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Differentially expressed genes between intestinal- and diffuse-type gastric cancers
Olga Kim,Jung Hwan Yoon,Hassan Ashktorab,Duane T. Smoot,남석우,이정용,박원상 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.3
Backgrounds: The two main types of gastric cancer, intestinal and diffuse, have different etiologies and pathogeneses, indicating different mechanisms of histogenesis and carcinogenesis that remain poorly understood. Methods: The expression and correlation patterns of 13 development-, differentiation-, proliferation-, and invasion- related genes were compared between 23 diffuseand 27 intestinal-type gastric cancers by quantitative RT-PCR. In addition, the most representative results were confirmed by western blot analysis and methylation analysis was also performed in the two gastric cancer types using methylation-specific PCR. Results: Seven genes, including SOX2, Muc5ac, CDH1, Muc4, TFF1, FGF7, and MMP10, with differential expression and correlation patterns between the two histological gastric cancer types were identified. Furthermore, Muc5ac, TFF1, MMP10, CDH1, and CDX2 expression levels were linked to DNA methylation status. Conclusion: These data provide insights into type-specific gastric carcinogenesis, suggesting new approaches for a more profound investigation of the pathologic events that drive intestinal- and diffuse-type gastric cancer.
Expression of Tight Junction Proteins According to Functional Dyspepsia Subtype and Sex
( Ju Yup Lee ),( Nayoung Kim ),( Yoon Jin Choi ),( Ji Hyun Park ),( Hassan Ashktorab ),( Duane T Smoot ),( Dong Ho Lee ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2020 Journal of Neurogastroenterology and Motility (JNM Vol.26 No.2
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. Helicobacter pylori infection status was evaluated by histology, rapid urease test, and culture. Questionnaires were analyzed. Results In all groups irrespective of H. pylori , FD group showed significantly higher CLDN2 mRNA levels than control group (P = 0.048). The level of CLDN4 mRNA expression was significantly lower in female FD group than in male FD group (P = 0.018). In H. pylori uninfected subjects, the level of CLDN1 mRNA expression in female FD group was significantly lower than that of male FD group (P = 0.014). The level of CLDN2 mRNA expression was significantly higher in the male postprandial distress syndrome (P = 0.001) and male epigastric pain syndrome (P = 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 H. pylori strain 43504. Conclusions H. pylori can affect a variety of TJPs, particularly claudin-4 and occludin. Claudin-2 is thought to be involved in FD irrespective of H. pylori status, especially in the pathophysiology of male FD. (J Neurogastroenterol Motil 2020;26:248-258)
Gastrokine 1 regulates NF‐κB signaling pathway and cytokine expression in gastric cancers
Yoon, Jung Hwan,La Cho, Mi,Choi, Yoo Jin,Back, Ji Yeon,Park, Mi Kyung,Lee, Suk Woo,Choi, Byung Joon,Ashktorab, Hassan,Smoot, Duane T.,Nam, Suk Woo,Lee, Jung Young,Park, Won Sang Wiley Subscription Services, Inc., A Wiley Company 2013 Journal of cellular biochemistry Vol.114 No.8
<P><B>Abstract</B></P><P>Gastrokine 1 (GKN1) plays an important role in the gastric mucosal defense mechanism and also acts as a functional gastric tumor suppressor. In this study, we examined the effect of GKN1 on the expression of inflammatory mediators, including NF‐κB, COX‐2, and cytokines in <I>GKN1</I>‐transfected AGS cells and sh<I>GKN1</I>‐transfected HFE‐145 cells. Lymphocyte migration and cell viability were also analyzed after treatment with GKN1 and inflammatory cytokines in AGS cells by transwell chemotaxis and an MTT assay, respectively. In <I>GKN1</I>‐transfected AGS cells, we observed inactivation and reduced expression of NF‐κB and COX‐2, whereas sh<I>GKN1</I>‐transfected HFE‐145 cells showed activation and increased expression of NF‐κB and COX‐2. GKN1 expression induced production of inflammatory cytokines including IL‐8 and ‐17A, but decreased expression of IL‐6 and ‐10. We also found IL‐17A expression in 9 (13.6%) out of 166 gastric cancer tissues and its expression was closely associated with GKN1 expression. GKN1 also acted as a chemoattractant for the migration of Jurkat T cells and peripheral B lymphocytes in the transwell assay. In addition, GKN1 significantly reduced cell viability in both AGS and HFE‐145 cells. These data suggest that the GKN1 gene may inhibit progression of gastric epithelial cells to cancer cells by regulating NF‐κB signaling pathway and cytokine expression. J. Cell. Biochem. 114: 1800–1809, 2013. © 2013 Wiley Periodicals, Inc.</P>
Cho, Soo-Jeong,Yoon, Changhwan,Lee, Jun Ho,Chang, Kevin K.,Lin, Jian-xian,Kim, Young-Ho,Kook, Myeong-Cherl,Aksoy, Bu¨lent Arman,Park, Do Joong,Ashktorab, Hassan,Smoot, Duane T.,Schultz, Nikolaus,Yoon, American Association for Cancer Research 2018 Clinical Cancer Research Vol.24 No.24
<P><B>Purpose:</B></P><P>Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C (<I>KMT2C</I>) as a frequently mutated gene and examined its role in DGA progression.</P><P><B>Experimental Design:</B></P><P>We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C (<I>KMT2C</I>) was analyzed in DGA cell lines and in patient tumors.</P><P><B>Results:</B></P><P><I>KMT2C</I> was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage (<I>P</I> = 0.023) and worse overall survival (<I>P</I> = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis.</P><P><B>Conclusions:</B></P><P><I>KMT2C</I> is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.</P>
Ramachandran, Lalitha,Manu, Kanjoormana Aryan,Shanmugam, Muthu K,Li, Feng,Siveen, Kodappully Sivaraman,Vali, Shireen,Kapoor, Shweta,Abbasi, Taher,Surana, Rohit,Smoot, Duane T,Ashktorab, Hassan,Tan, Pa American Society for Biochemistry and Molecular Bi 2012 The Journal of biological chemistry Vol.287 No.45
<P>Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor 관 (PPAR-관) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-관 inhibitor. We found that IH increased PPAR-관 activity and modulated the expression of PPAR-관 regulated genes in GC cells. Also, the increase in PPAR-관 activity was reversed in the presence of PPAR-관-specific inhibitor and a mutated PPAR-관 dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-관. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-관 that are reported to be critical for its activity and could competitively bind to PPAR-관. IH significantly increased the expression of PPAR-관 in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-관 activation pathway in GC.</P>