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Zhao Y, Liu Z, Deng K, Qu H, Zhang Q, Zhou P, Yang M, Yang X, Wang H, Li R, Xia J. Identification of TAP1 as a T-cell related therapeutic target in gastric cancer by mediating oxalipliatin-related synergistic enhancement of immunotherapy. Int Immunopharmacol 2024; 132:111998. [PMID: 38593510 DOI: 10.1016/j.intimp.2024.111998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/30/2023] [Accepted: 03/31/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Given the intricate molecular complexities and heterogeneity inherent in T-cell immunotherapy of gastric cancer (GC), elucidative T-cell-related biomarkers were imperative needed for facilitating the prediction of GC patient prognosis and identify potential synergistic therapeutic targets. METHODS We conducted COX regression analysis in TISIDB, TCGA-STAD, and GEO databases to identify 19 GC T-cell-mediated sensitivity tumor killing (TTK) genes (key GCTTKs). Based on key GCTTKs, we constructed two TTK patterns and analyzed their metabolic pathways, mutation features, clinical data distribution, immune cell infiltration, and prognosis. LASSO regression was performed to develop a T-cell-mediated GC Prognosis (TGCP) model. We validated the TGCP model in GC patients. TAP1 was further selected for investigation of its biological functions and molecular mechanisms. We assessed the potential of TAP1 as a promising therapeutic target for GC using Patient-derived organoids (PDOs)-derived xenografts (PDOXs) models of GC. RESULTS The TTK patterns display notable disparities. The TGCP model showcases its proficiency in predicting immune response efficacy, effectively distinguishes immunotherapy difference GC patients. Our findings find further confirmation in PDOX models, affirming TAP1 can enhance immunotherapy facilitated by PDL1 inhibitors. Furthermore, Oxaliplatin, by promoting TAP1 expression, augments PDL1 expression, thereby enhancing the efficacy of immunotherapy. CONCLUSIONS We constructed a TGCP model, which demonstrates satisfactory predictive accuracy. Out of 9 prognostic genes, TAP1 was validated as a synergistic target for Oxaliplatin and PDL1 inhibitors, offering a genetic-level explanation for the synergy observed in GC treatment involving Oxaliplatin in combination with PDL1 inhibitors.
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Affiliation(s)
- Yupeng Zhao
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Ziyuan Liu
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Kaiyuan Deng
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Huiheng Qu
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Qing Zhang
- Affiliated WuXi Clinical College of Nantong University, Wuxi, PR China
| | - Peng Zhou
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Mengqi Yang
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China
| | - Xiao Yang
- Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Hao Wang
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China
| | - Ranran Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Jiazeng Xia
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of General Surgery, Jiangnan University Medical Center, Wuxi, PR China; Affiliated WuXi Clinical College of Nantong University, Wuxi, PR China.
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Park SG, Ji MJ, Ham IH, Shin YH, Lee SM, Lee CH, Kim E, Hur H, Park HM, Kim JY. Secretome analysis reveals reduced expression of COL4A2 in hypoxic cancer-associated fibroblasts with a tumor-promoting function in gastric cancer. J Cancer Res Clin Oncol 2023; 149:4477-4487. [PMID: 36125535 DOI: 10.1007/s00432-022-04361-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME). Hypoxic TME is known to promote tumor progression. However, how a hypoxic condition regulates CAFs remains elusive. METHODS To investigate the underlying mechanism involved in the regulation of gastric cancer (GC) progression by hypoxic CAFs, we performed secretome profiling. Normoxic or hypoxic CAFs conditioned media (CM) were filter-concentrated and in-gel trypsin digested. Resulting peptides were analyzed with LC-MS/MS. RESULTS We observed that CM derived from hypoxic CAFs could promote migration of a panel of GC cell lines (AGS, SNU668, SNU638). Mass spectrometry analysis of hypoxic or normoxic CAFs CM identified 1595 proteins, of which 19 proteins (10 upregulated and 9 downregulated) were differentially expressed in the hypoxic secretome. We focused on COL4A2, whose expression was significantly decreased in hypoxic CAFs in HIF-1α-independent manner. Silencing of COL4A2 expression in normoxic CAFs phenocopied the effect of hypoxic CAFs in promoting GC cell migration. CONCLUSIONS The reduced expression of COL4A2 in a hypoxic environment might be associated with the tumor-promoting role of hypoxic CAFs in GC.
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Affiliation(s)
- Seo-Gyu Park
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Mi-Jung Ji
- Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul, 02456, Republic of Korea
| | - In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Suwon, 16499, Republic of Korea
- Inflammaging Translational Research Cancer, Ajou University School of Medicine, Suwon, 16499, Republic of Korea
| | - Yoon-Hee Shin
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Su-Min Lee
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Chang Hoon Lee
- Therapeutics and Biotechnology Division, Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea
- R and D center, SCBIO Co. Ltd, Daejeon, 34050, Republic of Korea
| | - Eunjung Kim
- Natural Product Informatics Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, 16499, Republic of Korea
- Inflammaging Translational Research Cancer, Ajou University School of Medicine, Suwon, 16499, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, 16499, Republic of Korea
| | - Hyun-Mee Park
- Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul, 02456, Republic of Korea
| | - Jae-Young Kim
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134, Republic of Korea.
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Sung JY, Kim JH, Kang HG, Park JW, Park SY, Park BK, Kim YN. ICSBP-induced PD-L1 enhances osteosarcoma cell growth. Front Oncol 2022; 12:918216. [PMID: 36249036 PMCID: PMC9555079 DOI: 10.3389/fonc.2022.918216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundInterferon (IFN) consensus sequence binding protein (ICSBP) is a transcription factor induced by IFN-γ. We previously reported that ICSBP expression promotes osteosarcoma progression by enhancing transforming growth factor-β signaling. In cancer cells, programmed death-ligand 1 (PD-L1) contributes to immune escape and may also be involved in tumor progression. Because IFN-γ induces the expression of both ICSBP and PD-L1, we explored the association between ICSBP and PD-L1 expression in terms of osteosarcoma progression.MethodsThree osteosarcoma cell lines (Saos2, U2OS, and 143B) were employed. Gene expression was measured by qRT-PCR, and protein levels were assessed by immunoblotting. PD-L1 expression was evaluated in cells overexpressing ICSBP and in ICSBP knockdown cells. The effects of PD-L1 expression on cell growth were examined by MTS assays, Incucyte analysis, soft agar assays, and three-dimensional (3D) culture. Cell cycle and apoptosis were evaluated by FACS analysis of cells stained with propidium iodide (PI) and annexin V/PI, respectively. The antitumor effects of PD-L1 knockdown without or with doxorubicin treatment were evaluated in vivo in nude mice bearing ICSBP-overexpressing 143B cell xenograft. The clinical relevance of PD-L1 and ICSBP expression was evaluated immunohistochemically using a human osteosarcoma microarray and through analysis of publicly available data using Gene Expression Profiling Interactive Analysis2.ResultsICSBP overexpression upregulated PD-L1 expression in all three cell lines, whereas ICSBP knockdown decreased the PD-L1 expression. PD-L1 knockdown attenuated the cell growth and reduced colony-forming capacity in both soft agar assays and 3D culture. PD-L1 knockdown increased apoptosis and induced G2/M arrest, which was associated with decreased expression of survivin, cyclin-dependent kinase 4 (CDK4), cyclin E, and cyclin D1 expression and increased the expression of p27, phosphorylated Cdc2, and phosphorylated Wee1. PD-L1 knockdown decreased the growth of tumor xenografts and increased the doxorubicin sensitivity of ICSBP-overexpressing 143B cells both in vitro and in vivo. PD-L1 was expressed in human osteosarcoma tissues, and its expression was moderately correlated with that of ICSBP in osteosarcoma patients.ConclusionICSBP regulates PD-L1 expression in osteosarcoma cells, and PD-L1 knockdown combined with doxorubicin treatment could represent a strategy for controlling osteosarcoma expressing ICSBP.
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Affiliation(s)
- Jee Young Sung
- Metastasis Branch, Division of Cancer Biology, National Cancer Center, Goyang, South Korea
| | - June Hyuk Kim
- Orthopedic Oncology Clinic, Center for Rare Cancers, National Cancer Center, Goyang, South Korea
| | - Hyun Guy Kang
- Orthopedic Oncology Clinic, Center for Rare Cancers, National Cancer Center, Goyang, South Korea
| | - Jong Woong Park
- Orthopedic Oncology Clinic, Center for Rare Cancers, National Cancer Center, Goyang, South Korea
| | - Seog-Yun Park
- Pathology Department, National Cancer Center, Goyang, South Korea
| | - Byung-Kiu Park
- Center for Pediatric Oncology, National Cancer Center, Goyang, South Korea
- *Correspondence: Yong-Nyun Kim, ; Byung-Kiu Park,
| | - Yong-Nyun Kim
- Metastasis Branch, Division of Cancer Biology, National Cancer Center, Goyang, South Korea
- *Correspondence: Yong-Nyun Kim, ; Byung-Kiu Park,
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Ucaryilmaz Metin C, Ozcan G. The HIF-1α as a Potent Inducer of the Hallmarks in Gastric Cancer. Cancers (Basel) 2022; 14:2711. [PMID: 35681691 PMCID: PMC9179860 DOI: 10.3390/cancers14112711] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/01/2023] Open
Abstract
Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxia-inducible factor-1α (HIF-1α) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1α potently induces sustained growth factor signaling, angiogenesis, epithelial-mesenchymal transition, and replicative immortality. Hypoxia leads to the selection of cancer cells that evade growth suppressors or apoptotic triggers and deregulates cellular energetics. HIF-1α is also associated with genetic instability, tumor-promoting inflammation, and escape from immunity. Therefore, HIF-1α may be an important therapeutic target in cancer. Despite that, the drug market lacks safe and efficacious anti-HIF-1α molecules, raising the quest for fully unveiling the complex interactome of HIF-1α in cancer to discover more effective strategies. The knowledge gap is even wider in gastric cancer, where the number of studies on hypoxia is relatively low compared to other well-dissected cancers. A comprehensive review of the molecular mechanisms by which HIF-1α induces gastric cancer hallmarks could provide a broad perspective to the investigators and reveal missing links to explore in future studies. Thus, here we review the impact of HIF-1α on the cancer hallmarks with a specific focus on gastric cancer.
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Affiliation(s)
| | - Gulnihal Ozcan
- Department of Medical Pharmacology, School of Medicine, Koç University, 34450 Istanbul, Turkey
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Na HY, Park Y, Nam SK, Koh J, Kwak Y, Ahn SH, Park DJ, Kim HH, Lee KS, Lee HS. Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry. J Transl Med 2021; 19:529. [PMID: 34952595 PMCID: PMC8710020 DOI: 10.1186/s12967-021-03203-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). METHODS We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. RESULTS Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. CONCLUSIONS Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.
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Affiliation(s)
- Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yujun Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Qian X, Zhang W, Yang H, Zhang L, Kang N, Lai J. Role of Yes-associated Protein-1 in Gastrointestinal Cancers and Hepatocellular Carcinoma. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021; 6:110-117. [PMID: 34589656 PMCID: PMC8478289 DOI: 10.14218/erhm.2021.00017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Yes-associated protein-1 (YAP1) is a potent transcriptional co-activator and functions as an important downstream effector of the Hippo signaling pathway, which is key to regulating cell proliferation, apoptosis, and organ growth. YAP1 has been implicated as an oncogene for various human cancers including gastrointestinal cancers and hepatocellular carcinoma (HCC). YAP1 promotes tumorigenesis and cancer progression by multiple mechanisms, such as by promoting malignant phenotypes, expanding cancer stem cells, and inducing epithelial-mesenchymal transition. YAP1 overexpression or its activated forms are associated with advanced pathological grades and poor prognosis of cancer, and therefore targeting YAP1 may open a fertile avenue for cancer therapy. In this review, we summarize the recent evidence regarding the role of YAP1 in the carcinogenesis of gastrointestinal cancers and HCC.
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Affiliation(s)
- Xia Qian
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Wei Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Hua Yang
- Department of Ophthalmology, Emory Eye Center, Emory University, Atlanta, GA, USA
| | - Lanjing Zhang
- Department of Pathology, Princeton Medical center, Rutgers University, Plainsboro, NJ, USA
| | - Ningling Kang
- Tumor Microenvironment and Metastasis, Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA, USA
- Correspondence to: Jinping Lai, Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA. Tel:+1 916-973-7260, Fax:+1 916-973-7283,
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Deng Y, Cai S, Shen J, Peng H. Tetraspanins: Novel Molecular Regulators of Gastric Cancer. Front Oncol 2021; 11:702510. [PMID: 34222025 PMCID: PMC8250138 DOI: 10.3389/fonc.2021.702510] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is the fourth and fifth most common cancer worldwide in men and women, respectively. However, patients with an advanced stage of gastric cancer still have a poor prognosis and low overall survival rate. The tetraspanins belong to a protein superfamily with four hydrophobic transmembrane domains and 33 mammalian tetraspanins are ubiquitously distributed in various cells and tissues. They interact with other membrane proteins to form tetraspanin-enriched microdomains and serve a variety of functions including cell adhesion, invasion, motility, cell fusion, virus infection, and signal transduction. In this review, we summarize multiple utilities of tetraspanins in the progression of gastric cancer and the underlying molecular mechanisms. In general, the expression of TSPAN8, CD151, TSPAN1, and TSPAN4 is increased in gastric cancer tissues and enhance the proliferation and invasion of gastric cancer cells, while CD81, CD82, TSPAN5, TSPAN9, and TSPAN21 are downregulated and suppress gastric cancer cell growth. In terms of cell motility regulation, CD9, CD63 and CD82 are metastasis suppressors and the expression level is inversely associated with lymph node metastasis. We also review the clinicopathological significance of tetraspanins in gastric cancer including therapeutic targets, the development of drug resistance and prognosis prediction. Finally, we discuss the potential clinical value and current limitations of tetraspanins in gastric cancer treatments, and provide some guidance for future research.
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Affiliation(s)
- Yue Deng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sicheng Cai
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Shen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiming Peng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Li HS, Liu X, Zhang MY, Cheng K, Chen Y, Zhou YW, Liu JY. Clinicopathologic characteristics, survival, and treatments for gastric adenosquamous carcinoma: a population-based study. Curr Oncol 2020; 27:e527-e536. [PMID: 33380867 PMCID: PMC7755430 DOI: 10.3747/co.27.6337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric adenosquamous carcinoma (gasc) is a rare entity with distinctive characteristics that are not fully understood. In the present study, we evaluated the characteristics of this rare disease. METHODS The U.S. Surveillance, Epidemiology, and End Results program database was searched to determine the clinicopathologic features, prognostic factors, and treatments for 246 patients with gasc and 42,735 patients with gastric adenocarcinoma (gac). RESULTS Relative to gac, gasc is associated with higher proportions of cardia involvement, high-grade tumours, deep tumour invasion, metastatic lymph nodes, and chemotherapy treatment. In patients who underwent potentially curative surgery (pcs), gasc was associated with a higher proportion of radiotherapy use and poorer overall survival (p < 0.001), although no significant difference (p = 0.802) was observed after propensity score matching (psm). Multivariate analysis after psm revealed that the independent prognostic factors for gasc were TNM stage [hazard ratio (hr): 1.512; p = 0.021] and regional nodes examined (hr: 0.588; p = 0.02). In patients with advanced disease, no significant difference in survival between gasc and gac was observed (p = 0.212), although survival was significantly poorer for gasc after psm (p = 0.019). Multivariate analysis after psm revealed that the independent prognostic factors for gasc were invasion depth (hr: 1.303; p = 0.036) and chemotherapy (hr: 0.444; p < 0.001). CONCLUSIONS Relative to gac, gasc was associated with more aggressive features, although survival outcomes were similar after pcs. Chemotherapy remains a mainstay of treatment for patients with advanced gasc, but its role remains unclear for patients who are undergoing pcs.
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Affiliation(s)
- H S Li
- Department of Biotherapy, Cancer Centre, and National Clinical Research Centre for Geriatrics, West China Hospital of Sichuan University, Chengdu, and Sichuan Clinical Research Centre of Biotherapy, Sichuan Province, P.R.C
- Department of Biotherapy, Cancer Centre, and National Clinical Research Centre for Geriatrics, West China Hospital of Sichuan University, Chengdu, and Sichuan Clinical Research Centre of Biotherapy, Sichuan Province, P.R.C
| | - X Liu
- Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu, P.R.C
| | - M Y Zhang
- Department of Biotherapy, Cancer Centre, and National Clinical Research Centre for Geriatrics, West China Hospital of Sichuan University, Chengdu, and Sichuan Clinical Research Centre of Biotherapy, Sichuan Province, P.R.C
| | - K Cheng
- Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu, P.R.C
| | - Y Chen
- Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu, P.R.C
| | - Y W Zhou
- Department of Biotherapy, Cancer Centre, and National Clinical Research Centre for Geriatrics, West China Hospital of Sichuan University, Chengdu, and Sichuan Clinical Research Centre of Biotherapy, Sichuan Province, P.R.C
| | - J Y Liu
- Department of Biotherapy, Cancer Centre, and National Clinical Research Centre for Geriatrics, West China Hospital of Sichuan University, Chengdu, and Sichuan Clinical Research Centre of Biotherapy, Sichuan Province, P.R.C
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Liu X, Gao L, Ni D, Ma C, Lu Y, Huang X. Candidate genes for predicting the survival of patients with gastric cancer: a study based on The Cancer Genome Atlas (TCGA) database. Transl Cancer Res 2020; 9:2599-2608. [PMID: 35117619 PMCID: PMC8798540 DOI: 10.21037/tcr.2020.02.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 02/08/2020] [Indexed: 01/17/2023]
Abstract
Background Gastric cancer (GC) is the second most frequent cause of cancer-related mortality in the world, and the five-year survival rate for GC remains very low universally. In recent years, it has become a consensus that genetic changes are associated with carcinogenesis of GC, and precision medicine based on genetic changes is one of the most popular treatments for GC patients. However, the association between some genes and GC-related protein signaling pathways is still not well understood. This study revealed that seven genes were closely related to the survival probability in GC patients. Methods We downloaded the gene expression data of GC patients from The Cancer Genome Atlas (TCGA) databases, and integrated bioinformatic analysis was performed, such as differential gene expression analysis, including Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathways analyses, as well as survival analysis. The r package “survival” was used to analyze the Kaplan-Meier survival analysis, which showed the associations between specific gene expressions and the outcomes of patients with GC to identify which genes could be potential prognostic biomarkers. Results This study revealed that seven genes: alcohol dehydrogenase 4 (ADH4), histamine receptor H3 (HRH3), neuropeptide Y2 receptor (NPY2R), apolipoprotein AI (APOA1), N-acetylgalactosaminyltransferase 14 (GALNT14), leucine-rich repeats and IQ motif containing 1 (LRRIQ1), and coiled-coil-domain-containing 57 (CCDC57). These seven genes were closely related to the survival probability of GC patients (P<0.05). Conclusions Our study found seven genes which could be considered as candidate prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Xiqiao Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Liying Gao
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Dongqiong Ni
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Chengao Ma
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Yuping Lu
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Xuan Huang
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
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Li W, Chen Y, Sun X, Yang J, Zhang DY, Wang D, Suo J. Protein expression profiles and clinicopathologic characteristics associate with gastric cancer survival. Biol Res 2019; 52:42. [PMID: 31399040 PMCID: PMC6689162 DOI: 10.1186/s40659-019-0249-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 08/01/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Prognosis remains one of most crucial determinants of gastric cancer (GC) treatment, but current methods do not predict prognosis accurately. Identification of additional biomarkers is urgently required to identify patients at risk of poor prognoses. METHODS Tissue microarrays were used to measure expression of nine GC-associated proteins in GC tissue and normal gastric tissue samples. Hierarchical cluster analysis of microarray data and feature selection for factors associated with survival were performed. Based on these data, prognostic scoring models were established to predict clinical outcomes. Finally, ingenuity pathway analysis (IPA) was used to identify a biological GC network. RESULTS Eight proteins were upregulated in GC tissues versus normal gastric tissues. Hierarchical cluster analysis and feature selection showed that overall survival was worse in cyclin dependent kinase (CDK)2, Akt1, X-linked inhibitor of apoptosis protein (XIAP), Notch4, and phosphorylated (p)-protein kinase C (PKC) α/β2 immunopositive patients than in patients that were immunonegative for these proteins. Risk score models based on these five proteins and clinicopathological characteristics were established to determine prognoses of GC patients. These proteins were found to be involved in cancer related-signaling pathways and upstream regulators were identified. CONCLUSION This study identified proteins that can be used as clinical biomarkers and established a risk score model based on these proteins and clinicopathological characteristics to assess GC prognosis.
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Affiliation(s)
- Wei Li
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.,Jilin Province Key Laboratory of Bioinformatics for Gastrointestinal Tumor, Changchun, Jilin, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Xuan Sun
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jupeng Yang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - David Y Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
| | - Daguang Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China. .,Jilin Province Key Laboratory of Bioinformatics for Gastrointestinal Tumor, Changchun, Jilin, China.
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11
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Koh J, Lee KW, Nam SK, Seo AN, Kim JW, Kim JW, Park DJ, Kim HH, Kim WH, Lee HS. Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications. Oncologist 2019; 24:e1321-e1330. [PMID: 31371521 DOI: 10.1634/theoncologist.2019-0058] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 06/10/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)- and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. MATERIALS AND METHODS A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. RESULTS We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV-, MSI-, non-epithelial-mesenchymal transition [non-EMT]-like, p53-), group 3 (EBV+), group 4 (EBV-, MSI-, non-EMT-like, p53+), and group 5 (EBV-, MSI-, EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. CONCLUSION We developed and validated a modified IHC- and PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. IMPLICATIONS FOR PRACTICE Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry- and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.
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Affiliation(s)
- Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
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12
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Qin J, Wang S, Shi J, Ma Y, Wang K, Ye H, Zhang X, Wang P, Wang X, Song C, Dai L, Wang K, Jiang B, Zhang J. Using recursive partitioning approach to select tumor-associated antigens in immunodiagnosis of gastric adenocarcinoma. Cancer Sci 2019; 110:1829-1841. [PMID: 30950146 PMCID: PMC6550128 DOI: 10.1111/cas.14013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/01/2019] [Accepted: 04/02/2019] [Indexed: 12/14/2022] Open
Abstract
The present study aimed to select anti-tumor-associated antigen (TAA) autoantibodies as biomarkers in the immunodiagnosis of gastric adenocarcinoma (GAC) by the recursive partitioning approach (RPA) and further construct and evaluate a predictive model. A case-control study was designed including 407 GAC patients as the case group and 407 normal controls. In addition, 67 serial serum samples from 25 GAC patients were collected at different time points before and after gastrectomy treatment. Autoantibodies against 14 TAA were measured in sera from all subjects by enzyme immunoassay. Finally, RPA resulted in the selection of nine-panel TAA (c-Myc, p16, HSPD1, PTEN, p53, NPM1, ENO1, p62, HCC1.4) from all detected TAA in the case-control study; the classification tree based on this nine-TAA panel had area under curve (AUC) of 0.857, sensitivity of 71.5% and specificity of 71.3%; The optimal panel also can identify GAC patients at an early stage from normal individuals, with AUC of 0.737, sensitivity of 64.9% and specificity of 70.5%. However, frequencies of the nine autoantibodies showed no correlation with GAC stage, tumor size, lymphatic metastasis or differentiation. GAC patients positive for more than two autoantibodies in the nine-TAA panel had a worse prognosis than that of the GAC patients positive for no or one antibody. Titers of 10 autoantibodies in serial serum samples were significantly higher in GAC patients after surgical resection than before. In conclusion, this study showed that the panel of nine multiple TAAs could enhance the detection of anti-TAA antibodies in GAC, and may be potential prognostic biomarkers in GAC.
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Affiliation(s)
- Jiejie Qin
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Shuaibing Wang
- Third Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jianxiang Shi
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Yan Ma
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Keyan Wang
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Hua Ye
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Xiaojun Zhang
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Peng Wang
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Xiao Wang
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Chunhua Song
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Liping Dai
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Kaijuan Wang
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Binghua Jiang
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Jianying Zhang
- Department of Epidemiology and Health Statistics & Henan Key Laboratory for Tumor EpidemiologyCollege of Public HealthZhengzhou UniversityZhengzhouChina
- Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
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13
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Ghasabi M, Majidi J, Mansoori B, Mohammadi A, Shomali N, Shirafkan N, Baghbani E, Kazemi T, Baradaran B. The effect of combined miR‐200c replacement and cisplatin on apoptosis induction and inhibition of gastric cancer cell line migration. J Cell Physiol 2019; 234:22581-22592. [DOI: 10.1002/jcp.28823] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/06/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Mehri Ghasabi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Jafar Majidi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine University of Southern Denmark Odense Denmark
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Mohammadi
- Aging Research Institute, Physical Medicine and Rehabilitation Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Navid Shomali
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Naghmeh Shirafkan
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Elham Baghbani
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Baradaran
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
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14
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Mechanotransduction and Cytoskeleton Remodeling Shaping YAP1 in Gastric Tumorigenesis. Int J Mol Sci 2019; 20:ijms20071576. [PMID: 30934860 PMCID: PMC6480114 DOI: 10.3390/ijms20071576] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/14/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023] Open
Abstract
The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 (YAP1) and WW domain that contain transcription regulator 1 (TAZ), two transcriptional co-activators with a PDZ-binding motif, function as critical effectors negatively regulated by the Hippo pathway. Previous studies indicate the involvement of YAP1/TAZ in mechanotransduction by crosstalking with the extracellular matrix (ECM) and the F-actin cytoskeleton associated signaling network. In gastric cancer (GC), YAP1/TAZ functions as an oncogene and transcriptionally promotes tumor formation by cooperating with TEAD transcription factors. Apart from the classic role of Hippo-YAP1 cascade, in this review, we summarize the current investigations to highlight the prominent role of YAP1/TAZ as a mechanical sensor and responder under mechanical stress and address its potential prognostic and therapeutic value in GC.
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15
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Gastric Carcinomas With Lymphoid Stroma: An Evaluation of the Histopathologic and Molecular Features. Am J Surg Pathol 2019; 42:453-462. [PMID: 29438172 DOI: 10.1097/pas.0000000000001018] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus (EBV) positivity and mismatch repair (MMR) deficiency. We performed this study to evaluate molecular alterations in this morphologically homogeneous subtype and compare them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. We identified 31 study cases and subjected them to in situ hybridization for EBV-encoded RNAs and assessment for MMR status. Immunostains for PD-L1, β-catenin, and HER2 were performed; extracted DNA was sequenced with a Comprehensive Cancer Panel. Most study patients were older adult men with stage I or II disease (76%). Tumors were classified as EBV/MMR-proficient (MMR-P) (n=7), EBV/MMR deficient (n=12), and EBV/MMR-P (n=12). EBV/MMR-P tumors were usually located in the proximal stomach (83%) and showed heterogenous growth patterns with glandular differentiation (83%). Tumors in all groups showed numerous tumor infiltrating lymphocytes and PD-L1 expression, infrequent nuclear β-catenin accumulation (10%), and lacked both membranous HER2 staining and HER2 amplification. EBV/MMR-deficient tumors showed significantly higher tumor mutation burden (P=0.001) and KRAS alterations (56%) compared with EBV/MMR-P tumors (9%, P=0.05). TP53 variants were more common among EBV/MMR-P tumors (82%) compared with EBV/MMR proficient (0%, P=0.01) and EBV/MMR-deficient (11%, P<0.01) tumors. Alterations in KRAS, ARID1A, PIK3CA, and TP53 followed similar patterns of distribution compared with The Cancer Genome Atlas dataset. We conclude that gastric carcinomas with lymphoid stroma show a spectrum of molecular changes and frequent PD-L1 expression, raising the possibility that this subgroup of tumors may be susceptible to checkpoint inhibitors and/or agents that target receptor tyrosine kinase-mediated signaling.
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16
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C/EBPβ Is a Transcriptional Regulator of Wee1 at the G₂/M Phase of the Cell Cycle. Cells 2019; 8:cells8020145. [PMID: 30754676 PMCID: PMC6407104 DOI: 10.3390/cells8020145] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/06/2019] [Accepted: 02/09/2019] [Indexed: 12/25/2022] Open
Abstract
The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G2/M transition in the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with simultaneously increased Wee1 and decreased Cdc25B expression. Chromatin immunoprecipitation (ChIP) analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through its interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G2/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G2/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.
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17
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Kosari‐Monfared M, Nikbakhsh N, Fattahi S, Ghadami E, Ranaei M, Taheri H, Amjadi‐Moheb F, Godazandeh GA, Shafaei S, Pilehchian‐Langroudi M, Samadani AA, Akhavan‐Niaki H. CTNNBIP1
downregulation is associated with tumor grade and viral infections in gastric adenocarcinoma. J Cell Physiol 2018; 234:2895-2904. [DOI: 10.1002/jcp.27106] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/29/2018] [Indexed: 01/06/2023]
Affiliation(s)
- Mohadeseh Kosari‐Monfared
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Department of GeneticsFaculty of Medicine, Babol University of Medical SciencesBabol Iran
| | - Novin Nikbakhsh
- Cancer Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
| | - Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Molecular Biology Laboratory, North Research Center of Pasteur InstituteAmol Iran
| | - Elham Ghadami
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Department of GeneticsFaculty of Medicine, Babol University of Medical SciencesBabol Iran
| | - Mohammad Ranaei
- Department of PathologyRouhani Hospital, Babol University of Medical SciencesBabol Iran
| | - Hassan Taheri
- Department of Internal MedicineRouhani Hospital, Babol University of Medical SciencesBabol Iran
| | - Fatemeh Amjadi‐Moheb
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Department of GeneticsFaculty of Medicine, Babol University of Medical SciencesBabol Iran
| | - Gholam A. Godazandeh
- Department of SurgeryImam Hospital, Mazandaran University of Medical SciencesSari Iran
| | - Shahryar Shafaei
- Department of PathologyRouhani Hospital, Babol University of Medical SciencesBabol Iran
| | - Maryam Pilehchian‐Langroudi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Department of GeneticsFaculty of Medicine, Babol University of Medical SciencesBabol Iran
| | - Ali Akbar Samadani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Gastrointestinal and Liver Diseases Research Center (GLDRC)Guilan University of Medical SciencesRasht Iran
| | - Haleh Akhavan‐Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
- Department of GeneticsFaculty of Medicine, Babol University of Medical SciencesBabol Iran
- Cancer Research Center, Health Research Institute, Babol University of Medical SciencesBabol Iran
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18
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Histologic and immunohistochemical differences between hereditary and sporadic diffuse gastric carcinoma. Hum Pathol 2018; 74:64-72. [PMID: 29307626 DOI: 10.1016/j.humpath.2017.12.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/15/2017] [Accepted: 12/20/2017] [Indexed: 01/13/2023]
Abstract
We aimed to identify histopathologic features unique in hereditary diffuse gastric cancer (HDGC) by comparing with its sporadic counterpart (SDGC). 11 patients with confirmed CDH1 mutation who were found to have HDGC in a prophylactic total gastrectomy were collected. Median age of HDGC patients was 39 years (range 24-57). All HDGC cases had intramucosal signet ring cell carcinoma. Twenty-three invasive tumor foci from 7 patients with HDGC were available for ancillary studies, and we evaluated each focus separately. Almost all foci (20/23) showed two distinct tumor cell populations, namely, large signet ring cells and small signet ring cells. The large cells were located just beneath the surface epithelium and were positive for mucicarmine and pCEA, while the small cells were found in the deeper lamina propria and were mostly negative for mucicarmine and pCEA. A subset of small cells (6 foci from two resected stomachs) showed poorly differentiated morphology with p16 positivity. All other tumor cells with well-differentiated signet ring cell morphology were negative for p16. In contrast, 18 of 20 SDGCs were positive for p16. In addition, all HDGCs were negative for CDX2, while 19 of 20 SDGCs were positive. We propose that there are three distinct tumor cell populations in HDGC: well-differentiated large cells, well-differentiated small cells, and poorly differentiated small cells, and that the latter group with aberrant p16 expression may represents a more aggressive phenotype. The absence of CDX2 in HDGC suggests that it may develop along a carcinogenetic pathway different from that of SDGC.
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19
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Zheng HC, Liu LL. FHIT down-regulation was inversely linked to aggressive behaviors and adverse prognosis of gastric cancer: a meta- and bioinformatics analysis. Oncotarget 2017; 8:108261-108273. [PMID: 29296239 PMCID: PMC5746141 DOI: 10.18632/oncotarget.22369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/03/2017] [Indexed: 11/25/2022] Open
Abstract
FHIT (fragile histine triad) acts as diadenosine P1, P3-bis (5'-adenosyl)-triphosphate adenylohydrolase involved in purine metabolism, and induces apoptosis as a tumor suppressor. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. The down-regulated FHIT expression was found in gastric cancer, compared with normal mucosa and dysplasia (p < 0.05). FHIT expression was negatively with depth of invasion, lymph node metastasis, distant metastasis, TNM staging and dedifferentiation of gastric cancer (p < 0.05). A positive association between FHIT expression and favorable overall survival was found in patients with gastric cancer (p < 0.05). According to Kaplan-Meier plotter, we found that a higher FHIT expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters (p < 0.05). These findings indicated that FHIT expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Li-Li Liu
- Department of Pathology, Harbin Medical University-Daqing, Daqing 163319, China
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20
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Chung Y, Wi YC, Kim Y, Bang SS, Yang JH, Jang K, Min KW, Paik SS. The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma. J Pathol Transl Med 2017; 52:37-44. [PMID: 29056035 PMCID: PMC5784229 DOI: 10.4132/jptm.2017.10.20] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/19/2017] [Accepted: 10/16/2017] [Indexed: 02/07/2023] Open
Abstract
Background Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. Methods Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. Results Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05). Conclusions Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.
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Affiliation(s)
- Yumin Chung
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Young Chan Wi
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Yeseul Kim
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seong Sik Bang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Jung-Ho Yang
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Kyueng-Whan Min
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Sam Paik
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
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21
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Ghatak S, Chakraborty P, Sarkar SR, Chowdhury B, Bhaumik A, Kumar NS. Novel APC gene mutations associated with protein alteration in diffuse type gastric cancer. BMC MEDICAL GENETICS 2017; 18:61. [PMID: 28576136 PMCID: PMC5457612 DOI: 10.1186/s12881-017-0427-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 05/24/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND The role of adenomatous polyposis coli (APC) gene in mitosis might be critical for regulation of genomic stability and chromosome segregation. APC gene mutations have been associated to have a role in colon cancer and since gastric and colon tumors share some common genetic lesions, it is relevant to investigate the role of APC tumor suppressor gene in gastric cancer. METHODS We investigated for somatic mutations in the Exons 14 and 15 of APC gene from 40 diffuse type gastric cancersamples. Rabbit polyclonal anti-APC antibody was used, which detects the wild-type APC protein and was recommended for detection of the respective protein in human tissues. Cell cycle analysis was done from tumor and adjacent normal tissue. RESULTS APC immunoreactivity showed positive expression of the protein in stages I, II, III and negative expression in Stages III and IV. Two novel deleterious variations (g.127576C > A, g.127583C > T) in exon 14 sequence were found to generate stop codon (Y622* and Q625*)in the tumor samples. Due to the generation of stop codon, the APC protein might be truncated and all the regulatory features could be lost which has led to the down-regulation of protein expression. Our results indicate that aneuploidy might occurdue to the codon 622 and 625 APC-driven gastric tumorigenesis, in agreement with our cell cycle analysis. The APC gene function in mitosis and chromosomal stability might be lost and G1 might be arrested with high quantity of DNA in the S phase. Six missense somatic mutations in tumor samples were detected in exon 15 A-B, twoof which showed pathological and disease causing effects based on SIFT, Polyphen2 and SNPs & GO score and were not previously reported in the literature or the public mutation databases. CONCLUSION The two novel pathological somatic mutations (g.127576C > A, g.127583C > T) in exon 14 might be altering the protein expression leading to development of gastric cancer in the study population. Our study showed that mutations in the APC gene alter the protein expression and cell cycle regulation in diffuse type gastric adenocarcinoma.
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Affiliation(s)
- Souvik Ghatak
- Department of Biotechnology, Mizoram University, Aizawl, 796004 Mizoram India
| | - Payel Chakraborty
- Department of Biotechnology, Mizoram University, Aizawl, 796004 Mizoram India
| | - Sandeep Roy Sarkar
- Department of Pathology, Agartala Government Medical College, Tripura, India
| | - Biswajit Chowdhury
- Department of Pathology, Agartala Government Medical College, Tripura, India
| | - Arup Bhaumik
- Department of Pathology, Agartala Government Medical College, Tripura, India
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22
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Petrelli F, Berenato R, Turati L, Mennitto A, Steccanella F, Caporale M, Dallera P, de Braud F, Pezzica E, Di Bartolomeo M, Sgroi G, Mazzaferro V, Pietrantonio F, Barni S. Prognostic value of diffuse versus intestinal histotype in patients with gastric cancer: a systematic review and meta-analysis. J Gastrointest Oncol 2017; 8:148-163. [PMID: 28280619 DOI: 10.21037/jgo.2017.01.10] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There are two distinct types of gastric carcinoma (GC), intestinal, more frequently sporadic and linked to environmental factors, and diffuse (undifferentiated) that is highly metastatic and characterized by rapid disease progression and a poor prognosis. However, there are many conflicting data in the literature concerning the association between histology and prognosis in GC. This meta-analysis was performed to provide demonstration if histology according to Lauren classification is associated with different prognosis in patients with GC. METHODS We searched PubMed, the Cochrane Library, SCOPUS, Web of Science, CINAHL, and EMBASE for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival (OS) were evaluated. RESULTS A total of 73 published studies including 61,468 patients with GC were included in this meta-analysis. Our analysis indicates that GC patients with diffuse-type histology have a worst prognosis than those with intestinal subgroup in all studies (HR 1.23; 95% CI, 1.17-1.29; P<0.0001), in both loco-regional confined (HR 1.21; 95% CI, 1.12-1.30; P<0.0001) and advanced disease (HR 1.25; 95% CI, 1.046-1.50; P=0.014), in Asiatic (HR 1.2; 95% CI, 1.14-1.27; P<0.0001) and Western patients (HR 1.3; 95% CI, 1.19-1.41; P<0.0001), and in those not exposed (HR 1.15; 95% CI, 1.07-1.24; P<0.0001) or exposed (HR 1.27; 95% CI, 1.17-1.37; P<0.0001) to (neo)adjuvant therapy. CONCLUSIONS Our results indicated that histology might be a useful prognostic marker for both early and advanced GC patients, with intestinal-type associated with a better outcome. This information could be used for stratification purpose in future clinical trials.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Turati
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Alessia Mennitto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Steccanella
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Pierpaolo Dallera
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ezio Pezzica
- Pathology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Sgroi
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Vincenzo Mazzaferro
- Hepatobiliopancreatic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sandro Barni
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
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23
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Huang Y, Chen Y, Lin X, Lin Q, Han M, Guo G. Clinical significance of SLP-2 in hepatocellular carcinoma tissues and its regulation in cancer cell proliferation, migration, and EMT. Onco Targets Ther 2017; 10:4665-4673. [PMID: 29033585 PMCID: PMC5614784 DOI: 10.2147/ott.s144638] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Stomatin-like protein 2 (SLP-2) gene was significantly upregulated in a variety of tumor tissues and found to be involved in proliferation and metastasis. However, its functional role in hepatocellular carcinoma (HCC) remains unknown. Our study was to investigate the function of SLP-2 in cell proliferation, migration, invasion, cell apoptosis, and the process of epithelial-mesenchymal transition (EMT) in HCC. SLP-2 mRNA and protein expression in HCC were assessed by qRT-PCR and immunohistochemical staining. In vitro, we determined cell proliferation, migration, invasion, and cell apoptosis by CCK-8, transwell, and flow cytometry assays, respectively. SLP-2 was found to be upregulated at both mRNA and protein levels in HCC tissues, and its aberrant overexpression was linked with poor prognosis in patients with HCC. SLP-2 downregulation by siRNAs significantly suppressed cell proliferation, migration, invasion, anti-apoptosis abilities, and inhibited EMT process in vitro. In conclusion, the present study demonstrated the overexpression of SLP-2 in HCC tissues for the first time. As an effective regulator involved in cell proliferation, migration, invasion, cell apoptosis, and EMT, SLP-2 could be a novel therapeutic target for patients with HCC who express high levels of SLP-2.
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Affiliation(s)
- Yijie Huang
- Department of General Surgery, Guangdong General Hospital, Guangzhou
| | - Yexi Chen
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China
| | - Xiaoqi Lin
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China
| | - Qingjun Lin
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China
| | - Ming Han
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China
- Correspondence: Guohu Guo; Ming Han, Department of General Surgery, The Second Affiliated Hospital of Shantou University, 69 Dongxia North Road, Shantou 515100, People’s Republic of China, Tel +86 135 0299 3993, Fax +86 754 8314 1101, Email ;
| | - Guohu Guo
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China
- Correspondence: Guohu Guo; Ming Han, Department of General Surgery, The Second Affiliated Hospital of Shantou University, 69 Dongxia North Road, Shantou 515100, People’s Republic of China, Tel +86 135 0299 3993, Fax +86 754 8314 1101, Email ;
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Choi Y, Ko YS, Park J, Choi Y, Kim Y, Pyo JS, Jang BG, Hwang DH, Kim WH, Lee BL. HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer. World J Gastroenterol 2016; 22:9141-9153. [PMID: 27895401 PMCID: PMC5107595 DOI: 10.3748/wjg.v22.i41.9141] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/12/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells.
METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments.
RESULTS In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.
CONCLUSION HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.
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25
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Lu W, Cao Y, Zhang Y, Li S, Gao J, Wang XA, Mu J, Hu YP, Jiang L, Dong P, Gong W, Liu Y. Up-regulation of PKM2 promote malignancy and related to adverse prognostic risk factor in human gallbladder cancer. Sci Rep 2016; 6:26351. [PMID: 27283076 PMCID: PMC4901292 DOI: 10.1038/srep26351] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 04/15/2016] [Indexed: 02/08/2023] Open
Abstract
Recently, pyruvate kinase M2 (PKM2) has been implicated in the progression of certain cancers and might play pivotal roles in the formation of malignancy. However, the role of PKM2 in gallbladder cancer had not been well investigated. This study analyzed associations between PKM2 expression status with various clinical and pathologic parameters in a large cohort of gallbladder cancer (GBC) patients from a long term follow up results. The expression level of pyruvate kinase isotypes in GBC tissues and their adjacent normal gallbladder tissues were estimated by qRT-PCR and Western blot. PKM2 mRNA level were significantly high in gallbladder cancer tissues than in adjacent noncancerous tissues (P < 0.001). High expression of the PKM2 was detected in 55.71% paraffin-embedded GBC tissue. The high PKM2 expression was independently associated with poorer overall survival in patients with GBC (median survival 11.9 vs 30.1 months; hazard ratio 2.79; 95% CI = 1.18 to 6.55; P = 0.02). These findings indicated elevated expression of PKM2 is a prognostic factor for poor GBC clinical outcomes, implied involving of PKM2 in GBC progression.
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Affiliation(s)
- Wei Lu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Social Cognitive and Behavioral Sciences, Shanghai JiaoTong University, No. 800 Dongchuan Road, Shanghai 200240, China
| | - Yang Cao
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yijian Zhang
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Sheng Li
- Department of Biochemistry, Dalian medical University, No. 9 Lvshun South Road, Dalian, Liaoning, 116044, China
| | - Jian Gao
- Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, No. 138 Yixueyuan Road, Shanghai 200032, China
| | - Xu-An Wang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Jiasheng Mu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yun-Ping Hu
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Lin Jiang
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Ping Dong
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai JiaoTong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Diseases Research, Shanghai JiaoTong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
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26
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Choi Y, Park J, Choi Y, Ko YS, Yu DA, Kim Y, Pyo JS, Jang BG, Kim MA, Kim WH, Lee BL. c-Jun N-terminal kinase activation has a prognostic implication and is negatively associated with FOXO1 activation in gastric cancer. BMC Gastroenterol 2016; 16:59. [PMID: 27268017 PMCID: PMC4895928 DOI: 10.1186/s12876-016-0473-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 05/27/2016] [Indexed: 12/27/2022] Open
Abstract
Background Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we investigated the clinical significance of JNK activation and its association with FOXO1 activation. Methods Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and the results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for pJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic staining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis. Results Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages of pTNM (P < 0.001). pJNK staining negatively correlated with lymphatic invasion (P = 0.034) and positively correlated with intestinal type by Lauren’s classification (P = 0.037), Ki-67-labeling index (P < 0.001), cyclin D1 (P = 0.045), cyclin E (P < 0.001) and pFOXO1 (P < 0.001). JNK activation correlated with a longer patients survival (P =0.008) and patients with a JNK-active and FOXO1-inactive tumor had a higher survival rate than the remainder of the population (P = 0.004). In vitro analysis showed that JNK inhibition by SP600125 in SNU-638 cells decreased cyclin D1 protein expression and increased FOXO1 activation. Further, JNK inhibition markedly suppressed colony formation, which was partially restored by FOXO1 shRNA expression. Conclusions Our results indicate that JNK activation may serve as a valuable prognostic factor in gastric cancer, and that it is implicated in gastric tumorigenesis, at least in part, through FOXO1 inhibition.
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Affiliation(s)
- Youngsun Choi
- Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Jinju Park
- Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Yiseul Choi
- Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Young San Ko
- Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Da-Ae Yu
- Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Bo Gun Jang
- Department of Pathology, Jeju National University Hospital, Jeju, 690-767, South Korea
| | - Min A Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea
| | - Byung Lan Lee
- Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea. .,Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea. .,Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
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27
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Jiang SB, He XJ, Xia YJ, Hu WJ, Luo JG, Zhang J, Tao HQ. MicroRNA-145-5p inhibits gastric cancer invasiveness through targeting N-cadherin and ZEB2 to suppress epithelial-mesenchymal transition. Onco Targets Ther 2016; 9:2305-15. [PMID: 27143926 PMCID: PMC4846054 DOI: 10.2147/ott.s101853] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
MicroRNA (miR)-145-5p has been reported to function as a suppressor of cancer and plays an important role in cancer invasiveness. Epithelial-mesenchymal transition (EMT) is an important process in cancer invasion and migration. However, the involvement of miR-145-5p in EMT in human gastric cancer (GC) remains unclear. In this study, we aimed to investigate the molecular mechanisms by which miR-145-5p regulates EMT in GC invasiveness. We used quantitative real-time polymerase chain reaction to investigate the miR-145-5p expression level in GC and matched normal tissues. The effects of miR-145-5p on GC cell invasion and migration abilities were evaluated using Transwell models. The relationships among miR-145-5p and zinc-finger E-box binding homeobox 2 (ZEB2), E-cadherin, and N-cadherin were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. miR-145-5p levels in primary GC tissues obtained from 60 patients were significantly downregulated, compared to those in paired normal tissues. Lauren classification, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and tumor-node-metastasis stage were associated with miR-145-5p expression. miR-145-5p inhibits the expression of the candidate target gene ZEB2 to delay the invasion and migration of GC cells. ZEB2 acts as transcriptional repressor of E-cadherin, while miR-145-5p is known to suppress N-cadherin directly to regulate EMT. Therefore, we concluded that miR-145-5p may target N-cadherin and ZEB2 directly to influence EMT.
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Affiliation(s)
- Shi-Bin Jiang
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Xu-Jun He
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Ying-Jie Xia
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Wei-Jian Hu
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun-Gang Luo
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun Zhang
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Hou-Quan Tao
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
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28
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Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget 2016; 6:12748-62. [PMID: 25909163 PMCID: PMC4494971 DOI: 10.18632/oncotarget.3327] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 02/09/2015] [Indexed: 12/22/2022] Open
Abstract
Here we showed that pAMPKα and PTEN were down-regulated and p-mTOR, p-S6, p-4EBP1, MMP7, and DCN1 were up-regulated in human gastric cancer tissue samples as compared to that in the noncancerous tissues. Metformin inhibited tumor growth in mice. Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone. In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1. We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin.
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Affiliation(s)
- Guanzhen Yu
- Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China.,Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Wenzheng Fang
- Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China.,Department of Oncology, Fuzhou General Hospital, Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, China
| | - Tian Xia
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, China.,Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ying Chen
- Department of Pathology, Changhai Hospital, Shanghai 200433, China
| | - Yunshu Gao
- Department of Oncology, Qingdao, Shandong 266000, China
| | - Xiaodong Jiao
- Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China
| | - Suyun Huang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jiejun Wang
- Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China
| | - Zhaosheng Li
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, China
| | - Keping Xie
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Qian J, Qian Y, Wang J, Gu B, Pei D, He S, Zhu F, Røe OD, Xu J, Liu L, Gu Y, Guo R, Yin Y, Shu Y, Chen X. A clinical prognostic scoring system for resectable gastric cancer to predict survival and benefit from paclitaxel- or oxaliplatin-based adjuvant chemotherapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:241-58. [PMID: 26966350 PMCID: PMC4771399 DOI: 10.2147/dddt.s88743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Gastrectomy with D2 lymphadenectomy is a standard procedure of curative resection for gastric cancer (GC). The aim of this study was to develop a simple and reliable prognostic scoring system for GC treated with D2 gastrectomy combined with adjuvant chemotherapy. Methods A prognostic scoring system was established based on clinical and laboratory data from 579 patients with localized GC without distant metastasis treated with D2 gastrectomy and adjuvant chemotherapy. Results From the multivariate model for overall survival (OS), five factors were selected for the scoring system: ≥50% metastatic lymph node rate, positive lymphovascular invasion, pathologic TNM Stage II or III, ≥5 ng/mL preoperative carcinoembryonic antigen level, and <110 g/L preoperative hemoglobin. Two models were derived using different methods. Model A identified low- and high-risk patients for OS (P<0.001), while Model B differentiated low-, intermediate-, and high-risk patients for OS (P<0.001). Stage III patients in the low-risk group had higher survival probabilities than Stage II patients. Both Model A (area under the curve [AUC]: 0.74, 95% confidence interval [CI]: 0.69–0.78) and Model B (AUC: 0.79, 95% CI: 0.72–0.83) were better predictors compared with the pathologic TNM classification (AUC: 0.62, 95% CI: 0.59–0.71, P<0.001). Adjuvant paclitaxel- or oxaliplatin-based or triple chemotherapy showed significantly better outcomes in patients classified as high risk, but not in those with low and intermediate risk. Conclusion A clinical three-tier prognostic risk scoring system was established to predict OS of GC treated with D2 gastrectomy and adjuvant chemotherapy. The potential advantage of this scoring system is that it can identify high-risk patients in Stage II or III who may benefit from paclitaxel- or oxaliplatin-based regimens. Prospective studies are needed to confirm these results before they are applied clinically.
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Affiliation(s)
- Jing Qian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Yingying Qian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Jian Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Bing Gu
- Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, People's Republic of China; Medical Technology Institute, Xuzhou Medical College, Xuzhou, People's Republic of China
| | - Dong Pei
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Shaohua He
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Fang Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Oluf Dimitri Røe
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Oncology, Clinical Cancer Research Center, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark; Department of Surgery, Cancer Clinic, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Jin Xu
- Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, People's Republic of China
| | - Lianke Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Renhua Guo
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Xuzhou, People's Republic of China
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Li K, Du H, Lian X, Chai D, Li X, Yang R, Wang C. Establishment and characterization of a metastasis model of human gastric cancer in nude mice. BMC Cancer 2016; 16:54. [PMID: 26847082 PMCID: PMC4741000 DOI: 10.1186/s12885-016-2101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 01/28/2016] [Indexed: 01/30/2023] Open
Abstract
Background A mouse model of metastasis of human gastric cancer is one of the most important tools for studying the biological mechanisms underlying human gastric cancer metastasis. In this paper, we established a mouse model of metastatic human gastric cancer in nude mice that has a higher rate of tumor formation and metastasis than existing models. Methods To generate the mouse model of metastatic human gastric cancer, fresh tumor tissues from patients that have undergone surgery for gastric cancer were subcutaneously implanted in the right and left groins of nude mice. When the implanted tissue grew to 1 cubic centimeter, the mice were killed, and the tumor tissues were examined and resected. The tumor tissues were implanted into nude mice and subjected to pathological examination, immunohistochemical staining, and real-time PCR for cytokeratin 8/18 (CK8/18), E-cadherin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). The mice were also analyzed for metastasis in their peritoneum, abdominal cavity, and internal organs by histopathological examination. Tissues collected from these organs were examined for pathology. Results After ten generations of implantation, all mice developed tumor growth at the implanted position, 94 % of the mice developed metastasis to the retroperitoneum and viscera. The implanted and metastatic tumor maintained the same histological features across all generations, and metastasis was observed in the esophagus, stomach, spleen, liver, kidney, adrenal, intestine, and pancreas. These metastatic tumors revealed no detectable expression of CK8/18, E-cadherin, VCAM-1, and ICAM-1. Conclusions This model will serve as valuable tool for understanding the metastatic process of human gastric cancer.
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Affiliation(s)
- Kesheng Li
- Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu province, Lanzhou, China.
| | - Huifen Du
- Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu province, Lanzhou, China
| | - Xiaowen Lian
- Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu province, Lanzhou, China
| | - Dandan Chai
- Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu province, Lanzhou, China
| | - Xinwen Li
- Department of Surgery, Tumor Hospital of Gansu province, Lanzhou, China
| | - Rong Yang
- Department of pathology, Tumor Hospital of Gansu province, Lanzhou, China
| | - Chunya Wang
- Department of Medicine Biotechnology, Medicine and Science Research Institute of Gansu province, Lanzhou, China
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Zhang J, Jin Y, Xu S, Zheng J, Zhang QI, Wang Y, Chen J, Huang Y, He X, Zhao Z. AGR2 is associated with gastric cancer progression and poor survival. Oncol Lett 2016; 11:2075-2083. [PMID: 26998125 PMCID: PMC4774612 DOI: 10.3892/ol.2016.4160] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Accepted: 11/05/2015] [Indexed: 12/19/2022] Open
Abstract
Anterior gradient protein 2 (AGR2) has been reported as a novel biomarker with a potential oncogenic role. However, its association with the prognosis and survival rate of gastric cancer (GC) has not yet been determined. Therefore, the present study aimed to examine the expression and prognostic significance of AGR2 in patients with GC. Immunohistochemistry was used to analyze AGR2 and cathepsin D (CTSD) protein expression in 436 clinicopathologically characterized GC cases and 92 noncancerous tissue samples. AGR2 and CTSD expression were both elevated in GC lesions compared with noncancerous tissues. In 204/436 (46.8%) GC patients, high expression of AGR2 was positively correlated with the expression of CTSD (r=0.577, P<0.01). Furthermore, several clinicopathological parameters were significantly associated with AGR2 expression level, including tumor size, depth of invasion and TNM stage (P<0.05). Using Kaplan-Meier survival analysis, it was determined that the mean survival time of patients with low levels of AGR2 expression was significantly longer than those with high ARG2 expression (in stages I, II and III; P<0.05). For stage IV disease, no significant difference in survival time was identified. Multivariate survival analysis demonstrated that AGR2 was an independent prognostic factor and was associated in the progression of GC. The findings of the present study indicate that AGR2 expression is significantly associated with location and size of GC, depth of invasion, TNM stage, lymphatic metastasis, vessel invasion, distant metastasis, Lauren's classification, high CTSD expression and poor prognosis. Thus, AGR2 may be a novel GC marker and may present a potential therapeutic target for GC.
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Affiliation(s)
- Jun Zhang
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Yongming Jin
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Shaonan Xu
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Jiayin Zheng
- Department of Probability and Statistics, School of Mathematical Sciences, Peking University, Beijing 100871, P.R. China
| | - Q I Zhang
- Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Yuanyu Wang
- Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Jinping Chen
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Yazeng Huang
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Xujun He
- Key Laboratory of Gastroenterology of Zhejiang, Hangzhou, Zhejiang 310014, P.R. China
| | - Zhongsheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
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Yang Q, Ye Z, Zhang Q, Zhao Z, Yuan H. Expression of eukaryotic translation initiation factor 5A-2 (eIF5A-2) associated with poor survival in gastric cancer. Tumour Biol 2016; 37:1189-95. [PMID: 26282002 DOI: 10.1007/s13277-015-3894-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/05/2015] [Indexed: 02/08/2023] Open
Abstract
Altered expression of eukaryotic translation initiation factor 5A-2 (eIF5A-2) was associated with human carcinogenesis and progression. This study assessed eIF5A-2 expression in gastric cancer tissues for association with clinicopathological parameters and survival of patients. A total of 436 gastric cancer tissues and 92 normal mucosal blocks were collected for construction of tissue microarrays and immunohistochemical assessment of eIF5A-2 expression. The data were statistically analyzed for association with clinicopathological factors and survival of patients. Immunohistochemical data showed that eIF5A-2 protein was highly expressed in gastric cancer tissues (p < 0.001). Upregulated expression of eIF5A-2 protein was associated with tumor Lauren classification, size, location, invasion, TNM stages, and lymph node and distant metastases. The 3- and 5-year cumulative survival rates of these 436 patients were 88.5 and 58.1 %, respectively. In contrast, the mean survival time of patients with increased tumor eIF5A-2 was 30.22 ± 1.23 vs. 51.29 ± 0.86 months for those with low tumor eIF5A-2 (p < 0.001). Multivariate analysis showed that eIF5A-2 expression and related tumor parameters were independent indicators of overall survival in gastric cancer patients. In conclusion, the current study indicates that overexpression of eIF5A-2 protein was associated with poor overall survival of gastric cancer patients.
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Affiliation(s)
- Qiong Yang
- Wenzhou Medical University, Wenzhou, China
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Zaiyuan Ye
- Wenzhou Medical University, Wenzhou, China.
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
| | - Qi Zhang
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Zhongsheng Zhao
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
| | - Hongjun Yuan
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
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Intact PTEN Expression by Immunohistochemistry is Associated With Decreased Survival in Advanced Stage Ovarian/Primary Peritoneal High-grade Serous Carcinoma. Int J Gynecol Pathol 2015; 34:497-506. [DOI: 10.1097/pgp.0000000000000205] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Ko YS, Cho SJ, Park J, Kim Y, Choi YJ, Pyo JS, Jang BG, Park JW, Kim WH, Lee BL. Loss of FOXO1 promotes gastric tumour growth and metastasis through upregulation of human epidermal growth factor receptor 2/neu expression. Br J Cancer 2015; 113:1186-96. [PMID: 26448177 PMCID: PMC4647872 DOI: 10.1038/bjc.2015.273] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 05/04/2015] [Accepted: 07/01/2015] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The biological significance of FOXO1, a member of the forkhead box O transcription factor family, in gastric cancer (GC) remains unclear. The present study provides direct evidence of the role of FOXO1 in tumour growth and metastasis of GC in relation to human epidermal growth factor receptor 2 (HER2). METHODS The expressions of FOXO1 and HER2 were modulated in GC cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by stable transfections. The effects of transfection on GC phenotypes were evaluated in vitro and in animal models. In addition, the relationship between FOXO1 and HER2 was analysed using GC clinical specimens, cell lines and xenografts. RESULTS FOXO1 silencing in GC cells increased colony formation and mesenchymal transition in vitro, as well as tumour growth and metastasis in nude mice, whereas HER2 silencing induced the opposite results.. Furthermore, an inverse relationship between FOXO1 and HER2 was found in clinical specimens of GC, GC cells and GC xenograft tumours. Although a negative crosstalk between these two molecules was shown, double knockdown of both FOXO1 and HER2 in GC cells revealed that HER2 silencing reversed the FOXO1 shRNA-induced migration and invasion even without the FOXO1 restoration. CONCLUSIONS Our results indicate that loss of FOXO1 promotes GC growth and metastasis by upregulating HER2 expression and that the HER2 expression is more critical to the induction of GC cell metastasis. The present study provides evidence that the FOXO1/HER2 pathway may regulate GC progression in a subgroup of GC patients.
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Affiliation(s)
- Young San Ko
- Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea
| | - Sung Jin Cho
- Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea
| | - Jinju Park
- Tumour Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 110-799, South Korea
| | - Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea
| | - Yong Joon Choi
- Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, South Korea
| | - Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, South Korea
| | - Bo Gun Jang
- Department of Pathology, Jeju National University Hospital, Jeju 690-767, South Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, South Korea.,Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea
| | - Byung Lan Lee
- Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.,Tumour Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 110-799, South Korea.,Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea
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Barchi LC, Yagi OK, Jacob CE, Mucerino DR, Ribeiro U, Marrelli D, Roviello F, Cecconello I, Zilberstein B. Predicting recurrence after curative resection for gastric cancer: External validation of the Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system. Eur J Surg Oncol 2015; 42:123-31. [PMID: 26365755 DOI: 10.1016/j.ejso.2015.08.164] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 08/09/2015] [Accepted: 08/13/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Most nomograms for Gastric Cancer (GC) were developed to predict overall survival (OS) after curative resection. The Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system (PSS) was designed to predict the recurrence risk after curative treatment based on pathologic tumor stage and treatment performed (D1-D2/D3 lymphadenectomy). This study was carried out to externally validate the GIRCG's PSS. PATIENTS AND METHODS Adopting the same criteria used by GIRCG to build the PSS, 185 patients with GC operated with curative intention were selected. The median follow-up period was 77.8 months (1.93-150.8) for all patients and 102.5 months (60.9-150.8) for patients free of disease. The NRI (net reclassification improvement) was calculated to estimate the overall improvement in the reclassification of patients using the PSS in place of the TNM stage system. RESULTS GC recurrence occurred in 70 (37.8%) patients. The mean time to recurrence was 22.2 (range 1.9-98.1) months. For patients with recurrence, the gain in the proportion of reclassification was 0.257 (p < 0.001), indicating an improvement of 26%. For patients without recurrence, the gain in the proportion of reclassification was -0.122 (p < 0.001), indicating a worsening of 12%. The NRI calculated was 0.135 (p = 0.0527). CONCLUSION The GIRCG's PSS, which predicts the likelihood of recurrence after radical surgical treatment for GC, is more accurate than TNM system to predict recurrence mainly for high-risk patients. Yet, the PSS does not have the same effectiveness for low-risk patients, overestimating the chance of recurrence occurs even for disease-free patients.
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Affiliation(s)
- L C Barchi
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - O K Yagi
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - C E Jacob
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - D R Mucerino
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - U Ribeiro
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - D Marrelli
- Department of General Surgery and Surgical Oncology, University of Siena, Via Banchi di Sotto, 55, 53100 Siena, SI, Italy.
| | - F Roviello
- Department of General Surgery and Surgical Oncology, University of Siena, Via Banchi di Sotto, 55, 53100 Siena, SI, Italy.
| | - I Cecconello
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
| | - B Zilberstein
- Digestive Surgery Division, Department of Gastroenterology, University of Sao Paulo School of Medicine - USP Brazil, Av. Dr. Enéas de Aguiar 255 - 9° andar 05403-000, São Paulo, SP, Brazil.
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Guo J, Fan KX, Xie LI, Xiao JJ, Chen K, Hui LN, Xu ZF. Effect and prognostic significance of the KAI1 gene in human gastric carcinoma. Oncol Lett 2015; 10:2035-2042. [PMID: 26622792 PMCID: PMC4579872 DOI: 10.3892/ol.2015.3604] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 06/03/2015] [Indexed: 11/14/2022] Open
Abstract
The present study aimed to explore the effect and mechanism of the Kangai 1 (KAI1) gene in regulating the migration and invasion of gastric carcinoma cells, and the prognostic significance of this gene in gastric cancer patients. Immunohistochemistry and in situ hybridization were used to investigate the role of KAI1 in the progression and prognosis of gastric cancer. The pEGFP-N1-KAI1 plasmid was transfected into human gastric carcinoma SGC7901 cells using liposomes. The effect of transfection with the KAI1 gene was measured using a reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) assay. The Transwell chamber assay was used to study the metastatic and invasive ability of SGC7901 cells. Gastric cancer metastasis-associated genes, including hypoxia-inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2, MMP-9, basic fibroblast growth factor (bFGF), and urease plasminogen activator (uPA) were measured by RT-sqPCR prior to and following transfection with the KAI1 gene. The expression of KAI1 protein and mRNA was associated with the differentiation degree of gastric cancer, presence of lymph node metastasis, tumor-node-metastasis stage, depth of invasion and the survival time of patients. The migratory and invasive abilities of SGC7901 cells were significantly decreased subsequent to transfection with the KAI1 gene, and the expression of bFGF and uPA was downregulated. It was concluded that the tumor suppressor gene KAI1 inhibits the migration and invasion of gastric carcinoma cells, possibly by suppressing the expression of uPA. Patients that expressed KAI1 may demonstrate an improved prognosis.
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Affiliation(s)
- Jing Guo
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - Kai-Xi Fan
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - L I Xie
- Basic Laboratory, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Jia-Jia Xiao
- Department of Neurology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Kai Chen
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Li-Na Hui
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
| | - Zhong-Fa Xu
- Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
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Kawano M, Tanaka K, Itonaga I, Ikeda S, Iwasaki T, Tsumura H. microRNA-93 promotes cell proliferation via targeting of PTEN in Osteosarcoma cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:76. [PMID: 26243299 PMCID: PMC4524362 DOI: 10.1186/s13046-015-0192-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 07/17/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Aberrant microRNA (miRNA) expression plays an essential role in osteosarcoma (OS) pathogenesis. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenesis and poor prognosis in several types of cancers, including OS. The aim of this study was to investigate the relevant microRNAs involved in the development of OS. METHODS To explore possible oncogenic factors in OS, we used a microarray-based approach to profile changes in the expression of miRNAs and their target mRNAs in five OS cell lines and human mesenchymal stem cells (hMSCs). An miRNA, miR-93, was significantly up-regulated, whereas phosphatase and tensin homologue (PTEN) expression was significantly down-regulated in all tested OS cells, when compared with hMSCs. RESULTS When anti-miR-93 was transfected into OS cell lines, PTEN expression was greatly increased, suggesting that PTEN might be a target of miR-93 in ES cells. The expression of phosphorylated Akt protein, which is known to be inversely correlated with that of PTEN, was significantly down-regulated in anti-miR-93-transfected cells. Furthermore, transfection of anti-miR-93 inhibited the proliferation and cell cycle progression of ES cells. In addition, the down-regulation of miR-93 in these cells significantly suppressed tumor growth in vivo. CONCLUSION Ectopic expression of miR-93 decreased PTEN protein levels. Furthermore, miR-93 increased proliferation and decreased apoptosis in OS cells, whereas its silencing in these cells inhibited such carcinogenic processes. Taking these observations together, miR-93 can be seen to play a critical role in carcinogenesis through suppression of PTEN, and may serve as a therapeutic target for the treatment of OS.
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Affiliation(s)
- Masanori Kawano
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Kazuhiro Tanaka
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Ichiro Itonaga
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Shinichi Ikeda
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Tatsuya Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Hiroshi Tsumura
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
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Yoon J, Ko YS, Cho SJ, Park J, Choi YS, Choi Y, Pyo JS, Ye SK, Youn HD, Lee JS, Chang MS, Kim MA, Lee BL. Signal transducers and activators of transcription 3-induced metastatic potential in gastric cancer cells is enhanced by glycogen synthase kinase-3β. APMIS 2015; 123:373-82. [PMID: 25846563 DOI: 10.1111/apm.12370] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 01/02/2015] [Indexed: 01/29/2023]
Abstract
The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3β (GSK-3β) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3β (pGSK-3β) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001). Cell culture experiments using gastric cancer cell lines SNU-638 and SNU-668 revealed that STAT3 suppression did not affect pGSK-3β expression, whereas GSK-3β inhibition reduced pSTAT3 expression. With respect to metastatic potential in gastric cancer cells, both STAT3 suppression and GSK-3β inhibition decreased cell migration, invasion, and mesenchymal marker (Snail, Vimentin, and MMP9) expression. Moreover, the inhibitory effects of STAT3 and GSK-3β on cell migration were synergistic. These results demonstrated that STAT3 and GSK-3β are positively associated and synergistically contribute to metastatic potential in gastric cancer cells. Thus, dual use of STAT3 and GSK-3β inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
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Affiliation(s)
- Jiyeon Yoon
- Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea
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Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, Hansen JM, Rupaimoole R, Huang J, Dalton HJ, Ali-Fehmi R, Coleman RL, Sood AK. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther 2015; 14:1466-1475. [PMID: 25833835 DOI: 10.1158/1535-7163.mct-14-1077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 03/23/2015] [Indexed: 11/16/2022]
Abstract
PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAK(Y397) in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAK(Y397) expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAK(Y397) expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAK(Y397) expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development.
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Affiliation(s)
- Duangmani Thanapprapasr
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Rebecca A Previs
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cristina Ivan
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guillermo N Armaiz-Pena
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Piotr L Dorniak
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jean M Hansen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rajesha Rupaimoole
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jie Huang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Heather J Dalton
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rouba Ali-Fehmi
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Kim SY, Ko YS, Park J, Choi Y, Park JW, Kim Y, Pyo JS, Yoo YB, Lee JS, Lee BL. Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1. Cancer Res Treat 2015; 48:345-54. [PMID: 25761483 PMCID: PMC4720104 DOI: 10.4143/crt.2014.247] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 12/05/2014] [Indexed: 01/26/2023] Open
Abstract
Purpose We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. Materials and Methods Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. Results In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. Conclusion Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α–VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
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Affiliation(s)
- Sue Youn Kim
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea
| | - Young San Ko
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea
| | - Jinju Park
- Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yiseul Choi
- Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea ; Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Bok Yoo
- Department of Anatomy, Dankook University School of Medicine, Cheonan, Korea
| | - Jae-Seon Lee
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea
| | - Byung Lan Lee
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea ; Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea ; Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
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Kordi Tamandani DM, Hemati S, Davani SK, Arbabi F. Association between promoter methylation and expression of thyroid hormone receptor beta (THRβ) gene in patients with gastric cancer in an Iranian population. J Gastroenterol Hepatol 2015; 30:485-9. [PMID: 25302749 DOI: 10.1111/jgh.12808] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM There is evidence that gastric cancer patients suffer from thyroid disorders. However, the relationship between thyroid receptor (TR) expression and gastric cancer remains unknown. The aim of this study was to evaluate the status of promoter methylation and expression of the thyroid hormone receptor beta (THRβ) gene in gastric cancer patients in an Iranian population. METHODS Analysis of THRβ promoter methylation was performed on 85 pairs of formalin-fixed, paraffin-embedded (FFPE) tissue samples as cases and controls via methylation-specific polymerase chain reaction (PCR [MSP]). The samples were obtained from tumors and surrounding healthy tissues from resected gastric cancers. The expression assay was also performed with 25 FFPE tissue pairs (tumor and surrounding healthy tissues of the same individual) using real-time PCR. RESULTS The results of the present study show that there is a statistically significant difference between tumor and adjacent normal tissues regarding promoter methylation status and THRβ expression (P = 0.04 and P = 0.036, respectively). CONCLUSION Therefore, promoter methylation of THRβ may be involved in the development of gastric cancer.
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Lee EC, Yang JY, Lee KG, Oh SY, Suh YS, Kong SH, Yang HK, Lee HJ. The value of postoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels for the early detection of gastric cancer recurrence after curative resection. J Gastric Cancer 2014; 14:221-8. [PMID: 25580353 PMCID: PMC4286900 DOI: 10.5230/jgc.2014.14.4.221] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 10/04/2014] [Accepted: 10/05/2014] [Indexed: 12/15/2022] Open
Abstract
PURPOSE This study aimed to evaluate the value of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels to detect gastric cancer recurrence. MATERIALS AND METHODS We retrospectively reviewed 154 patients who developed recurrence within 2 years after curative gastric cancer surgery and analyzed the relationship between postoperative CEA and CA19-9 levels and recurrence. We readjusted the cut-off values to improve the detection of recurrence. Subgroup analysis according to clinicopathologic variables was performed to further investigate the relationship between recurrence and CEA and CA19-9 levels. RESULTS The sensitivity and specificity for elevated CEA levels to detect recurrence were 40.6% and 89.5%, respectively, and those for CA19-9 were 34.2% and 93.6%, respectively. The sensitivity and specificity for elevation of either tumor marker were 54.3% and 84.0%, respectively; those for elevation of both tumor markers were 19.2% and 98.4%, respectively. By readjusting the cut-off values from 5.0 ng/ml to 5.2 ng/ml for CEA and from 37.00 U/ml to 30.0 U/ml for CA19-9, the sensitivity was increased from 34.2% to 40.2% for CA19-9, while there was no increase in sensitivity for CEA. In subgroup analysis, the sensitivity of CEA was higher in patients with elevated preoperative CEA levels than in patients with normal preoperative CEA levels (86.7% versus 33.7%; P<0.001). Furthermore, the sensitivity of CA19-9 was higher in patients with elevated preoperative CA19-9 levels than in patients with normal preoperative CA19-9 levels (82.61% versus 26.83%; P<0.001). CONCLUSIONS CEA and/or CA19-9 measurement with the readjusted cut-off values allows for more effective detection of gastric cancer recurrence.
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Affiliation(s)
- Eung-Chang Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jun-Young Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Goo Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Young Oh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Nam KH, Kim MA, Choe G, Kim WH, Lee HS. Deregulation of the cell polarity protein Lethal giant larvae 2 (Lgl2) correlates with gastric cancer progression. Gastric Cancer 2014; 17:610-20. [PMID: 24337435 DOI: 10.1007/s10120-013-0324-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 11/24/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND We investigated the roles of Lethal giant larvae 2 (Lgl2), an epithelial cell polarity protein, during gastric carcinogenesis and gastric cancer (GC) progression and evaluated the correlation of Lgl2 with epithelial-mesenchymal transition (EMT) markers. METHODS Lgl2 protein and mRNA expression were determined by immunohistochemistry and mRNA in situ hybridization in a large series of GC and preneoplastic lesions. Additionally, expression of 7 EMT markers was examined by immunohistochemistry. RESULTS Loss of membrane Lgl2 staining in GC was observed in 347 of 409 GCs. Lgl2 loss was associated with diffuse histological type (P < 0.001), advanced stage (P = 0.021), and worse prognosis (P = 0.047). Furthermore, Lgl2 loss correlated with reduced E-cadherin expression (P < 0.01) and increased expression of vimentin (P < 0.01). Combined analysis of Lgl2 and the EMT markers, S100A4 and MMP2, improved predictions of patient outcomes. During gastric carcinogenesis, membrane expression of Lgl2 was progressively lost in 4 % of normal mucosa, 75 % of intestinal metaplasia, 58 % of gastric dysplasia, 69 % of intestinal type GC, and 96 % of diffuse type GC. CONCLUSIONS Our results suggest that Lgl2 loss occurs at an early stage of gastric carcinogenesis and contributes to GC progression.
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Affiliation(s)
- Kyung Han Nam
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea
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Kageyama-Yahara N, Yamamichi N, Takahashi Y, Nakayama C, Shiogama K, Inada KI, Konno-Shimizu M, Kodashima S, Fujishiro M, Tsutsumi Y, Ichinose M, Koike K. Gli regulates MUC5AC transcription in human gastrointestinal cells. PLoS One 2014; 9:e106106. [PMID: 25166306 PMCID: PMC4148389 DOI: 10.1371/journal.pone.0106106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 07/28/2014] [Indexed: 01/05/2023] Open
Abstract
MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. Immunohistochemistry revealed that expression of MUC5AC decreases accompanied with increased malignant property of gastric mucosa, which further suggests the importance of MUC5AC gene regulation. Alignment of the 5′-flanking regions of MUC5AC gene of 13 mammal species denoted high homology within 200 bp upstream of the coding region. Luciferase activities of the deletion constructs containing upstream 451 bp or shorter fragments demonstrated that 15 bp region between −111 and −125 bp plays a critical role on MUC5AC promoter activity in gastrointestinal cells. We found a putative Gli-binding site in this 15 bp sequence, and named this region a highly conserved region containing a Gli-binding site (HCR-Gli). Overexpression of Gli homologs (Gli1, Gli2, and Gli3) clearly enhanced MUC5AC promoter activity. Exogenous modulation of Gli1 and Gli2 also affected the endogenous MUC5AC gene expression in gastrointestinal cells. Chromatin immunoprecipitation assays demonstrated that Gli1 directly binds to HCR-Gli: Gli regulates MUC5AC transcription via direct protein-DNA interaction. Conversely, in the 30 human cancer cell lines and various normal tissues, expression patterns of MUC5AC and Gli did not coincide wholly: MUC5AC showed cell line-specific or tissue-specific expression whereas Gli mostly revealed ubiquitous expression. Luciferase promoter assays suggested that the far distal MUC5AC promoter region containing upstream 4010 bp seems to have several enhancer elements for gene transcription. In addition, treatments with DNA demethylation reagent and/or histone deacetylase inhibitor induced MUC5AC expression in several cell lines that were deficient in MUC5AC expression. These results indicated that Gli is necessary but not sufficient for MUC5AC expression: namely, the multiple regulatory mechanisms should work in the distal promoter region of MUC5AC gene.
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Affiliation(s)
- Natsuko Kageyama-Yahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- * E-mail:
| | - Yu Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Chiemi Nakayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kazuya Shiogama
- 1st Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Ken-ichi Inada
- 1st Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Maki Konno-Shimizu
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shinya Kodashima
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yutaka Tsutsumi
- 1st Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Masao Ichinose
- Second Department of Internal Medicine, Wakayama Medical College, Kimiidera, Wakayama, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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Duan H, Chen L, Qu L, Yang H, Song SW, Han Y, Ye M, Chen W, He X, Shou C. Mycoplasma hyorhinis infection promotes NF-κB-dependent migration of gastric cancer cells. Cancer Res 2014; 74:5782-94. [PMID: 25136068 DOI: 10.1158/0008-5472.can-14-0650] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chronic infection of Mycoplasma hyorhinis (M. hyorhinis) has been postulated to be associated with several types of cancer, but its effect on patients' survival and host factors mediating its infection remain unclear. Herein, we demonstrated that M. hyorhinis p37 protein expression in gastric cancer tissues predicts poor survival and associates with metastasis. M. hyorhinis infects mammalian cells and promotes gastric cancer cell invasiveness via its membrane protein p37. Synthesized peptide corresponding to the N-terminus of p37 prevents M. hyorhinis infection. Host Annexin A2 (ANXA2) interacts with the N-terminus of p37. In addition, EGFR forms a complex with p37 and ANXA2, and is required for M. hyorhinis-induced phosphorylation and membrane recruitment of ANXA2. M. hyorhinis infection is inhibited by siRNA-mediated knockdown of ANXA2 or EGFR, but is enhanced by expression of ectopic ANXA2 or EGFR. Downstream of ANXA2 and EGFR, the NF-κB pathway is activated and mediates M. hyorhinis-driven cell migration. In conclusion, our study unveils the effect of M. hyorhinis infection on gastric cancer survival and uncovers the mechanisms by which M. hyorhinis infects mammalian cells and promotes cancer cell migration.
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Affiliation(s)
- Hongying Duan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Ling Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Hua Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Sonya Wei Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yong Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Meihua Ye
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Wanyuan Chen
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Xianglei He
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China.
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Sun G, Zhao G, Lu Y, Wang Y, Yang C. Association of EMP1 with gastric carcinoma invasion, survival and prognosis. Int J Oncol 2014; 45:1091-8. [PMID: 24920167 DOI: 10.3892/ijo.2014.2488] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/19/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to determine the expression and function of epithelial membrane protein 1 (EMP1) in gastric carcinoma. Gastric samples were taken from cancer lesions and adjacent normal tissue in gastric cancer patients immediately after endoscopic biopsy. A portion of the sample was either fixed in 4% paraformaldehyde and embedded in paraffin for immunohistochemistry or stored in liquid nitrogen for western blotting. In order to determine protein expression of EMP1 in gastric cancer (n=65) and normal tissue (n=27), semi-quantitative immunohistochemistry and western blotting were utilized. For in vitro studies, the human gastric cancer cell line SGC-7901 was maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum. Recombinant lentivirus mediated overexpression of EMP1 in SGC-7901 cells was quantified with quantitative polymerase chain reaction (qPCR) and western blotting. Control SGC-7901 cells were transfected with an empty vector. To further study the effect of EMP1 overexpression in SGC-7901 cells, cell proliferation, cell apoptosis and migration and invasion assays were conducted. The expression of EMP1 was significantly lower in gastric cancer tissue compared to normal tissue using both immunohistochemistry (41.5 vs. 70.4% of tissues, P<0.05) and western blotting (0.153 ± 0.012 vs. 0.626 ± 0.058, P<0.05). Decreased expression of EMP1 was significantly correlated with tumor invasion, lymph node metastasis, clinical stage and histological grade of patients with gastric cancer (P<0.05). According to Kaplan-Meier analysis, low EMP1 expression correlated significantly with poor overall 5-year survival (47.4 vs. 70.3% survival, P<0.05). SGC-7901 cells transfected with EMP1 had a lower survival fraction, higher cell apoptosis (13.2 ± 1.5% vs. 2.2 ± 0.5%, P<0.05), significant decrease in migration and invasion (157.0 ± 16.0 and 112.0 ± 12.0, respectively vs. 243.0 ± 21.0 and 203.0 ± 19.0, respectively, P<0.05), higher caspase-9 (0.501 ± 0.050 vs. 0.114 ± 0.010, P<0.05) and lower VEGFC protein expression 0.135 ± 0.011 vs. 0.619 ± 0.074, P<0.05) relative to cells not transfected with EMP1. Low EMP1 expression in gastric cancer is associated with increased disease severity, suggesting that EMP1 may be a negative regulator of gastric cancer.
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Affiliation(s)
- Guogui Sun
- Department of Chemoradiotherapy, Tangshan People's Hospital, Tangshan 063000, P.R. China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, The Second Tangshan Hospital, Tangshan 063000, P.R. China
| | - Yifang Lu
- Department of Endocrinology, Tangshan Workers Hospital, Tangshan 063000, P.R. China
| | - Yadi Wang
- Department of Radiotherapy, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Congrong Yang
- Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050017, P.R. China
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Interferon consensus sequence-binding protein (ICSBP) promotes epithelial-to-mesenchymal transition (EMT)-like phenomena, cell-motility, and invasion via TGF-β signaling in U2OS cells. Cell Death Dis 2014; 5:e1224. [PMID: 24832596 PMCID: PMC4047854 DOI: 10.1038/cddis.2014.189] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/23/2014] [Accepted: 03/31/2014] [Indexed: 11/09/2022]
Abstract
Interferon consensus sequence-binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-γ) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial-to-mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-γ treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knockdown. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP upregulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the upregulation of Snail. Knockdown of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Upregulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF-β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r=0.47, P=0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-β and Snail signaling pathways.
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Guo SL, Ye H, Teng Y, Wang YL, Yang G, Li XB, Zhang C, Yang X, Yang ZZ, Yang X. Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency. Nat Commun 2014; 4:2544. [PMID: 24149576 PMCID: PMC3826643 DOI: 10.1038/ncomms3544] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 09/04/2013] [Indexed: 12/27/2022] Open
Abstract
Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.
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Affiliation(s)
- Shui-Long Guo
- 1] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, China [2] Institute of Geriatrics, PLA Postgraduate School of Medicine, PLA General Hospital, Beijing 100853, China [3]
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Lim B, Park JL, Kim HJ, Park YK, Kim JH, Sohn HA, Noh SM, Song KS, Kim WH, Kim YS, Kim SY. Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer. Carcinogenesis 2014; 35:1020-1027. [PMID: 24325916 DOI: 10.1093/carcin/bgt409] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Tumorigenesis is a consequence of failures of multistep defense mechanisms against deleterious perturbations that occur at the genomic, epigenomic, transcriptomic and proteomic levels. To uncover previously unrecognized genes that undergo multilevel perturbations in gastric cancer (GC), we integrated epigenomic and transcriptomic approaches using two recently developed tools: MENT and GENT. This integrative analysis revealed that nine Hippo pathway-related genes, including components [FAT, JUB, LATS2, TEA domain family member 4 (TEAD4) and Yes-associated protein 1 (YAP1)] and targets (CRIM1, CYR61, CTGF and ITGB2), are concurrently hypomethylated at promoter CpG sites and overexpressed in GC tissues. In particular, TEAD4, a link between Hippo pathway components and targets, was significantly hypomethylated at CpG site cg21637033 (P = 3.8 × 10(-) (20)) and overexpressed (P = 5.2 × 10(-) (10)) in 108 Korean GC tissues compared with the normal counterparts. A reduced level of methylation at the TEAD4 promoter was significantly associated with poor outcomes, including large tumor size, high-grade tumors and low survival rates. Compared with normal tissues, the TEAD4 protein was more frequently found in the nuclei of tumor cells along with YAP1 in 53 GC patients, demonstrating the posttranslational activation of this protein. Moreover, the knockdown of TEAD4 resulted in the reduced growth of GC cells both in vitro and in vivo. Finally, chromatin immunoprecipitation-sequencing and microarray analysis revealed the oncogenic properties of TEAD4 and its novel targets (ADM, ANG, ARID5B, CALD1, EDN2, FSCN1 and OSR2), which are involved in cell proliferation and migration. In conclusion, the multilevel perturbations of TEAD4 at epigenetic, transcriptional and posttranslational levels may contribute to GC development.
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Affiliation(s)
- Byungho Lim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Republic of Korea
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Abnormal FHIT protein expression may be correlated with poor prognosis in gastric cancer: a meta-analysis. Tumour Biol 2014; 35:6815-21. [PMID: 24729090 DOI: 10.1007/s13277-014-1936-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Accepted: 04/03/2014] [Indexed: 01/11/2023] Open
Abstract
Our current meta-analysis is aimed to investigate the relationships between fragile histidine triad (FHIT) protein expression and prognosis in gastric cancer patients. We searched MEDLINE (1966 ~ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) without any language restrictions. The meta-analysis was conducted using the STATA 12.0 software. Crude hazard ratios (HR) with its 95 % confidence interval (95 % CI) were calculated. Eight clinical cohort studies with a total of 1,361 gastric cancer patients were involved in our meta-analysis. Our results revealed that FHIT-negative patients exhibited a shorter overall survival (OS) time than FHIT-positive patients (HR = 1.23, 95 % CI = 1.01 ~ 1.44, P < 0.001). Ethnicity-stratified analysis demonstrated that FHIT-negative patients have significantly poorer prognosis than FHIT-positive patients among both Caucasians and Asians (all P < 0.05). In conclusion, our meta-analysis provides evidences that negative expression of FHIT protein may be correlated with poor prognosis in patients with gastric cancer. Thus, FHIT expression level may be utilized as an independent prognostic marker for gastric cancer.
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