binding with MDM2, and so can be used more effectively in p53 wild-type cancers by combination with RITA or doxorubicin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11040582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520892PMC
April 2019

A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells.

Mol Oncol 2018 09 29;12(9):1526-1539. Epub 2018 Aug 29.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed an IC of 0.39-1.13 μm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6-TG. Lastly, we used a patient-derived xenograft model to confirm that 6-TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6-TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120251PMC
September 2018

Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma.

Neoplasia 2018 08 4;20(8):800-812. Epub 2018 Jul 4.

Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Interactions between cancer cells and cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play an important role in promoting the profibrotic microenvironment and epithelial-mesenchymal transition (EMT), resulting in tumor progression and drug resistance in hepatocellular carcinoma (HCC). In the present study, we developed a mixed-cell spheroid model using Huh-7 HCC cells and LX-2 stellate cells to simulate the in vivo tumor environment with respect to tumor-CAF interactions. Spheroids were cultured from cancer cells alone (monospheroids) or as a mixture (mixed-cell spheroids) in ultra-low-attachment plates. Compact, well-mixed, and stroma-rich mixed-cell spheroids were successfully established with heterotypic cell-cell contacts shown by the presence of gap junctions and desmosomes. Mixed-cell spheroids showed enhanced expression of collagen type-I (Col-I) and pro-fibrotic factors such as, transforming growth factor beta1 (TGF-β1), and connective tissue growth factor (CTGF) compared to the levels expressed in mono-spheroids. The EMT phenotype was evident in mixed-cell spheroids as shown by the altered expression of E-cadherin and vimentin. Differential drug sensitivity was observed in mixed-cell spheroids, and only sorafenib and oxaliplatin showed dose-dependent antiproliferative effects. Simultaneous treatment with TGF-β inhibitors further improved sorafenib efficacy in the mixed-cell spheroids, indicating the involvement of TGF-β in the mechanism of sorafenib resistance. In 3D matrix invasion assay, mixed-cell spheroids exhibited fibroblast-led collective cell movement. Overall, our results provide evidence that mixed-cell spheroids formed with Huh-7 and LX-2 cells well represent HCC tumors and their TME in vivo and hence are useful in studying tumor-stroma interactions as mechanisms associated with drug resistance and increased cell motility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2018.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034588PMC
August 2018

Integrative Bioinformatics and Functional Analyses of GEO, ENCODE, and TCGA Reveal FADD as a Direct Target of the Tumor Suppressor BRCA1.

Int J Mol Sci 2018 May 14;19(5). Epub 2018 May 14.

Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul 05505, Korea.

BRCA1 is a multifunctional tumor suppressor involved in several essential cellular processes. Although many of these functions are driven by or related to its transcriptional/epigenetic regulator activity, there has been no genome-wide study to reveal the transcriptional/epigenetic targets of BRCA1. Therefore, we conducted a comprehensive analysis of genomics/transcriptomics data to identify novel BRCA1 target genes. We first analyzed ENCODE data with BRCA1 chromatin immunoprecipitation (ChIP)-sequencing results and identified a set of genes with a promoter occupied by BRCA1. We collected 3085 loci with a BRCA1 ChIP signal from four cell lines and calculated the distance between the loci and the nearest gene transcription start site (TSS). Overall, 66.5% of the BRCA1-bound loci fell into a 2-kb region around the TSS, suggesting a role in transcriptional regulation. We selected 45 candidate genes based on gene expression correlation data, obtained from two GEO (Gene Expression Omnibus) datasets and TCGA data of human breast cancer, compared to BRCA1 expression levels. Among them, we further tested three genes (, and ) and verified as a novel direct target of BRCA1 by ChIP, RT-PCR, and a luciferase reporter assay. Collectively, our data demonstrate genome-wide transcriptional regulation by BRCA1 and suggest target genes as biomarker candidates for BRCA1-associated breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19051458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983697PMC
May 2018

Combinatory RNA-Sequencing Analyses Reveal a Dual Mode of Gene Regulation by ADAR1 in Gastric Cancer.

Dig Dis Sci 2018 07 25;63(7):1835-1850. Epub 2018 Apr 25.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea.

Background: Adenosine deaminase acting on RNA 1 (ADAR1) is known to mediate deamination of adenosine-to-inosine through binding to double-stranded RNA, the phenomenon known as RNA editing. Currently, the function of ADAR1 in gastric cancer is unclear.

Aims: This study was aimed at investigating RNA editing-dependent and editing-independent functions of ADAR1 in gastric cancer, especially focusing on its influence on editing of 3' untranslated regions (UTRs) and subsequent changes in expression of messenger RNAs (mRNAs) as well as microRNAs (miRNAs).

Methods: RNA-sequencing and small RNA-sequencing were performed on AGS and MKN-45 cells with a stable ADAR1 knockdown. Changed frequencies of editing and mRNA and miRNA expression were then identified by bioinformatic analyses. Targets of RNA editing were further validated in patients' samples.

Results: In the Alu region of both gastric cell lines, editing was most commonly of the A-to-I type in 3'-UTR or intron. mRNA and protein levels of PHACTR4 increased in ADAR1 knockdown cells, because of the loss of seed sequences in 3'-UTR of PHACTR4 mRNA that are required for miRNA-196a-3p binding. Immunohistochemical analyses of tumor and paired normal samples from 16 gastric cancer patients showed that ADAR1 expression was higher in tumors than in normal tissues and inversely correlated with PHACTR4 staining. On the other hand, decreased miRNA-148a-3p expression in ADAR1 knockdown cells led to increased mRNA and protein expression of NFYA, demonstrating ADAR1's editing-independent function.

Conclusions: ADAR1 regulates post-transcriptional gene expression in gastric cancer through both RNA editing-dependent and editing-independent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-018-5081-9DOI Listing
July 2018

Novel cancer gene variants and gene fusions of triple-negative breast cancers (TNBCs) reveal their molecular diversity conserved in the patient-derived xenograft (PDX) model.

Cancer Lett 2018 08 22;428:127-138. Epub 2018 Apr 22.

Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea. Electronic address:

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairs with Ion AmpliSeq CCP revealed high degree of variant conservation (85.0%-96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, and Col1a1. Among them, we confirmed frequent Notch1 variant. Furthermore, RNA-seq analysis of 24 PDXs revealed 594 gene fusions, of which 163 were in-frame, including AZGP1-GJC3 and NF1-AARSD1. Finally, western blot analysis of oncogenic signaling proteins supporting molecular diversity of TNBC PDXs. Overall, our report provides a molecular basis for the usefulness of the TNBC PDX model in preclinical study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2018.04.020DOI Listing
August 2018

microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer.

Oncogene 2018 05 12;37(22):2982-2991. Epub 2018 Mar 12.

Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 05505, Korea.

MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various biological processes including tumorigenesis. Here, we addressed the function of miR-155 using LC-MS/MS-based metabolic profiling of miR-155 deficient breast cancer cells. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. We showed this is due to the down-regulation of cMYC, controlled through phosphoinositide-3-kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a pathway. UTR analysis of the PIK3R1 and FOXO3a indicated miR-155 directly represses these genes. A stable expression of miR-155 in patient-derived cells (PDCs) showed activated glucose metabolism whereas a stable inhibition of miR-155 reduced in vivo tumor growth with retarded glucose metabolism. Furthermore, analysis of 50 triple-negative breast cancer (TNBC) specimens and specific uptake value (SUV) of PET images revealed a positive correlation between miR-155 level and glucose usage in human breast tumors via PIK3R1-PDK/AKT-FOXO3a-cMYC axis. Collectively, these data demonstrate the miR-155 is a key regulator of glucose metabolism in breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978802PMC
May 2018

Genetic and metabolic comparison of orthotopic and heterotopic patient-derived pancreatic-cancer xenografts to the original patient tumors.

Oncotarget 2018 Jan 21;9(8):7867-7881. Epub 2017 Dec 21.

Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea.

Tumors from 25 patients with pancreatic cancer were used to establish two patient-derived xenograft (PDX) models: orthotopic PDX (PDOX) and heterotopic (subcutaneous) PDX (PDHX). We compared gene expression by immunohistochemistry, single-nucleotide polymorphism (SNP), DNA methylation, and metabolite levels. The 4 cases, of the total of 13 in which simultaneous PDHX & PDOX models were established, were randomly selected. The molecular-genetic characteristics of the patient's tumor were well maintained in the two PDX models. SNP analysis demonstrated that both groups were more than 90% identical to the original patient's tumor, and there was little difference between the two models. DNA methylation of most genes was similar among the two models and the original patients tumor, but some gene sets were hypermethylated the in PDOX model and hypomethylated in the PDHX model. Most of the metabolites had a similar pattern to those of the original patient tumor in both PDX tumor models, but some metabolites were more prominent in the PDOX and PDHX models. This is the first simultaneous molecular-genetic and metabolite comparison of patient tumors and their tumors established in PDOX and PDHX models. The results indicate high fidelity of these critical properties of the patient tumors in the two models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.23567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814265PMC
January 2018
-->