Publications by authors named "Duane Smoot"

113 Publications

MiRNA-20b/SUFU/Wnt axis accelerates gastric cancer cell proliferation, migration and EMT.

Heliyon 2021 Apr 12;7(4):e06695. Epub 2021 Apr 12.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China.

Previous research has found that miRNA-20b is highly expressed in gastric cancer (GC), however, its function and underlying mechanism are not clear. Wnt signaling pathway, implicated in tumorigeneisis, is activated in more than 30% of GC. We would like to characterize the biological behavior of miRNA-20b in terms of modulating Wnt/β-catenin signaling and EMT. We showed that miRNA-20b inhibitors suppressed Topflash/Fopflash dependent luciferase activity and the β-catenin nuclear translocation, resulting in inhibition of Wnt pathway activity and EMT. SUFU, negatively regulating Wnt and Hedgehog signaling pathway, was proved to be targeted by miRNA-20b. Moreover, additional knockdown of SUFU alleviated the inhibitory effect on Wnt pathway activity, EMT, cell proliferation/migration and colony formation caused by miRNA-20b inhibition. In summary, miRNA-20b is an oncogenic miRNA and promoted cell proliferation, migration and EMT in GC partially by activating Wnt pathway via targeting SUFU.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065298PMC
April 2021

Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer.

Aging (Albany NY) 2021 Apr 12;13(7):10749-10769. Epub 2021 Apr 12.

Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China.

Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration . We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions , suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.
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http://dx.doi.org/10.18632/aging.202895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064165PMC
April 2021

Tumor-specific overexpression of histone gene, H3C14 in gastric cancer is mediated through EGFR-FOXC1 axis.

Biochim Biophys Acta Gene Regul Mech 2021 Apr-May;1864(4-5):194703. Epub 2021 Mar 13.

KS313, Epigenetics and Chromatin Biology Group, Gupta Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, MH, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH, India. Electronic address:

Incorporation of different H3 histone isoforms/variants have been reported to differentially regulate gene expression via alteration in chromatin organization during diverse cellular processes. However, the differential expression of highly conserved histone H3.2 genes, H3C14 and H3C13 in human cancer has not been delineated. In this study, we investigated the expression of H3.2 genes in primary human gastric, brain, breast, colon, liver, and head and neck cancer tissues and tumor cell lines. The data showed overexpression of H3.2 transcripts in tumor samples and cell lines with respect to normal counterparts. Furthermore, TCGA data of individual and TCGA PANCAN cohort also showed significant up-regulation of H3.2 genes. Further, overexpressed H3C14 gene coding for H3.2 protein was regulated by FOXC1 transcription factor and G4-cassette in gastric cancer cell lines. Elevated expression of FOXC1 protein and transcripts were also observed in human gastric cancer samples and cell lines. Further, FOXC1 protein was predominantly localized in the nuclei of neoplastic gastric cells compared to normal counterpart. In continuation, studies with EGF induction, FOXC1 knockdown, and ChIP-qPCR for the first time identified a novel axis, EGFR-FOXC1-H3C14 for regulation of H3C14 gene overexpression in gastric cancer. Therefore, the changes the epigenomic landscape due to incorporation of differential expression H3 variant contributes to change in gene expression pattern and thereby contributing to pathogenesis of cancer.
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http://dx.doi.org/10.1016/j.bbagrm.2021.194703DOI Listing
March 2021

Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn's colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease.

PLoS One 2021 9;16(3):e0246393. Epub 2021 Mar 9.

Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College School of Medicine, Nashville, Tennessee, United States of America.

Evidence link bacterial enterotoxins to apparent crypt-cell like cells (CCLCs), and Alpha Defensin 5 (DEFA5) expansion in the colonic mucosa of Crohn's colitis disease (CC) patients. These areas of ectopic ileal metaplasia, positive for Paneth cell (PC) markers are consistent with diagnosis of CC. Retrospectively, we: 1. Identified 21 patients with indeterminate colitis (IC) between 2000-2007 and were reevaluation their final clinical diagnosis in 2014 after a followed-up for mean 8.7±3.7 (range, 4-14) years. Their initial biopsies were analyzed by DEFA5 bioassay. 2. Differentiated ulcer-associated cell lineage (UACL) analysis by immunohistochemistry (IHC) of the CC patients, stained for Mucin 6 (MUC6) and DEFA5. 3. Treated human immortalized colonic epithelial cells (NCM460) and colonoids with pure DEFA5 on the secretion of signatures after 24hr. The control colonoids were not treated. 4. Treated colonoids with/without enterotoxins for 14 days and the spent medium were collected and determined by quantitative expression of DEFA5, CCLCs and other biologic signatures. The experiments were repeated twice. Three statistical methods were used: (i) Univariate analysis; (ii) LASSO; and (iii) Elastic net. DEFA5 bioassay discriminated CC and ulcerative colitis (UC) in a cohort of IC patients with accuracy. A fit logistic model with group CC and UC as the outcome and the DEFA5 as independent variable differentiator with a positive predictive value of 96 percent. IHC staining of CC for MUC6 and DEFA5 stained in different locations indicating that DEFA5 is not co-expressed in UACL and is therefore NOT the genesis of CC, rather a secretagogue for specific signature(s) that underlie the distinct crypt pathobiology of CC. Notably, we observed expansion of signatures after DEFA5 treatment on NCM460 and colonoids cells expressed at different times, intervals, and intensity. These factors are key stem cell niche regulators leading to DEFA5 secreting CCLCs differentiation 'the colonic ectopy ileal metaplasia formation' conspicuously of pathogenic importance in CC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246393PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942995PMC
March 2021

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation.

J Biomed Sci 2021 Feb 3;28(1):12. Epub 2021 Feb 3.

School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, HBNI, P.O. Bhimpur-Padanpur, Via Jatni, Khurda, 752050, Odisha, India.

Background: Helicobacter pylori-mediated gastric carcinogenesis is initiated by a plethora of signaling events in the infected gastric epithelial cells (GECs). The E3 ubiquitin ligase seven in absentia homolog 2 (Siah2) is induced in GECs in response to H. pylori infection. Posttranslational modifications of Siah2 orchestrate its function as well as stability. The aim of this study was to evaluate Siah2 phosphorylation status under the influence of H. pylori infection and its impact in gastric cancer progression.

Methods: H. pylori-infected various GECs, gastric tissues from H. pylori-infected GC patients and H. felis-infected C57BL/6 mice were evaluated for Siah2 phosphorylation by western blotting or immunofluorescence microscopy. Coimmunoprecipitation assay followed by mass spectrometry were performed to identify the kinases interacting with Siah2. Phosphorylation sites of Siah2 were identified by using various plasmid constructs generated by site-directed mutagenesis. Proteasome inhibitor MG132 was used to investigate proteasome degradation events. The importance of Siah2 phosphorylation on tumorigenicity of infected cells were detected by using phosphorylation-null mutant and wild type Siah2 stably-transfected cells followed by clonogenicity assay, cell proliferation assay, anchorage-independent growth and transwell invasion assay.

Results: Siah2 was phosphorylated in H. pylori-infected GECs as well as in metastatic GC tissues at residues serine (Ser) and threonine (Thr). Phosphorylation of Siah2 was mediated by MRCKβ, a Ser/Thr protein kinase. MRCKβ was consistently expressed in uninfected GECs and noncancer gastric tissues but its level decreased in infected GECs as well as in metastatic tissues which had enhanced Siah2 expression. Infected murine gastric tissues showed similar results. MRCKβ could phosphorylate Siah2 but itself got ubiquitinated from this interaction leading to the proteasomal degradation of MRCKβ and use of proteasomal inhibitor MG132 could rescue MRCKβ from Siah2-mediated degradation. Ser and Thr phosphorylated-Siah2 was more stable and tumorigenic than its non-phosphorylated counterpart as revealed by the proliferation, invasion, migration abilities and anchorage-independent growth of stable-transfected cells.

Conclusions: Increased level of Ser and Thr-phosphorylated-Siah2 and downregulated MRCKβ were prominent histological characteristics of Helicobacter-infected gastric epithelium and metastatic human GC. MRCKβ-dependent Siah2 phosphorylation stabilized Siah2 which promoted anchorage-independent survival and proliferative potential of GECs. Phospho-null mutants of Siah2 (S6A and T279A) showed abated tumorigenicity.
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http://dx.doi.org/10.1186/s12929-021-00710-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856738PMC
February 2021

Lymphatic metastasis-related TBL1XR1 enhances stemness and metastasis in gastric cancer stem-like cells by activating ERK1/2-SOX2 signaling.

Oncogene 2021 Feb 7;40(5):922-936. Epub 2020 Dec 7.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.
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http://dx.doi.org/10.1038/s41388-020-01571-xDOI Listing
February 2021

Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.

Cell Death Dis 2020 10 30;11(10):937. Epub 2020 Oct 30.

Guangdong Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, People's Republic of China.

Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
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http://dx.doi.org/10.1038/s41419-020-03130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599338PMC
October 2020

SUFU mediates EMT and Wnt/β-catenin signaling pathway activation promoted by miRNA-324-5p in human gastric cancer.

Cell Cycle 2020 Oct 5;19(20):2720-2733. Epub 2020 Oct 5.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine , Shenzhen, Guangdong, China.

The poor prognosis of late gastric carcinomas (GC) underscores the necessity to identify novel biomarkers for earlier diagnosis and effective therapeutic targets. MiRNA-324-5p has been shown to be over-expressed in GC, however the biological function of miRNA-324-5p implicated in gastric cancer and its downstream targets were not well understood. Wnt/β-catenin signaling pathway is aberrantly regulated in GC. We sought to explore if miRNA-324-5p promotes oncogenesis through modulating Wnt signaling and EMT. MiRNA-324-5p is highly expressed in GC based on qRT-PCR and TCGA data. In addition, in vitro cell proliferation, cell migration assays and in vivo animal exenograft were executed to show that miRNA-324-5p is an oncogenic miRNA in GC. MiRNA-324-5p activates Wnt signaling and induces EMT in GC. Further, SUFU was identified as a target of miRNA-324-5p confirmed by western blotting and luciferase assays. Spearson analysis and TCGA data indicate that the expression of SUFU is negatively associated with the expression of miRNA-324-5p. Rescue experiments were performed to determine if SUFU mediates the Wnt activation, EMT and oncogenic function of miRNA-324-5p. MiRNA-324-5p inhibitors plus SUFU siRNAs rescue partially the inhibitory effect on Wnt signaling and EMT caused by miRNA-324-5p inhibitors. Finally, the suppression of cell proliferation, migration, and colony formation ability induced by miRNA-324-5p inhibitors is alleviated by addition of SUFU siRNAs. In summary, miRNA-324-5p is overexpressed and exerts cell growth and migration-promoting effects through activating Wnt signaling and EMT by targeting SUFU in GC. It represents a potential miRNA with an oncogenic role in human gastric cancer.
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http://dx.doi.org/10.1080/15384101.2020.1826632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644164PMC
October 2020

TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression.

Cell Death Discov 2020 6;6:56. Epub 2020 Jul 6.

State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032 China.

Intestinal metaplasia (IM) increases the risk of gastric cancer. Our previous results indicated that bile acids (BAs) reflux promotes gastric IM development through kruppel-like factor 4 (KLF4) and caudal-type homeobox 2 (CDX2) activation. However, the underlying mechanisms remain largely elusive. Herein, we verified that secondary BAs responsive G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) was increased significantly in IM specimens. Moreover, TGR5 contributed to deoxycholic acid (DCA)-induced metaplastic phenotype through positively regulating KLF4 and CDX2 at transcriptional level. Then we employed PCR array and identified hepatocyte nuclear factor 4α (HNF4α) as a candidate mediator. Mechanically, DCA treatment could induce HNF4α expression through TGR5 and following ERK1/2 pathway activation. Furthermore, HNF4α mediated the effects of DCA treatment through directly regulating KLF4 and CDX2. Finally, high TGR5 levels were correlated with high HNF4α, KLF4, and CDX2 levels in IM tissues. These findings highlight the TGR5-ERK1/2-HNF4α axis during IM development in patients with BAs reflux, which may help to understand the mechanism underlying IM development and provide prospective strategies for IM treatment.
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http://dx.doi.org/10.1038/s41420-020-0290-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338499PMC
July 2020

Molecular Signatures of MINA53 in Gastric Cancer.

Cancers (Basel) 2020 May 2;12(5). Epub 2020 May 2.

Department of Integrative Biotechnology, Sungkyunkwan University, and Biomedical Institute for Convergence at SKKU (BICS), Suwon 16419, Korea.

The gene and its encoded protein MYC-induced nuclear antigen (MINA53) are associated with multiple cancers. Besides having both an oncogenic and tumor suppressor function, the intricate role of in cancer is complex as it depends on the cancer type. In particular, the functional role of /MINA53 in gastric cancer has been poorly understood. In this study, we have unraveled the molecular signatures and functional roles of /MINA53 in gastric cancer by multiple approaches, i.e., multi-omics bioinformatics study, analysis of human gastric cancer tissues, and studies in vitro using knockdown or overexpression strategies in gastric cancer cell lines. The results indicated that the gene and MINA53 protein are commonly overexpressed in cancer patients. JMJD10/MINA53 is involved in the regulation of proliferation and survival of gastric cancer by controlling cell cycle gene expression. These processes are highly associated with MINA53 enzymatic activity in the regulation of H3K9me3 methylation status and controlling activation of AP-1 signaling pathways. This highlights the oncogenic role of /MINA53 in gastric cancer and opens the opportunity to develop therapeutic targeting of /MINA53 in gastric cancer.
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http://dx.doi.org/10.3390/cancers12051141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281541PMC
May 2020

Uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells.

Gastric Cancer 2020 09 6;23(5):848-862. Epub 2020 Apr 6.

Department of Pathology, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.

Background: Gastrokine 1 (GKN1) is a stomach-specific tumor suppressor that is secreted into extracellular space as an exosomal cargo protein. The objective of this study was to investigate the uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells.

Methods: Immunofluorescent and Western blot analysis were used to investigate gastric-specific uptake of HFE-145-derived exosomes. Binding affinity of HFE-145 derived exosomes with integrin proteins was examined using protein microarray chip. Tumor suppressor activities of exosome-carrying GKN1 protein were analyzed using transwell co-culture, MTT assay, BrdU incorporation, immunoprecipitation, and Western blot analysis.

Results: HFE-145-derived exosomes were internalized only into HFE-145 gastric epithelial cells and gastric cancer cells. Gastric-specific uptake of stomach-derived exosomes required integrin α6 and αX proteins. Clathrin and macropinocytosis increased the uptake of exosomes into gastric epithelial cells, whereas caveolin inhibited the uptake of exosomes. Transwell co-culture of AGS cells with HFE-145 cells markedly inhibited viability and proliferation of AGS cells. Following uptake of HFE-145-derived exosomes in recipient cells, GKN1 protein bound to HRas and inhibited the binding of HRas to b-Raf and c-Raf which subsequently downregulated HRas/Raf/MEK/ERK signaling pathways in AGS, MKN1 cells, and MKN1-derived xenograft tumor tissues. In addition, exosomal GKN1 protein suppressed both migration and invasion of gastric cancer cells by inhibiting epithelial-mesenchymal transition.

Conclusions: Gastric-specific uptake of exosomes derived from gastric epithelial cells requires integrin α6 and αX proteins in both gastric epithelial cells and exosomes. Exosomal GKN1 protein inhibits gastric carcinogenesis by downregulating HRas/Raf/MEK/ERK signaling pathways.
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http://dx.doi.org/10.1007/s10120-020-01068-2DOI Listing
September 2020

Expression of Tight Junction Proteins According to Functional Dyspepsia Subtype and Sex.

J Neurogastroenterol Motil 2020 Apr;26(2):248-258

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea.

Background/aims: To determine whether the expression of tight junction proteins (TJPs) differs depending on the subtype of functional dyspepsia (FD) and sex.

Methods: Control (n = 95) and FD (n = 165) groups based on Rome III criteria were prospectively enrolled. Gastric mucosal mRNA expression levels of various TJPs (claudins [CLDN] 1, 2, and 4; zonula occludens-1; occludin [OCLN]) were assessed by reverse transcription polymerase chain reaction. Western blot was performed to determine the levels of various TJPs. infection status was evaluated by histology, rapid urease test, and culture. Questionnaires were analyzed.

Results: In all groups irrespective of , FD group showed significantly higher CLDN2 mRNA levels than control group ( = 0.048). The level of CLDN4 mRNA expression was significantly lower in female FD group than in male FD group ( = 0.018). In uninfected subjects, the level of CLDN1 mRNA expression in female FD group was significantly lower than that of male FD group ( = 0.014). The level of CLDN2 mRNA expression was significantly higher in the male postprandial distress syndrome ( = 0.001) and male epigastric pain syndrome ( = 0.023) groups than in the male control group. In Western blot analysis, the expression of OCLN was significantly elevated 48 hour after the culture with strain 43504.

Conclusions: can affect a variety of TJPs, particularly claudin-4 and occludin. Claudin-2 is thought to be involved in FD irrespective of status, especially in the pathophysiology of male FD.
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http://dx.doi.org/10.5056/jnm19208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176499PMC
April 2020

Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer.

World J Gastroenterol 2020 Feb;26(6):598-613

Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India.

Background: The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments.

Aim: To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.

Methods: The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death.

Results: In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.

Conclusion: Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis.
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http://dx.doi.org/10.3748/wjg.v26.i6.598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029347PMC
February 2020

miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC.

J Cell Physiol 2020 09 24;235(9):6218-6229. Epub 2020 Feb 24.

Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.
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http://dx.doi.org/10.1002/jcp.29550DOI Listing
September 2020

Genipin increases oxaliplatin-induced cell death through autophagy in gastric cancer.

J Cancer 2020 1;11(2):460-467. Epub 2020 Jan 1.

Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.

Oxaliplatin is used for treatment in combination with many drugs. However, the survival rate is still low due to side effects and drug resistance. Therefore, the combination with natural products was required for increasing efficacy and reducing side effects. Genipin, a natural product derived from the , associated with anti-angiogenic, anti-proliferative, hypertension, inflammatory, and the Hedgehog pathway. It is not known that genipin increases the therapeutic effect of oxaliplatin in gastric cancer. In this study, we found that genipin sensitizes oxaliplatin-induced apoptosis for the first time using colony forming assay, FACS analysis, and western blotting in gastric cancer. Additionally, genipin induced p53 expression in AGS, MKN45, and MKN28 cells. Also, genipin induced autophagy and LC3 expression. Knockdown of LC3 decreased cell death enhanced by the combination of oxaliplatin and genipin. In summary, we showed that genipin increases the oxaliplatin-induced cell death via p53-DRAM autophagy. Based on this, we suggest that genipin is a sensitizer of oxaliplatin.
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http://dx.doi.org/10.7150/jca.34773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930423PMC
January 2020

Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer.

Cell Death Dis 2019 11 7;10(11):846. Epub 2019 Nov 7.

Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 08308, Republic of Korea.

According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.
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http://dx.doi.org/10.1038/s41419-019-2001-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838113PMC
November 2019

Using Patients' Social Network to Improve Compliance to Outpatient Screening Colonoscopy Appointments Among Blacks: A Randomized Clinical Trial.

Am J Gastroenterol 2019 10;114(10):1671-1677

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objectives: Patient navigation improves colorectal cancer screening among underserved populations, but limited resources preclude widespread adoption in minority-serving institutions. We evaluated whether a patient's self-selected social contact person can effectively facilitate outpatient screening colonoscopy.

Methods: From September 2014 to March 2017 in an urban tertiary center, 399 black participants scheduled for outpatient screening colonoscopy self-selected a social contact person to be a facilitator and provided the person's phone number. Of these, 201 participants (50.4%) were randomly assigned to the intervention arm for their social contact persons to be engaged by phone. The study was explained to the social contact person with details about colonoscopy screening and bowel preparation process. The social contacts were asked to assist the participants, provide support, and encourage compliance with the procedures. The social contact person was not contacted in the usual care arm, n = 198 (49.6%). We evaluated attendance to the scheduled outpatient colonoscopy and adequacy of bowel preparation. Analysis was performed by intention to treat.

Results: The social contact person was reached and agreed to be involved for 130 of the 201 participants (64.7%). No differences were found in the proportion of participants who underwent screening colonoscopy (77.3% vs 77.2%; relative risk = 1.01; 95% confidence interval: 0.91-1.12), but there was a modest increase in the proportion with adequate bowel preparation with social contact involvement (89.1% vs 80.9%; relative risk = 1.10; 95% confidence interval: 1.00-1.21).

Discussion: Engaging a patient's social network to serve in the role of a patient navigator did not improve compliance to outpatient screening colonoscopy but modestly improved the adequacy of bowel preparation.
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http://dx.doi.org/10.14309/ajg.0000000000000387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776677PMC
October 2019

CDX1 Expression Induced by CagA-Expressing Promotes Gastric Tumorigenesis.

Mol Cancer Res 2019 11 15;17(11):2169-2183. Epub 2019 Aug 15.

Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea.

Intestinal-type gastric cancer often results from infection through intestinal metaplasia, a transdifferentiated premalignant phenotype. Because virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with infection and function during gastric carcinogenesis in normal gastric epithelial cells and gastric cancer cell lines. Infection of HFE 145 cells with CagA increased expression of CDX1, as well as the epithelial-to-mesenchymal transition (EMT) markers Snail and Slug, increased invasion and migration, but those effects were not found in HFE 145 cells infected with CagA-deficient . CDX1 overexpression increased expression of the intestinal markers Villin, sucrose isomaltase (SI), and MUC2, induced spheroid formation, and enhanced expression of the stem cell markers CD44, SOX2, Oct4, and Nanog, while CDX1 knockdown inhibited proliferation and intestinal stemness. Treatment of CDX1-expressing cells with metformin, an antidiabetic drug known to decrease the risk of gastric cancer, decreased expression of EMT and stemness markers, and reduced spheroid formation. In a murine xenograft model, combining metformin or shCDX1 with cisplatin reduced tumor growth, increased caspase-3 cleavage, and reduced expression of CD44 and MMP-9 to a greater degree than cisplatin alone. Patients with more advanced intestinal metaplasia staging exhibited higher CDX1 expression than those with earlier intestinal metaplasia staging ( = 0.039), and those with tended to have more CDX1 expression than noninfected patients ( = 0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/SOX2 expression. Our findings indicate CagA-induced CDX1 expression may enhance gastric cancer tumorigenesis and progression, and support therapeutic targeting of CDX1 in gastric cancer. IMPLICATIONS: This study shows that CDX1 contributes to the tumorigenesis and progression of gastric cancer and suggests the potential of targeting CDX1 to treat this malignancy.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0181DOI Listing
November 2019

Genipin induces mitochondrial dysfunction and apoptosis via downregulation of Stat3/mcl-1 pathway in gastric cancer.

BMC Cancer 2019 Jul 27;19(1):739. Epub 2019 Jul 27.

Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, 148, Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea.

Background: Genipin is a compound derived from gardenia fruit extract. Although Genipin has anti-tumor effects in various cancers, its effect and mechanism in gastric cancer remain unclear. Here, we investigated the relationship between the anticancer effect of Genipin and signal transducer and activator of transcription (Stat3)/myeloid cell leukemia-1 (Mcl-1) in human gastric cancers.

Methods: MTT assays were performed to determine the cell viability of gastric cancer and gastric epithelial cell lines (AGS, MKN45, SNU638, MKN74, HFE-145). A TUNEL assay and Western blotting were carried out to investigate apoptosis. Stat3 activity was measured by proteome profiler phospho kinase array, immunofluorescence and immunoblotting. Mitochondria function was monitored with an XF24 analyzer and by flow cytometry, confocal microscopy using fluorescent probes for general mitochondrial membrane potential (MMP).

Results: Genipin induced apoptosis in gastric cancer cells, including AGS and MKN45 cells. Genipin also reduced Mcl-1 mRNA and protein levels. Furthermore, we found that phosphorylation of Stat3 is regulated by Genipin. Additionally, the protein level of phospho Janus kinase 2 (JAK2) was decreased by Genipin treatment, indicating that the Stat3/JAK2/Mcl-1 pathway is suppressed by Genipin treatment in gastric cancer cells. Mcl-1 is closely related to mitochondrial function. These findings suggest that Genipin contributes to the collapse of mitochondrial functions like MMP.

Conclusions: Genipin induced apoptosis by suppressing the Stat3/Mcl-1 pathway and led to mitochondrial dysfunction. Our results reveal a novel mechanism for the anti-cancer effect of Genipin in gastric cancer.
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http://dx.doi.org/10.1186/s12885-019-5957-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661087PMC
July 2019

pathway mapping identifies wild-type as a targetable metabolic node in gastric cancer.

Gut 2020 02 8;69(2):231-242. Epub 2019 May 8.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Objective: Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.

Design: We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of and relevance. To investigate mechanistic roles of and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.

Results: Gene expression analysis across 19 tumour types revealed to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top -regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 () emerged as a convergent direct target gene regulating GC metabolism. We show that wild-type is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.

Conclusions: Our results highlight a role for in sustaining GC oncogenic metabolism, through the regulation of . Drugs targeting wild-type may thus have clinical utility in GCs exhibiting overexpression, expanding the role of in cancer beyond mutated malignancies.
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http://dx.doi.org/10.1136/gutjnl-2018-318025DOI Listing
February 2020

NKX6.3 protects against gastric mucosal atrophy by downregulating β-amyloid production.

World J Gastroenterol 2019 Jan;25(3):330-345

Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.

Background: Atrophic gastritis is characterized by loss of appropriate glands and reduction in gastric secretory function due to chronic inflammatory processes in gastric mucosa. Moreover, atrophic gastritis is considered as a precancerous condition of gastric cancer. However, little is known about the molecular mechanism underlying gastric mucosal atrophy and its contribution to gastric carcinogenesis. Thus, we hypothesized that transcription factor NKX6.3 might be involved in maintaining gastric epithelial homeostasis by regulating amyloid β (Aβ) production.

Aim: To determine whether NKX6.3 might protect against gastric mucosal atrophy by regulating Aβ production.

Methods: We identified NKX6.3 depletion induced cell death by cell count and Western blot assay. Production and mechanism of Aβ oligomer were analyzed by enzyme-linked immunosorbent assay, Western blot, immunoprecipitation, real-time quantitative polymerase chain reaction and immunofluorescence analysis. We further validated the correlation between expression of NKX6.3, CagA, Aβ oligomer, apolipoprotein E (ApoE), and β-secretase 1 (Bace1) in 55 gastric mucosae.

Results: NKX6.3 depletion increased both adherent and floating cell populations in HFE-145 cells. Expression levels of cleaved caspase-3, -9, and poly ADP ribose polymerase were elevated in floating HFE-145 cells. NKX6.3 depletion produced Aβ peptide oligomers, and increased expression of ApoE, amyloid precursor protein, Aβ, Bace1, low-density lipoprotein receptor, nicastrin, high mobility group box1, and receptor for advanced glycosylation end product proteins. In immunoprecipitation assay, γ-secretase complex was stably formed only in HFE-145 cells. In gastric mucosae with atrophy, expression of Aβ peptide oligomer, , and was detected and inversely correlated with NKX6.3 expression. Treatment with recombinant Aβ 1-42 produced Aβ oligomeric forms and decreased cell viability in HFE-145 cells. Additionally, NKX6.3 depletion increased expression of inflammatory cytokines and cyclooxygenase-2.

Conclusion: NKX6.3 inhibits gastric mucosal atrophy by regulating Aβ accumulation and inflammatory reaction in gastric epithelial cells.
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http://dx.doi.org/10.3748/wjg.v25.i3.330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343100PMC
January 2019

Association of Health Literacy and Numeracy with Interest in Research Participation.

J Gen Intern Med 2019 04 25;34(4):544-551. Epub 2019 Jan 25.

Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA.

Background: There is much attention to recruitment of diverse populations in research, but little is known about the influence of health literacy and numeracy skills.

Objective: To determine if health literacy and numeracy affect individuals' interest to participate in research studies.

Design: Cross-sectional survey data were pooled from 3 large studies conducted in the Mid-South Clinical Data Research Network.

Participants: Adult patients enrolled in 1 of 3 Mid-South Clinical Data Research Network studies.

Main Measures: The survey domains included demographic items, the 3-item Brief Health Literacy Screen (range 3-15), and the 3-item Subjective Numeracy Scale (range 3-18). The outcome was a sum index measure of a 7-item instrument (range 7-21) assessing individuals' interest in participating in different types of research, including research that involves taking surveys, giving a blood sample, participating via phone or internet, taking an investigational medication, meeting at a local community center or school, including family, or staying overnight at a hospital.

Key Results: Respondents (N = 15,973) were predominately women (65.5%), White (81.4%), and middle aged (M = 52.8 years, SD = 16.5); 32.4% previously participated in research. Self-reported health literacy was relatively high (M = 13.5 out of 15, SD = 2.1), and subjective numeracy skills were somewhat lower (M = 14.3 out of 18, SD = 3.6). After adjustment for age, gender, race, income, education, and other characteristics, lower health literacy and numeracy skills were each independently associated with less interest in research participation (p < 0.001 for each). Prior research participation was associated with greater interest in future research participation (p < 0.001).

Conclusions: After adjustment for factors known to be predictive of interest, individuals with lower health literacy or numeracy scores were less interested in participating in research. Additional work is needed to elucidate reasons for this finding and to determine strategies to engage these populations.
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http://dx.doi.org/10.1007/s11606-018-4766-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445877PMC
April 2019

Identification of Specific Oral and Gut Pathogens in Full Thickness Colon of Colitis Patients: Implications for Colon Motility.

Front Microbiol 2018 4;9:3220. Epub 2019 Jan 4.

Department of ODS & Research, School of Dentistry, Meharry Medical College, Nashville, TN, United States.

Impaired colon motility is one of the leading problems associated with inflammatory bowel disease (IBD). An expanding body of evidence supports the role of microbiome in normal gut function and in progression of IBD. The objective of this work is to determine whether diseased full thickness colon specimens, including the neuromuscular region (critical for colon motility function), contain specific oral and gut pathogens. In addition, we compared the differences in colon microbiome between Caucasians (CA) and African Americans (AA). Thirty-nine human full thickness colon (diseased colon and adjacent healthy colon) specimens were collected from Crohn's Colitis (CC) or Ulcerative Colitis (UC) patients while they underwent elective colon surgeries. We isolated and analyzed bacterial ribosomal RNA (rRNA) from colon specimens by amplicon sequencing of the 16S rRNA gene region. The microbiome proportions were quantified into Operational Taxonomic Units (OTUs) by analysis with Quantitative Insights Into Microbial ecology (QIIME) platform. Two hundred twenty-eight different bacterial species were identified by QIIME analysis. However, we could only decipher the species name of fifty-three bacteria. Our results show that proportion of non-detrimental bacteria in CC or UC colon samples were altered compared to adjacent healthy colon specimens. We further show, for the first time in full thickness colon specimens, that microbiome of CC and UC diseased specimens is dominated by putative oral pathogens belonging to the Phyla Firmicutes (), and Fusobacteria (). In addition, we have identified patterns of differences in microbiome levels between CA and AA specimens with potential implications for health disparities research. Overall, our results suggest a significant association between oral and gut microbes in the modulation of colon motility in colitis patients.
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http://dx.doi.org/10.3389/fmicb.2018.03220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330997PMC
January 2019

Correction: Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1.

Oncotarget 2018 12 14;9(98):37268. Epub 2018 Dec 14.

Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.

[This corrects the article DOI: 10.18632/oncotarget.21946.].
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http://dx.doi.org/10.18632/oncotarget.26488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324691PMC
December 2018

Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells.

Autophagy 2019 04 6;15(4):707-725. Epub 2019 Jan 6.

c Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy , Southwest Medical University , Luzhou , China.

Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans. Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor.
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http://dx.doi.org/10.1080/15548627.2018.1557835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526874PMC
April 2019

Novel circular RNA circNF1 acts as a molecular sponge, promoting gastric cancer by absorbing miR-16.

Endocr Relat Cancer 2019 03;26(3):265-277

Division of Gastroenterology, Department of Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Circular RNAs (circRNAs) are a new class of RNA involved in multiple human malignancies. However, limited information exists regarding the involvement of circRNAs in gastric carcinoma (GC). Therefore, we sought to identify novel circRNAs, their functions and mechanisms in gastric carcinogenesis. We analyzed next-generation RNA sequencing data from GC tissues and cell lines, identifying 75,201 candidate circRNAs. Among these, we focused on one novel circRNA, circNF1 , which was upregulated in GC tissues and cell lines. Loss- and gain-of-function studies demonstrated that circNF1 significantly promotes cell proliferation. Furthermore, luciferase reporter assays showed that circNF1 binds to miR-16, thereby derepressing its downstream target mRNAs, MAP7 and AKT3. Targeted silencing or overexpression of circNF1 had no effect on levels of its linear RNA counterpart, NF1. Taken together, these results suggest that circNF1 acts as a novel oncogenic circRNA in GC by functioning as a miR-16 sponge.
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http://dx.doi.org/10.1530/ERC-18-0478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545167PMC
March 2019

Inhibition of miR‑194 suppresses the Wnt/β‑catenin signalling pathway in gastric cancer.

Oncol Rep 2018 Dec 8;40(6):3323-3334. Epub 2018 Oct 8.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, P.R. China.

A mounting body of evidence has revealed that microRNAs (miRs) serve pivotal roles in various developmental processes, and in tumourigenesis, by binding to target genes and subsequently regulating gene expression. Continued activation of the Wnt/β‑catenin signalling is positively associated with human malignancy. In addition, miR‑194 dysregulation has been implicated in gastric cancer (GC); however, the molecular mechanisms underlying the effects of miR‑194 on GC carcinogenesis remain to be elucidated. The present study demonstrated that miR‑194 was upregulated in GC tissues and SUFU negative regulator of Ηedgehog signaling (SUFU) was downregulated in GC cell lines. Subsequently, inhibition of miR‑194 attenuated nuclear accumulation of β‑catenin, which consequently blocked Wnt/β‑catenin signalling. In addition, the cytoplasmic translocation of β‑catenin induced by miR‑194 inhibition was mediated by SUFU. Furthermore, genes associated with the Wnt/β‑catenin signalling pathway were revealed to be downregulated following inhibition of the Wnt signalling pathway by miR‑194 suppression. Finally, the results indicated that cell apoptosis was markedly increased in response to miR‑194 inhibition, strongly suggesting the carcinogenic effects of miR‑194 in GC. Taken together, these findings demonstrated that miR‑194 may promote gastric carcinogenesis through activation of the Wnt/β‑catenin signalling pathway, making it a potential therapeutic target for GC.
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http://dx.doi.org/10.3892/or.2018.6773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196585PMC
December 2018

Multiple genetic mutations caused by NKX6.3 depletion contribute to gastric tumorigenesis.

Sci Rep 2018 12 4;8(1):17609. Epub 2018 Dec 4.

Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.

NKX family members are involved in a variety of developmental processes such as cell fate determination in the central nervous system, gastrointestinal tract, and pancreas. However, whether NKX6.3 contributes to gastric carcinogenesis remains unclear. The objective of this study was to examine roles of NKX6.3 depletion in mutagenesis and gastric carcinogenesis, focusing on its effects on genetic alterations and expression of genes. Our results revealed that NKX6.3 depletion induced multiple genetic mutations in coding regions, including high frequency of point mutations such as cytosine-to-thymine and guanine-to-adenine transitions caused by aberrant expression of AICDA/APOBEC family in human gastric epithelial cells. Interestingly, NKX6.3 downregulated AICDA/APOBEC family, NFκB, and CBFβ genes by acting as a transcription factor while inhibiting deaminase activity in gastric epithelial cells. Functional relevance of NKX6.3 was validated in xenograft mice injected with NKX6.3 depleting cells. NKX6.3 depletion resulted in tumor formation and mutations of tumor-associated genes, including p53 and E-cadherin. Moreover, expression levels of NKX6.3 and its target genes were analyzed in tumors derived from mice implanted with NKX6.3 depleting cells and tissue samples of gastric cancer patients. Our results indicate that NKX6.3 depletion in gastric epithelial cells activates AICDA/APOBEC family, leading to accumulation of genetic mutations and eventually driving the development of gastric cancers.
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http://dx.doi.org/10.1038/s41598-018-35733-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279800PMC
December 2018

Correction to: Histone isoform H2A1H promotes attainment of distinct physiological states by altering chromatin dynamics.

Epigenetics Chromatin 2018 11 16;11(1):67. Epub 2018 Nov 16.

Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, MH, 410210, India.

After publication of this article [1], it was noticed Duane Smoot and Hassan Ashktorab who made and provided the cell line HFE145 were not included in the author list.
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http://dx.doi.org/10.1186/s13072-018-0238-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238400PMC
November 2018

Synthetic Circular RNA Functions as a miR-21 Sponge to Suppress Gastric Carcinoma Cell Proliferation.

Mol Ther Nucleic Acids 2018 Dec 22;13:312-321. Epub 2018 Sep 22.

Division of Gastroenterology, Department of Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Division of Gastroenterology, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. Electronic address:

MicroRNA (miR) sponges containing miR binding sequences constitute a potentially powerful molecular therapeutic strategy. Recently, naturally occurring circular RNAs (circRNAs) were shown to function as efficient miR sponges in cancer cells. We hypothesized that synthetic circRNA sponges could achieve therapeutic loss-of-function targeted against specific miRs. Linear RNA molecules containing miR-21 binding sites were transcribed in vitro; after dephosphorylation and phosphorylation, circularization was achieved using 5'-3' end-ligation by T4 RNA ligase 1. circRNA stability was assessed using RNase R and fetal bovine serum. Competitive inhibition of miR-21 activity by a synthetic circRNA sponge was assessed using luciferase reporter, cell proliferation, and cell apoptosis assays in three gastric cancer cell lines. circRNA effects on downstream proteins were also delineated by Tandem Mass Tag (TMT) labeling (data available via ProteomeXchange identifier PRIDE: PXD008584), followed by western blotting. We conclude that artificial circRNA sponges resistant to nuclease digestion can be synthesized using simple enzymatic ligation steps. These sponges inhibit cancer cell proliferation and suppress the activity of miR-21 on downstream protein targets, including the cancer protein DAXX. In summary, synthetic circRNA sponges represent a simple, effective, convenient strategy for achieving targeted loss of miR function in vitro, with potential future therapeutic application in human patients.
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http://dx.doi.org/10.1016/j.omtn.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197335PMC
December 2018