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Berrino C, Omar A. Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation. Curr Issues Mol Biol 2024; 46:5397-5419. [PMID: 38920995 PMCID: PMC11202538 DOI: 10.3390/cimb46060323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/24/2024] [Accepted: 05/25/2024] [Indexed: 06/27/2024] Open
Abstract
The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.
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Hirata Y, Noorani A, Song S, Wang L, Ajani JA. Early stage gastric adenocarcinoma: clinical and molecular landscapes. Nat Rev Clin Oncol 2023; 20:453-469. [PMID: 37264184 DOI: 10.1038/s41571-023-00767-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 06/03/2023]
Abstract
Gastric adenocarcinoma, even when diagnosed at an early (localized) disease stage, poses a major health-care burden with cure rates that remain unsatisfactorily low, particularly in Western countries. This lack of progress reflects, among other aspects, the impracticality of early diagnosis, considerable variations in therapeutic approaches that is partly based on regional preferences, and the ingrained heterogeneity of gastric adenocarcinoma cells and their associated tumour microenvironment (TME). Clinical trials have long applied empirical interventions with the assumption that all early stage gastric adenocarcinomas are alike. Despite certain successes, the shortcomings of these approaches can potentially be overcome by targeting the specific molecular subsets of gastric adenocarcinomas identified by genomic and/or multi-omics analyses, including microsatellite instability-high, Epstein-Barr virus-induced, DNA damage repair-deficient, HER2-positive and PD-L1-high subtypes. Future approaches, including the availability of sophisticated vaccines, novel antibody technologies, agents targeting TME components (including fibroblasts, macrophages, cytokines or chemokines, and T cells) and novel immune checkpoint inhibitors, supported by improved tissue-based and blood-based diagnostic assays, seem promising. In this Review, we highlight current knowledge of the molecular and cellular biology of gastric adenocarcinomas, summarize the current approaches to clinical management of the disease, and consider the role of novel management and/or treatment strategies.
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Affiliation(s)
- Yuki Hirata
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ayesha Noorani
- Cancer Ageing and Somatic Mutation Group, Wellcome Sanger Institute, Hinxton, UK
- Cambridge Oesophago-gastric Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis. Cancers (Basel) 2023; 15:cancers15030736. [PMID: 36765694 PMCID: PMC9913146 DOI: 10.3390/cancers15030736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/15/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis.
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Jiang J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 2022; 85:107-122. [PMID: 33836254 PMCID: PMC8492792 DOI: 10.1016/j.semcancer.2021.04.003] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022]
Abstract
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
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Affiliation(s)
- Jin Jiang
- Department of Molecular Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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Chai JY, Sugumar V, Alshawsh MA, Wong WF, Arya A, Chong PP, Looi CY. The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis. Biomedicines 2021; 9:1188. [PMID: 34572373 PMCID: PMC8466551 DOI: 10.3390/biomedicines9091188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 12/22/2022] Open
Abstract
The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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Affiliation(s)
- Jian Yi Chai
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
| | - Vaisnevee Sugumar
- School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia;
| | | | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Aditya Arya
- School of Biosciences, Faculty of Science, Building 184, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
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Ghasemi H, Mousavibahar SH, Hashemnia M, Karimi J, Khodadadi I, Tavilani H. Transitional cell carcinoma matrix stiffness regulates the osteopontin and YAP expression in recurrent patients. Mol Biol Rep 2021; 48:4253-4262. [PMID: 34086159 DOI: 10.1007/s11033-021-06440-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/26/2021] [Indexed: 10/21/2022]
Abstract
Cells translate the mechanosensing of extracellular matrix component dysregulation and stiffness into the signal transduction including Osteopontin (OPN) through the Hippo pathway. But how extracellular matrix (ECM) component dysregulation and stiffness are ultimately linked to transitional cell carcinoma (TCC) development remains poorly understood. This study was aimed to evaluate the possible links between ECM component alteration after cancer surgery and OPN and Yes-associated protein (YAP) expression in TCC and adjacent tissues. In this study, we used 50 TCC (25 newly diagnosed and 25 recurrent) and 50 adjacent tissues to determine the tissue stiffness using atomic force microscopy. The mRNA expression of SPP1, Indian hedgehog (IHH), and YAP was also determined using qRT-PCR. Western blotting and ELISA were performed to assess the tissue and serum levels of OPN, respectively. To assess the glycoproteins and elastic fibers content, Periodic Acid Schiff, and Verhoeff-Van Gieson Staining were performed, respectively. Matrix stiffness was markedly higher in TCCs than adjacent tissues (p < 0.05). Gene expression analysis showed that YAP, SPP1, and IHH genes were upregulated in TCC tissues (p < 0.05). Additionally, the OPN protein overexpression was observed in the tissue and the serum of TCC patients (p < 0.05). We also found that glycoproteins, elastic fibers content of recurrent TCC tissues was remarkably higher as compared to adjacent tissues (p < 0.05). Our results suggest that glycoproteins and elastic fibers content modulation and ECM stiffness may upregulates the expression of YAP, SPP1 and IHH genes, and possibly contribute to the TCC development and relapse.
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Affiliation(s)
- Hadi Ghasemi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Mohammad Hashemnia
- Department of Pathobiology, Veterinary Medicine Faculty, Razi University, Kermanshah, Iran
| | - Jamshid Karimi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Khodadadi
- Department of Clinical Biochemistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heidar Tavilani
- Urology & Nephrology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
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Peng Y, Zhang X, Lin H, Deng S, Qin Y, He J, Hu F, Zhu X, Feng X, Wang J, Wei Y, Fan X, Lin H, Ashktorab H, Smoot D, Lv Y, Li S, Meltzer SJ, Jin Z. Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer. Aging (Albany NY) 2021; 13:10749-10769. [PMID: 33848981 PMCID: PMC8064165 DOI: 10.18632/aging.202895] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/22/2020] [Indexed: 02/06/2023]
Abstract
Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration in vitro. We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions in vivo, suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.
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Affiliation(s)
- Yin Peng
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, P.R. China
| | - Xiaojing Zhang
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, P.R. China,Department of Pathology, Guangdong Province Key Laboratory of Molecular Oncologic Pathology, Guangzhou 510515, Guangdong, P.R. China
| | - Huijuan Lin
- Department of Ultrasound, Guangdong Women and Children Hospital, Guangzhou 510000, Guangdong, P.R. China,Department of Pathology and Pathophysiology, Guangzhou Medical University, Guangzhou 510000, Guangdong, P.R. China
| | - Shiqi Deng
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Ying Qin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, Guangdong, P.R. China
| | - Jieqiong He
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Fan Hu
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Xiaohui Zhu
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Xianling Feng
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Jian Wang
- Department of Pathology and Pathophysiology, Guangzhou Medical University, Guangzhou 510000, Guangdong, P.R. China
| | - Yanjie Wei
- Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Shenzhen 518000, Guangdong, P.R. China
| | - Xinmin Fan
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Huan Lin
- Department of Vascular Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen 518060, Guangdong, P.R. China
| | - Hassan Ashktorab
- Department of Medicine and Cancer Center, Howard University, College of Medicine, Washington, DC 20060, USA
| | - Duane Smoot
- Department of Medicine, Meharry Medical Center, Nashville, TN 37208, USA
| | - Yansi Lv
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China
| | - Song Li
- Shenzhen Science and Technology Development Exchange Center, Shenzhen 518060, Guangdong, P.R. China
| | - Stephen J. Meltzer
- Department of Medicine, GI Division, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Zhe Jin
- Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, P.R. China
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Han T, Cheng Z, Xu M, Wang X, Wu J, Fang X. Yes-Associated Protein Contributes to Cell Proliferation and Migration of Gastric Cancer via Activation of Gli1. Onco Targets Ther 2020; 13:10867-10876. [PMID: 33149604 PMCID: PMC7603417 DOI: 10.2147/ott.s266449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 09/04/2020] [Indexed: 12/21/2022] Open
Abstract
Objective In the present study, we aimed to explore the potential oncogenic property and the internal mechanism of yes-associated protein (YAP) in gastric cancer (GC). Materials and Methods YAP protein levels were evaluated in human GC tissues and paired normal tissues using immunohistochemistry (IHC). The role of YAP in regulating GC cell proliferation and migration was verified by genetic manipulation in vitro. Western blot analysis was used to determine the molecular signaling to explain the mechanism of the observed YAP effects in GC. Results Nuclear YAP protein expression was upregulated in GC tissues, and high nuclear YAP level was significantly correlated with lymph node metastasis (LNM) and tumor node metastasis (TNM) stage in patients suffered from GC. YAP knockdown inhibited GC cell proliferation, migration and epithelial-mesenchymal transition (EMT) progress in vitro, whereas YAP elevation did the opposite. YAP regulated glioma-associated oncogene-1 (Gli1) expression independent of smoothened homolog (SMO). YAP modulated protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Conclusion YAP enhanced GC cell proliferation and migration potentially via its regulation of Gli1 expression through the non-classical Hedgehog pathway, indicating suppression of YAP/Gli1 signaling axis may highlight a new entry point for combination therapy of GC.
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Affiliation(s)
- Ting Han
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
| | - Zhengwu Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
| | - Menglin Xu
- Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
| | - Jian Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
| | - Xiaosan Fang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People's Republic of China
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Arasu UT, Deen AJ, Pasonen-Seppänen S, Heikkinen S, Lalowski M, Kärnä R, Härkönen K, Mäkinen P, Lázaro-Ibáñez E, Siljander PRM, Oikari S, Levonen AL, Rilla K. HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells. Cell Mol Life Sci 2020; 77:4093-4115. [PMID: 31820036 PMCID: PMC7532973 DOI: 10.1007/s00018-019-03399-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 11/11/2019] [Accepted: 11/26/2019] [Indexed: 12/17/2022]
Abstract
Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
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Affiliation(s)
- Uma Thanigai Arasu
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
| | - Ashik Jawahar Deen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Sami Heikkinen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
- Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Maciej Lalowski
- Faculty of Medicine, Biochemistry and Developmental Biology, Meilahti Clinical Proteomics Core Facility, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Riikka Kärnä
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Kai Härkönen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Petri Mäkinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Elisa Lázaro-Ibáñez
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland
| | - Pia R-M Siljander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland
- EV Group and EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Sanna Oikari
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Anna-Liisa Levonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Kirsi Rilla
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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11
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Xu Y, Song S, Wang Z, Ajani JA. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun Signal 2019; 17:157. [PMID: 31775795 PMCID: PMC6882007 DOI: 10.1186/s12964-019-0479-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
Patients with advanced gastric cancer usually have a poor prognosis and limited therapeutic options. Overcoming this challenge requires novel targets and effective drugs. The Hedgehog (Hh) signaling pathway plays a crucial role in the development of the gastrointestinal tract and maintenance of the physiologic function of the stomach. Aberrantly activated Hh signaling is implicated in carcinogenesis as well as maintenance of cancer stem cells. Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed. To date, two inhibitors (GDC-0449 and LDE225) have been approved by the U.S. Food and Drug Administration to treat basal cell carcinoma and medulloblastoma. Here, we review the role of the Hh signaling in the carcinogenesis and progression of gastric cancer and summarize recent findings on Hh inhibitors in gastric cancer. Hedgehog signaling is often aberrantly activated and plays an important role during inflammation and carcinogenesis of gastric epithelial cells. Further study of the precise mechanisms of Hh signaling in this disease is needed for the validation of therapeutic targets and evaluation of the clinical utility of Hh inhibitors for gastric cancer.
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Affiliation(s)
- Yan Xu
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
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12
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Guo LH, Cao Y, Zhuang RT, Han Y, Li J. Astragaloside IV promotes the proliferation and migration of osteoblast-like cells through the hedgehog signaling pathway. Int J Mol Med 2018; 43:830-838. [PMID: 30535481 PMCID: PMC6317662 DOI: 10.3892/ijmm.2018.4013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 08/30/2018] [Indexed: 12/20/2022] Open
Abstract
The present study aimed to investigate the effects of astragaloside IV on osteoblast-like cell proliferation and migration, in addition to the underlying signaling pathway. In order to observe the effect on proliferation, a Cell Counting Kit-8 assay and flow cytometry were used. To detect cell migration ability, cell scratch and Transwell cell migration assays were performed. The RNA and protein expression levels of hedgehog signaling molecules, including Sonic hedgehog (SHH) and GLI family zinc finger 1 (GLI1), were examined by reverse transcription-quantitative polymerase chain reaction and western blot analyses. To inhibit the hedgehog signaling pathway, cyclopamine was used. Astragaloside IV, at a dosage of 1×10−2µg/ml in MG-63 cells and 1×10−3µg/ml in U-2OS cells, resulted in the enhanced proliferation and migration of cells, and the gene expression levels of the SHH and GLI1 were significantly increased. The combination of astragaloside IV and cyclopamine reduced MG-63 and U-2OS cell proliferation and migration, and inhibited the gene expression of SHH and GLI1. Astragaloside IV enhanced the proliferation and migration of human osteoblast-like cells through activating the hedgehog signaling pathway. The results of the present study provide a rational for the mechanistic link in astragaloside IV promoting the proliferation and migration of osteoblasts via the hedgehog signaling pathway.
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Affiliation(s)
- Li-Hua Guo
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing 100050, P.R. China
| | - Yu Cao
- Department of Integrated Emergency Dental Care, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing 100050, P.R. China
| | - Run-Tao Zhuang
- Department of Stomatology, Beijing Jiaotong University Community Health Center, Beijing 100044, P.R. China
| | - Yan Han
- Department of Stomatology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Jun Li
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing 100050, P.R. China
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13
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Molaei F, Forghanifard MM, Fahim Y, Abbaszadegan MR. Molecular Signaling in Tumorigenesis of Gastric Cancer. IRANIAN BIOMEDICAL JOURNAL 2018; 22:217-230. [PMID: 29706061 PMCID: PMC5949124 DOI: 10.22034/ibj.22.4.217] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/28/2018] [Accepted: 02/03/2018] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is regarded as the fifth most common cancer and the third cause of cancer-related deaths worldwide. Mechanism of GC pathogenesis is still unclear and relies on multiple factors, including environmental and genetic characteristics. One of the most important environmental factors of GC occurrence is infection with Helicobacter pylori that is classified as class one carcinogens. Dysregulation of several genes and pathways play an essential role during gastric carcinogenesis. Dysregulation of developmental pathways such as Wnt/β-catenin signaling, Hedgehog signaling, Hippo pathway, Notch signaling, nuclear factor-kB, and epidermal growth factor receptor have been found in GC. Epithelial-mesenchymal transition, as an important process during embryogenesis and tumorigenesis, is supposed to play a role in initiation, invasion, metastasis, and progression of GC. Although surgery is the main therapeutic modality of the disease, the understanding of biological processes of cell signaling pathways may help to develop new therapeutic targets for GC.
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Affiliation(s)
- Fatemeh Molaei
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Yasaman Fahim
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Jia X, Min L, Zhu S, Zhang S, Huang X. Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice. FASEB J 2018; 32:5703-5715. [DOI: 10.1096/fj.201701581r] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Xueting Jia
- Department of GastroenterologyNational Clinical Research Center for Digestive Diseases, Beijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive Diseases
- Department of StomatologyBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Li Min
- Department of GastroenterologyNational Clinical Research Center for Digestive Diseases, Beijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive Diseases
| | - Shengtao Zhu
- Department of GastroenterologyNational Clinical Research Center for Digestive Diseases, Beijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive Diseases
| | - Shutian Zhang
- Department of GastroenterologyNational Clinical Research Center for Digestive Diseases, Beijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive Diseases
| | - Xiaofeng Huang
- Department of StomatologyBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
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15
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Sun L, Yao Y, Pan G, Zhan S, Shi W, Lu T, Yuan J, Tian K, Jiang L, Song S, Zhu X, He S. Small interfering RNA-mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR/Gli1 signaling pathway. Oncol Lett 2018; 16:594-602. [PMID: 29928446 DOI: 10.3892/ol.2018.8648] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 03/07/2018] [Indexed: 12/21/2022] Open
Abstract
Fatty acid synthase (FASN), the main enzyme involved in de novo lipogenesis, is overexpressed in several types of tumor tissues. In addition, it is associated with tumor cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) and a poor prognosis. However, the precise functions and internal mechanisms of FASN with regard to the proliferation, metastasis and EMT in gastric cancer (GC) cells remain elusive. The present study investigated FASN protein expression in 18 randomly selected pairs of GC tumors and matched normal tissues by western blot analysis. FASN-specific small interfering RNA (siRNA) was then transfected into SGC-7901 cells to examine the effect of FASN on proliferation and migration in vitro. Western blotting was used to detect the protein expression of FASN, EMT-related markers and key signaling molecules of the mechanistic target of rapamycin/zinc finger protein GLI1 (mTOR/Gli1) pathway. Reverse transcription-quantitative polymerase chain reaction was conducted to detect the mRNA expression of FASN and EMT-related markers. The FASN level was higher in the GC tissues compared with that in the surrounding normal tissues. Knockdown of FASN suppressed GC cell proliferation and metastasis in vitro. The silencing of FASN expression using siRNA reversed EMT at the protein and mRNA levels and decreased the expression of Gli1 via regulation of AMP-activated protein kinase/mTOR and protein kinase B/mTOR signaling in GC cells. Inhibition of FASN suppresses GC proliferation and metastasis through targeting of the mTOR/Gli1 signaling pathway, indicating that it may serve as a potential target for the treatment of GC.
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Affiliation(s)
- Liang Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yizhou Yao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Guofeng Pan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Shenghua Zhan
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Weiqiang Shi
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ting Lu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jinfeng Yuan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Kangjun Tian
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Linhua Jiang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Shiduo Song
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xinguo Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Songbing He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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16
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Abstract
Ever since its initial discovery in Drosophila, hedgehog signaling has been linked to foregut development, The mammalian genome expresses three Hedgehog paralogues, sonic hedgehog (Shh), Indian Hedgehog, and desert hedgehog. In the mucosa of the embryonic and adult foregut, Shh expression is the highest. It has now become clear that hedgehog signaling is of pivotal importance in gastric homeostasis. Aberrant activation of hedgehog signaling is associated with a range of pathological consequences including various cancers. Also in gastric cancer, clinical and preclinical data support a role of Hedgehog signaling in neoplastic transformation, and gastrointestinal cancer development, also through cancer stroma interaction. Technological advance are facilitating monitoring Hedgehog signaling broadening options for the more efficient screening of individuals predisposed to eventually developing gastric cancer and targeting Hedgehog signaling may provide opportunities for prophylactic therapy once atrophic gastritis develops. Nevertheless, convincing evidence that Hedgehog antagonists are of clinically useful in the context of gastric cancer is still conspicuously lacking. Here we analyze review the role of Hedgehog in gastric physiology and the potential usefulness of targeting Hedgehog signaling in gastric cancer.
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Affiliation(s)
- Adamu Ishaku Akyala
- Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University, Rotterdam, Rotterdam, The Netherlands.,Department of Microbiology, Faculty of Natural and Applied Sciences Nasarawa State University, Keffi, Nasarawa, Nigeria
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University, Rotterdam, Rotterdam, The Netherlands
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17
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Wiegering A, Rüther U, Gerhardt C. The Role of Hedgehog Signalling in the Formation of the Ventricular Septum. J Dev Biol 2017; 5:E17. [PMID: 29615572 PMCID: PMC5831794 DOI: 10.3390/jdb5040017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/08/2017] [Accepted: 12/09/2017] [Indexed: 12/11/2022] Open
Abstract
An incomplete septation of the ventricles in the vertebrate heart that disturbes the strict separation between the contents of the two ventricles is termed a ventricular septal defect (VSD). Together with bicuspid aortic valves, it is the most frequent congenital heart disease in humans. Until now, life-threatening VSDs are usually treated surgically. To avoid surgery and to develop an alternative therapy (e.g., a small molecule therapy), it is necessary to understand the molecular mechanisms underlying ventricular septum (VS) development. Consequently, various studies focus on the investigation of signalling pathways, which play essential roles in the formation of the VS. In the past decade, several reports found evidence for an involvement of Hedgehog (HH) signalling in VS development. In this review article, we will summarise the current knowledge about the association between HH signalling and VS formation and discuss the use of such knowledge to design treatment strategies against the development of VSDs.
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Affiliation(s)
- Antonia Wiegering
- Institute for Animal Developmental and Molecular Biology, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
| | - Ulrich Rüther
- Institute for Animal Developmental and Molecular Biology, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
| | - Christoph Gerhardt
- Institute for Animal Developmental and Molecular Biology, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
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18
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Pandey MK, Gupta SC, Nabavizadeh A, Aggarwal BB. Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin Cancer Biol 2017; 46:158-181. [PMID: 28823533 DOI: 10.1016/j.semcancer.2017.07.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/05/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022]
Abstract
Although it is widely accepted that better food habits do play important role in cancer prevention and treatment, how dietary agents mediate their effects remains poorly understood. More than thousand different polyphenols have been identified from dietary plants. In this review, we discuss the underlying mechanism by which dietary agents can modulate a variety of cell-signaling pathways linked to cancer, including transcription factors, nuclear factor κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein-1 (AP-1), β-catenin/Wnt, peroxisome proliferator activator receptor- gamma (PPAR-γ), Sonic Hedgehog, and nuclear factor erythroid 2 (Nrf2); growth factors receptors (EGFR, VEGFR, IGF1-R); protein Kinases (Ras/Raf, mTOR, PI3K, Bcr-abl and AMPK); and pro-inflammatory mediators (TNF-α, interleukins, COX-2, 5-LOX). In addition, modulation of proteasome and epigenetic changes by the dietary agents also play a major role in their ability to control cancer. Both in vitro and animal based studies support the role of dietary agents in cancer. The efficacy of dietary agents by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against different kinds of cancer. Overall both in vitro and in vivo studies performed with dietary agents strongly support their role in cancer prevention. Thus, the famous quote "Let food be thy medicine and medicine be thy food" made by Hippocrates 25 centuries ago still holds good.
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Affiliation(s)
- Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
| | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ali Nabavizadeh
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
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19
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Shao J, Xu L, Chen L, Lu Q, Xie X, Shi W, Xiong H, Shi C, Huang X, Mei J, Rao H, Lu H, Lu N, Luo S. Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway. Cancer Res 2017; 77:4000-4013. [PMID: 28611043 PMCID: PMC5540784 DOI: 10.1158/0008-5472.can-16-2461] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 03/21/2017] [Accepted: 06/05/2017] [Indexed: 12/23/2022]
Abstract
Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking, and localization, which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration, and invasion in vitro and in vivo In clinical specimens of gastric cancer, Arl13b expression correlated strongly with tumor size and depth of invasion; patients with high levels of Arl13b had a poor prognosis. Our results show how Arl13b participates in Hh pathway activation in gastric cancer. Cancer Res; 77(15); 4000-13. ©2017 AACR.
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Affiliation(s)
- Jia Shao
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Linlin Xu
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Limin Chen
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Quqin Lu
- Department of Epidemiology & Biostatistics, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Xinsheng Xie
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Shi
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huanting Xiong
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chao Shi
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xuan Huang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jinhong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hai Rao
- Department of Molecular Medicine, University of Texas Health, San Antonio, Texas
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana
| | - Nonghua Lu
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shiwen Luo
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
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20
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Tajima Y, Murakami T, Saito T, Hiromoto T, Akazawa Y, Sasahara N, Mitomi H, Yao T, Watanabe S. Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma. Digestion 2017; 96:81-91. [PMID: 28738329 DOI: 10.1159/000478999] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 06/26/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. METHODS We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). RESULTS GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. CONCLUSION GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.
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Affiliation(s)
- Yuzuru Tajima
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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21
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Lee DH, Lee SY, Oh SC. Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. Tumour Biol 2017. [DOI: 10.1177/1010428317692266] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Dae-Hee Lee
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Suk-young Lee
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Sang Cheul Oh
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
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22
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Wessler S, Krisch LM, Elmer DP, Aberger F. From inflammation to gastric cancer - the importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun Signal 2017; 15:15. [PMID: 28427431 PMCID: PMC5397778 DOI: 10.1186/s12964-017-0171-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/07/2017] [Indexed: 02/07/2023] Open
Abstract
Infections with the human pathogen Helicobacter pylori (H. pylori) are closely associated with the development of inflammatory disorders and neoplastic transformation of the gastric epithelium. Drastic changes in the micromilieu involve a complex network of H. pylori-regulated signal transduction pathways leading to the release of proinflammatory cytokines, gut hormones and a wide range of signaling molecules. Besides controlling embryonic development, the Hedgehog/GLI signaling pathway also plays important roles in epithelial proliferation, differentiation, and regeneration of the gastric physiology, but also in the induction and progression of inflammation and neoplastic transformation in H. pylori infections. Here, we summarize recent findings of H. pylori-associated Hedgehog/GLI signaling in gastric homeostasis, malignant development and the modulation of the gastric tumor microenvironment.
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Affiliation(s)
- Silja Wessler
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria.
| | - Linda M Krisch
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria
| | - Dominik P Elmer
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria
| | - Fritz Aberger
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria.
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23
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Hu Q, Hou YC, Huang J, Fang JY, Xiong H. Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:50. [PMID: 28399898 PMCID: PMC5387201 DOI: 10.1186/s13046-017-0526-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 04/05/2017] [Indexed: 01/22/2023]
Abstract
BACKGROUND Itraconazole has been proved therapeutically effective against a variety of human cancers. This study assessed the effect of itraconazole on the Hedgehog (Hh) pathway and proliferation of human gastric cancer cells. METHODS CCK-8 assay and colony formation assay were used to assess the effects of itraconazole on proliferation of gastric cancer cells. The expression of Hh signaling components in gastric cancer cells treated with itraconazole was evaluated by reverse-transcription polymerase chain reaction, immunoblotting and dual luciferase assay. Tumor xenograft models were used to assess the inhibitory effect of itraconazole on the proliferation of gastric cancer cells in vivo. RESULTS Itraconazole could remarkably inhibit the proliferation of gastric cancer cells. When in combination with 5-FU, itraconazole significantly reduced the proliferation rate of cancer cells. Furthermore, itraconazole could regulate the G1-S transition and induce apoptosis of gastric cancer cells. Hh signaling was abnormally activated in human gastric cancer samples. In vitro, studies showed that the expression of glioma-associated zinc finger transcription factor 1 (Gli1) was decreased at both transcriptional and translational levels after treatment with itraconazole. Dual luciferase assay also indicated that itraconazole could inhibit the transcription of Gli1. In vivo studies demonstrated that monotherapy with itraconazole by oral administration could inhibit the growth of xenografts, and that itraconazole could significantly enhance the antitumor efficacy of the chemotherapeutic agent 5-FU. CONCLUSIONS Hh signaling is activated in gastric tumor and itraconazole can inhibit the growth of gastric cancer cells by inhibiting Gli1 expression.
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Affiliation(s)
- Qiang Hu
- Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yi-Chao Hou
- Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jiao Huang
- Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Hua Xiong
- Division of Gastroenterology and Hepatology; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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24
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Merchant JL, Ding L. Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 2017; 3:201-210. [PMID: 28275687 PMCID: PMC5331830 DOI: 10.1016/j.jcmgh.2017.01.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 12/24/2022]
Abstract
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation. SHH is highly expressed in parietal cells and is required for these cells to produce gastric acid. Furthermore, myofibroblasts are the predominant cell type responding to HH ligand in the uninfected stomach. Chronic infection caused by Helicobacter pylori and associated inflammation induces parietal cell atrophy and the expansion of metaplastic cell types, a precursor to gastric cancer in human subjects. During Helicobacter infection in mice, canonical HH signaling is required for inflammatory cells to be recruited from the bone marrow to the stomach and for metaplastic development. Specifically, polarization of the invading myeloid cells to myeloid-derived suppressor cells requires the HH-regulated transcription factor GLI1, thereby creating a microenvironment favoring wound healing and neoplastic transformation. In mice, GLI1 mediates the phenotypic shift to gastric myeloid-derived suppressor cells by directly inducing Schlafen 4 (slfn4). However, the human homologs of SLFN4, designated SLFN5 and SLFN12L, also correlate with intestinal metaplasia and could be used as biomarkers to predict the subset of individuals who might progress to gastric cancer and benefit from treatment with HH antagonists.
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Key Words
- ATPase, adenosine triphosphatase
- DAMP, damage-associated molecular pattern
- DAMPs
- GLI, glioma-associated protein
- GLI1
- Gr-MDSC, granulocytic myeloid-derived suppressor cell
- HH, hedgehog
- HHIP, hedgehog-interacting protein
- IFN, interferon
- IL, interleukin
- MDSC, myeloid-derived suppressor cell
- MDSCs
- Metaplasia
- Mo-MDSC, monocytic myeloid-derived suppressor cell
- PTCH, Patched
- SHH
- SHH, sonic hedgehog
- SLFN4, Schlafen 4
- SMO, Smoothened
- SP, spasmolytic polypeptide
- SPEM
- SPEM, spasmolytic polypeptide–expressing mucosa
- SST, somatostatin
- TLR, Toll-like receptor
- mRNA, messenger RNA
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Affiliation(s)
- Juanita L. Merchant
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan,Correspondence Address correspondence to: Juanita L. Merchant, MD, PhD, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. fax: (734) 763-4686.University of Michigan109 Zina Pitcher PlaceAnn ArborMichigan 48109-2200
| | - Lin Ding
- Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan
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25
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Chong Y, Tang D, Gao J, Jiang X, Xu C, Xiong Q, Huang Y, Wang J, Zhou H, Shi Y, Wang D. Galectin-1 induces invasion and the epithelial-mesenchymal transition in human gastric cancer cells via non-canonical activation of the hedgehog signaling pathway. Oncotarget 2016; 7:83611-83626. [PMID: 27835885 PMCID: PMC5347792 DOI: 10.18632/oncotarget.13201] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 10/21/2016] [Indexed: 02/07/2023] Open
Abstract
Galectin-1 (Gal-1) has been reported to be an independent prognostic indicator of poor survival in gastric cancer and overexpression of Gal-1 enhances the invasiveness of gastric cancer cells. However, the downstream mechanisms by which Gal-1 promotes invasion remains unclear. Moreover, the function of Gal-1 in the epithelial-mesenchymal transition (EMT) in gastric cancer has not yet been elucidated. In this study, we observed Gal-1 expression was upregulated and positively associated with metastasis and EMT markers in 162 human gastric cancer tissue specimens. In vitro studies showed Gal-1 induced invasion, the EMT phenotype and activated the non-canonical hedgehog (Hh) pathway in gastric cancer cell lines. Furthermore, our data revealed that Gal-1 modulated the non-canonical Hh pathway by increasing the transcription of glioma-associated oncogene-1 (Gli-1) via a Smoothened (SMO)-independent manner, and that upregulation of Gal-1 was strongly associated with gastric cancer metastasis. We conclude that Gal-1 promotes invasion and the EMT in gastric cancer cells via activation of the non-canonical Hh pathway, suggesting Gal-1 could represent a promising therapeutic target for the prevention and treatment of gastric cancer metastasis.
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Affiliation(s)
- Yang Chong
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Dong Tang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Jun Gao
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Xuetong Jiang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Chuanqi Xu
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Qingquan Xiong
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Yuqin Huang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Jie Wang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Huaicheng Zhou
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Youquan Shi
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Daorong Wang
- Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou 225001, China
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26
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Konstantinou D, Bertaux-Skeirik N, Zavros Y. Hedgehog signaling in the stomach. Curr Opin Pharmacol 2016; 31:76-82. [PMID: 27750091 PMCID: PMC5154826 DOI: 10.1016/j.coph.2016.09.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023]
Abstract
The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection. Dysregulation of the Shh signaling pathway leads to the disruption of gastric differentiation, loss of gastric acid secretion and the development of cancer. In this chapter, we will review the most recent findings that reveal the role of Shh as a regulator of gastric physiology, regeneration, and disease.
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Affiliation(s)
- Daniel Konstantinou
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
| | - Nina Bertaux-Skeirik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA.
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27
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Merker SR, Weitz J, Stange DE. Gastrointestinal organoids: How they gut it out. Dev Biol 2016; 420:239-250. [PMID: 27521455 DOI: 10.1016/j.ydbio.2016.08.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 07/09/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023]
Abstract
The gastrointestinal tract is characterized by a self-renewing epithelium fueled by adult stem cells residing at the bottom of the intestinal crypt and gastric glands. Their activity and proliferation is strongly dependent on complex signaling pathways involving other crypt/gland cells as well as surrounding stromal cells. In recent years organoids are becoming increasingly popular as a new and powerful tool to study developmental or other biological processes. Organoids retain morphological and molecular patterns of the tissue they are derived from, are self-organizing, relatively simple to handle and accessible to genetic engineering. This review focuses on the developmental processes and signaling molecules involved in epithelial homeostasis and how a profound knowledge of these mechanisms allowed the establishment of a three dimensional organoid culture derived from adult gastrointestinal stem cells.
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Affiliation(s)
- Sebastian R Merker
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Daniel E Stange
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
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28
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Oue N, Mukai S, Imai T, Pham TTB, Oshima T, Sentani K, Sakamoto N, Yoshida K, Yasui W. Induction of KIFC1 expression in gastric cancer spheroids. Oncol Rep 2016; 36:349-55. [PMID: 27176706 DOI: 10.3892/or.2016.4781] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 01/22/2016] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer (GC) is one of the most common human cancers. Spheroid colony formation is an effective model for characterization of cancer stem cells. However, gene expression profiles of spheroid colonies obtained from GC cells have not been examined. We performed microarray analyses by Human Genome U133 Plus 2.0 Array in spheroid body-forming and parental cells from MKN-45 and MKN-74 GC cell lines. Kinesin family member C1 (KIFC1) was expressed >2-fold higher in spheroid body-forming cells than in parental cells in both GC lines. Both the number and size of spheres from MKN-45 cells were significantly reduced upon KIFC1 siRNA-transfection compared with negative control siRNA-transfection. Immunohistochemical analysis of 114 GC tissue samples revealed that 42 (37%) of GC cases were positive for KIFC1 expression. GC cases positive for KIFC1 were found more frequently in stage III/IV cases than in stage I/II cases. GC cases positive for KIFC1 were found more frequently in intestinal type GC cases than in diffuse type GC cases. Furthermore, KIFC1-positive GC cases showed high Ki-67 labeling index. Kaplan-Meier analysis demonstrated that KIFC1 expression was not associated with survival. We found positive expression of KIFC1 in CD44‑positive GC and aldehyde dehydrogenase 1 (ALDH1)-positive GC cells. Our results showed that KIFC1 is overexpressed in GC. Since knockdown of KIFC1 inhibited sphere formation, KIFC1 likely plays an important role in cancer stem cells.
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Affiliation(s)
- Naohide Oue
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Shoichiro Mukai
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Takeharu Imai
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Trang T B Pham
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Takashi Oshima
- Department of Surgery, Yokohama City University, Yokohama 236-0004, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu 501‑1194, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
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29
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Yoon JH, Choi SS, Kim O, Choi WS, Park YK, Nam SW, Lee JY, Park WS. Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation. Mod Pathol 2016; 29:194-208. [PMID: 26743476 DOI: 10.1038/modpathol.2015.150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023]
Abstract
Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS(NKX6.3) and MKN1(NKX6.3) cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6.3 inactivation may result in intestinal metaplasia in gastric epithelial cells.
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MESH Headings
- Animals
- Antigens, Bacterial/genetics
- Antigens, Bacterial/metabolism
- Area Under Curve
- Bacterial Proteins/genetics
- Bacterial Proteins/metabolism
- Binding Sites
- Bone Morphogenetic Protein 4/genetics
- Bone Morphogenetic Protein 4/metabolism
- CDX2 Transcription Factor
- Cell Line, Tumor
- Cell Transdifferentiation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Disease Models, Animal
- Female
- Gastric Mucosa/metabolism
- Gastric Mucosa/microbiology
- Gastric Mucosa/pathology
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Genetic Predisposition to Disease
- Helicobacter Infections/genetics
- Helicobacter Infections/metabolism
- Helicobacter Infections/pathology
- Helicobacter pylori/genetics
- Helicobacter pylori/metabolism
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Metaplasia
- Mice, Inbred C57BL
- Phenotype
- Precancerous Conditions/genetics
- Precancerous Conditions/metabolism
- Precancerous Conditions/microbiology
- Precancerous Conditions/pathology
- Promoter Regions, Genetic
- Proteins/genetics
- Proteins/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- ROC Curve
- Risk Assessment
- Risk Factors
- SOXB1 Transcription Factors/genetics
- SOXB1 Transcription Factors/metabolism
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/microbiology
- Stomach Neoplasms/pathology
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Transfection
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Affiliation(s)
- Jung H Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sung S Choi
- College of Pharmacy, Sahmyook University, Seoul, South Korea
| | - Olga Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Won S Choi
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yong K Park
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Suk W Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jung Y Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Won S Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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30
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Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:441-78. [PMID: 27573785 DOI: 10.1007/978-3-319-41388-4_22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.
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31
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FU YINGZI, YAN YUANYUAN, HE MIAO, XIAO QINGHUAN, YAO WEIFAN, ZHAO LIN, WU HUIZHE, YU ZHAOJIN, ZHOU MINGYI, LV MUTIAN, ZHANG SHANSHAN, CHEN JIANJUN, WEI MINJIE. Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway. Oncol Rep 2015; 35:912-22. [DOI: 10.3892/or.2015.4434] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 09/26/2015] [Indexed: 11/06/2022] Open
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32
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Fujita T, Chiwaki F, Takahashi RU, Aoyagi K, Yanagihara K, Nishimura T, Tamaoki M, Komatsu M, Komatsuzaki R, Matsusaki K, Ichikawa H, Sakamoto H, Yamada Y, Fukagawa T, Katai H, Konno H, Ochiya T, Yoshida T, Sasaki H. Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells. PLoS One 2015; 10:e0130808. [PMID: 26110809 PMCID: PMC4481351 DOI: 10.1371/journal.pone.0130808] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 05/25/2015] [Indexed: 12/18/2022] Open
Abstract
Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.
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Affiliation(s)
- Takeshi Fujita
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
- Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Fumiko Chiwaki
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Ryou-u Takahashi
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuhiko Aoyagi
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuyoshi Yanagihara
- Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Takao Nishimura
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Masashi Tamaoki
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Masayuki Komatsu
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Rie Komatsuzaki
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Hitoshi Ichikawa
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiromi Sakamoto
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasuhide Yamada
- Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takeo Fukagawa
- Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hitoshi Katai
- Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroyuki Konno
- Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroki Sasaki
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan
- * E-mail:
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33
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Gu H, Li XU, Zhou C, Wen Y, Shen Y, Zhou L, Li J. Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells. Oncol Lett 2015; 9:1997-2002. [PMID: 26137001 DOI: 10.3892/ol.2015.3032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 12/09/2014] [Indexed: 11/05/2022] Open
Abstract
Excessive activation of the hedgehog (Hh) signaling pathway is important in a variety of human cancer cell types, including gastric cancer. However, the underlying mechanisms of the Hh signaling pathway in inducing gastric tumorigenesis and its downstream target genes are largely unknown. In the present study, the inhibitory effect of cyclopamine on the Hh signaling pathway was investigated in the human gastric cancer AGS cell line. It was identified that cyclopamine treatment inhibited the proliferation, migration and invasion of the AGS cells in a dose- and time-dependent manner, and resulted in the downregulation of a number of key Hh signaling pathway-associated factors [glioma-associated oncogene homolog 1, C-X-C chemokine receptor type 4 and transforming growth factor (TGF)-β1] at the RNA and protein levels. Furthermore, the secretion of TGF-β1 was significantly reduced following the administration of cyclopamine to the AGS cells. The results of the present study provided insight into the mechanisms by which the Hh signaling pathway regulates gastric cancer formation and identified the Hh signaling pathway as a potential novel therapeutic target in human gastric cancer.
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Affiliation(s)
- Hongbing Gu
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - X U Li
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Congzhi Zhou
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Yugang Wen
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Yang Shen
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Lisheng Zhou
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Jikun Li
- Department of Surgery, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, P.R. China
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34
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Abdel-Rahman O. Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials. Tumour Biol 2015; 36:1367-74. [PMID: 25680409 DOI: 10.1007/s13277-015-3216-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 02/03/2015] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is an important cause for mortality and morbidity worldwide; it lies in the fourt rank as a cause of cancer-related death in males and in the fifth rank of cancer-related death in women. The prognosis of advanced/metastatic gastric cancer cases looks poor with the majority of available therapeutics. Thus, novel therapeutic strategies in this setting have been considered a priority for leading cooperative oncology groups. Hedgehog(Hh) pathway aberrations have sparked particular interest as prognostic markers with data from multiple studies showing consistent evidence of a poor prognostic value of Gli over expression in gastric cancer while on the other hand the prognostic significance of Hh protein over expression (particularly SHH) was not consistent among different studies. This review article revises the prognostic and potential therapeutic opportunities in the targeting of hedgehog pathway in gastric cancer.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain shams University, Cairo, Egypt,
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35
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Elaboration of tubules with active hedgehog drives parenchymal fibrogenesis in gestational alloimmune liver disease. Hum Pathol 2015; 46:84-93. [DOI: 10.1016/j.humpath.2014.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/17/2014] [Accepted: 09/19/2014] [Indexed: 12/28/2022]
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36
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Won KY, Kim GY, Lim SJ, Sung JY, Kim YW, Park YK, Lee J, Choi HS. Autophagy is related to the hedgehog signaling pathway in human gastric adenocarcinoma: prognostic significance of Beclin-1 and Gli2 expression in human gastric adenocarcinoma. Pathol Res Pract 2014; 211:308-15. [PMID: 25512258 DOI: 10.1016/j.prp.2014.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 10/14/2014] [Accepted: 11/07/2014] [Indexed: 12/21/2022]
Abstract
Beclin-1 induces autophagy, which is known to be involved in many physiopathological processes such as cell development, aging, stress response, immune response and cancer. Several studies showed that Beclin-1 expression is associated with several prognostic factors of gastric carcinomas. Recently, the connection between autophagy and the hedgehog (HH) signaling pathway has been studied. Here, we investigated the relationship between the autophagy and hedgehog (HH) signaling pathways in gastric adenocarcinoma. We evaluated Beclin-1 and Gli2 expression in 108 gastric adenocarcinoma tissues via immunohistochemical analysis, using a tissue microarray, in relation to survival and other prognostic factors. Our results show that increased Beclin-1 expression is correlated with favorable clinicopathological variables including histologic grade, tumor size, primary tumor (T) stage, lymph node metastasis, lymphatic invasion, neural invasion, and tumor recurrence. Furthermore, increased Gli-2 expression was correlated with several favorable clinicopathological variables including primary tumor (T) stage, lymphatic invasion, and tumor recurrence. Increased Beclin-1 expression was significantly correlated with increased Gli2. Univariate analyses for disease-free survival and overall survival revealed that the higher Beclin-1 and Gli2 expression group had a more favorable prognosis compared with the lower Beclin-1 and Gli2 expression group. Our results suggest that progressively increased Beclin-1 and Gli2 expression contributes to the inhibition of tumor growth and metastasis in gastric adenocarcinoma and Beclin-1 acts as a tumor suppressor by regulating the HH signaling pathway through Gli2 expression in gastric adenocarcinoma.
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Affiliation(s)
- Kyu Yeoun Won
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Republic of Korea
| | - Gou Young Kim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Republic of Korea.
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Republic of Korea
| | - Ji-Youn Sung
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Youn Wha Kim
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Yong-Koo Park
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Juhie Lee
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Hee Seung Choi
- Department of Pathology, Graduate School of Medicine, Kyung Hee University, Seoul, Republic of Korea
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Feng R, Aihara E, Kenny S, Yang L, Li J, Varro A, Montrose MH, Shroyer NF, Wang TC, Shivdasani RA, Zavros Y. Indian Hedgehog mediates gastrin-induced proliferation in stomach of adult mice. Gastroenterology 2014; 147:655-666.e9. [PMID: 24859162 PMCID: PMC4211430 DOI: 10.1053/j.gastro.2014.05.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Revised: 05/05/2014] [Accepted: 05/07/2014] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS Loss of expression of Sonic Hedgehog (Shh) from parietal cells results in hypergastrinemia in mice, accompanied by increased expression of Indian Hedgehog (Ihh) and hyperproliferation of surface mucous cells. We investigated whether hypergastrinemia induces gastric epithelial proliferation by activating Ihh signaling in mice. METHODS We studied mice with parietal cell-specific deletion of Shh (PC-Shh(KO)) and hypergastrinemia, crossed with gastrin-deficient (GKO) mice (PC-Shh(KO)/GKO). When mice were 3-4 months old, gastric tissues were collected and analyzed by histology, for incorporation of bromodeoxyuridine, and for expression of the surface mucous cell marker Ulex europaeus. PC-Shh(KO)/GKO mice were given gastrin infusions for 7 days; gastric surface epithelium was collected and expression of Ihh was quantified by laser capture microdissection followed by quantitative reverse transcriptase polymerase chain reaction. Mouse stomach-derived organoids were incubated with or without inhibitors of WNT (DKK1) or Smoothened (vismodegib) and then cocultured with immortalized stomach mesenchymal cells, to assess proliferative responses to gastrin. RESULTS Gastric tissues from PC-Shh(KO)/GKO mice with hypergastrinemia had an expanded surface pit epithelium, indicated by a significant increase in numbers of bromodeoxyuridine- and Ulex europaeus-positive cells, but there was no evidence for hyperproliferation. Gastrin infusion of PC PC-Shh(KO)/GKO mice increased expression of Ihh and proliferation within the surface epithelium compared with mice given infusions of saline. In gastric organoids cocultured with immortalized stomach mesenchymal cells, antagonists of WNT and Smoothened inhibited gastrin-induced proliferation and WNT activity. Activity of WNT in media collected from immortalized stomach mesenchymal cells correlated with increased expression of glioma-associated oncogene homolog 1, and was inhibited by DKK1 or vismodegib. CONCLUSIONS Ihh signaling mediates gastrin-induced proliferation of epithelial cells in stomachs of adult mice.
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Affiliation(s)
- Rui Feng
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, USA
| | - Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, USA
| | - Susan Kenny
- The Physiological Laboratory, School of Biomedical Sciences, Crown Street, University of Liverpool, Liverpool, UK
| | - Li Yang
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, USA
| | - Jing Li
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, USA
| | - Andrea Varro
- The Physiological Laboratory, School of Biomedical Sciences, Crown Street, University of Liverpool, Liverpool, UK
| | - Marshall H. Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, USA
| | - Noah F. Shroyer
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, USA
| | - Timothy C. Wang
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, NY, USA
| | - Ramesh A. Shivdasani
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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Ishimoto T, Sawayama H, Sugihara H, Baba H. Interaction between gastric cancer stem cells and the tumor microenvironment. J Gastroenterol 2014; 49:1111-20. [PMID: 24652101 DOI: 10.1007/s00535-014-0952-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/05/2014] [Indexed: 02/04/2023]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are selectively capable of tumor initiation and are implicated in tumor relapse and metastasis, thus, governing the prognosis of GC patients. Stromal cells and extracellular matrix adjacent to cancer cells are known to form a supportive environment for cancer progression. CSC properties are also regulated by their microenvironment through cell signaling and related factors. This review presents the current findings regarding the influence of the tumor microenvironment on GC stem cells, which will support the development of novel therapeutic strategies for patients with GC.
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Affiliation(s)
- Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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Tanabe S, Aoyagi K, Yokozaki H, Sasaki H. Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition. Int J Oncol 2014; 44:1955-1970. [PMID: 24728500 DOI: 10.3892/ijo.2014.2387] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/28/2014] [Indexed: 02/07/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is associated with tumor malignancy. The hedgehog-EMT pathway is preferentially activated in diffuse-type gastric cancer (GC) compared with intestinal-type GC; however, histological typing is currently the only method for distinguishing these two major types of GC. We compared the gene expression profiles of 12 bone marrow-derived mesenchymal stem cell cultures and 5 diffuse-type GC tissue samples. Numerous upregulated or downregulated genes were identified in diffuse-type GC, including CDH1, CDH2, VIM, WNT4 and WNT5. Among these genes, the mRNA ratio of CDH2 to CDH1 could distinguish the 15 diffuse-type GC samples from the 17 intestinal-type GC samples. Our results suggested that the mesenchymal features were more prominent in diffuse-type GC than in intestinal-type GC, but were weaker in diffuse-type GC than in mesenchymal stem cells. Diffuse-type GC that has undergone extensive EMT, which has a poor prognosis, can be identified by quantitative PCR analysis of only two genes.
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Affiliation(s)
- Shihori Tanabe
- Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan
| | - Kazuhiko Aoyagi
- Department of Translational Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
| | - Hiroshi Yokozaki
- Department of Pathology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan
| | - Hiroki Sasaki
- Department of Translational Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
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40
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Popa EC, Shah MA. Met, IGF1R, and other new targets in upper GI malignancies. Curr Treat Options Oncol 2014; 14:321-36. [PMID: 23873272 DOI: 10.1007/s11864-013-0245-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OPINION STATEMENT Upper gastrointestinal (GI) malignancies comprise some of the most aggressive human cancers. Expanding knowledge of molecular mechanisms is finally translating into clinical application, and this has occurred at a relatively rapid rate in the past several years. However, despite recent advances in targeted therapies in upper GI cancers our overall success with targeted therapeutics in this disease area remains dismal. This statement is particularly troubling given some sobering facts: upper GI malignancies are prevalent as well as aggressive with a high morbidity and mortality. Esophagus and gastric cancer combined have an annual global incidence of over 1.2 million new cases annually while median survival is less than 1 year for most patients with metastatic disease. Progress has been limited due to several factors including: disease heterogeneity and variance of phenotype across the globe, clinical trial design strategies that have not yet incorporated selective mechanisms to afford individualized matching of drug to tumor molecular profile and last, a lack of validated predictive markers. Nevertheless there is evidence that many targeted agents can be administered safely at doses that achieve the required effect at the protein level. Several drugs that have negative early trial results can be potentially vital therapeutic agents if patient selection is appropriate.
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Affiliation(s)
- Elizabeta C Popa
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, 1305 York Avenue 12th floor, New York, NY, 10021, USA,
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41
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Bai R, Zhao H, Zhang X, DU S. Characterization of sonic hedgehog inhibition in gastric carcinoma cells. Oncol Lett 2014; 7:1381-1384. [PMID: 24765141 PMCID: PMC3997708 DOI: 10.3892/ol.2014.1964] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 01/23/2014] [Indexed: 01/06/2023] Open
Abstract
Aberrant activation of the sonic hedgehog (Shh) signaling pathway plays an important role in gastric cancer. The exact mechanisms defining how the Shh pathway promotes tumorigenesis or regulates its downstream targets remains elusive. In the present study, the effects of inhibiting the Shh signaling pathway in gastric cancer AGS cells was examined. It was identified that the Shh antagonist, cyclopamine, inhibited cancer proliferation, migration and invasion in a dose- and time-dependent manner. Additionally, it was revealed that several key targets that are activated by the Shh signaling pathway, Gli1 and CXCR4, were downregulated at an RNA and protein level by cyclopamine. The results from the present study may be of benefit in facilitating the development of novel therapeutic strategies to treat gastric cancer in human patients.
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Affiliation(s)
- Ruxue Bai
- Department of Gastroenterology, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Hongchuan Zhao
- Department of Gastroenterology, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Xiang Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shiyu DU
- Department of Gastroenterology, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
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Stojnev S, Krstic M, Ristic-Petrovic A, Stefanovic V, Hattori T. Gastric cancer stem cells: therapeutic targets. Gastric Cancer 2014; 17:13-25. [PMID: 23563919 DOI: 10.1007/s10120-013-0254-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 03/15/2013] [Indexed: 02/07/2023]
Abstract
During the past decade, a growing body of evidence has implied that cancer stem cells (CSCs) play an important role in the development of gastric cancer (GC). The notion that CSCs give rise to GC and may be responsible for invasion, metastasis, and resistance to treatment has profound implications for anti-cancer therapy. Recent major advances in the rapidly evolving field of CSCs have opened novel exciting opportunities for developing CSC-targeted therapies. Discovery of specific markers and signaling pathways in gastric CSCs (GCSCs), with the perfecting of technologies for identification, isolation, and validation of CSCs, may provide the basis for a revolutionary cancer treatment approach based on the eradication of GCSCs. Emerging therapeutic tools based on specific properties and functions of CSCs, including activation of self-renewal signaling pathways, differences in gene expression profiles, and increased activity of telomerase or chemoresistance mechanisms, are developing in parallel with advances in nanotechnology and bioengineering. The addition of GCSC-targeted therapies to current oncological protocols and their complementary application may be the key to successfully fighting GC.
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Affiliation(s)
- Slavica Stojnev
- Faculty of Medicine, Institute of Pathology, University of Nis, Zorana Djindjica Blvd 81, 18000, Nis, Serbia,
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Abstract
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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Affiliation(s)
- Roopma Wadhwa
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, 77030
| | - Yixin Yao
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Qingyi Wei
- Department of Epidemiology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas, 77030
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
- Department of Epidemiology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas, 77030
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Ahmad A, Maitah MY, Ginnebaugh KR, Li Y, Bao B, Gadgeel SM, Sarkar FH. Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs. J Hematol Oncol 2013; 6:77. [PMID: 24199791 PMCID: PMC3852827 DOI: 10.1186/1756-8722-6-77] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 09/30/2013] [Indexed: 12/14/2022] Open
Abstract
Background Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells. Methods Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism. Results siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance. Conclusions We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients.
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Affiliation(s)
| | | | | | | | | | | | - Fazlul H Sarkar
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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45
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Abstract
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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46
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Yan R, Peng X, Yuan X, Huang D, Chen J, Lu Q, Lv N, Luo S. Suppression of growth and migration by blocking the Hedgehog signaling pathway in gastric cancer cells. Cell Oncol (Dordr) 2013; 36:421-35. [PMID: 24027019 DOI: 10.1007/s13402-013-0149-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2013] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Previous studies have indicated that Hedgehog signaling is essential for gastric cancer development, but its precise role is still unclear. The aim of this study was to clarify the role of Hedgehog signaling in gastric cancer development. METHODS The expression of key Hedgehog signaling components in clinical samples of sequential gastric cancer stages was assessed by immunohistochemistry. The roles and regulatory mechanisms of Hedgehog signaling in human gastric cancer cells and normal gastric epithelial cells were investigated using multiple cell biological approaches and cDNA microarray analyses. RESULTS Hedgehog signaling was found to be abnormally activated in a ligand-independent manner during gastric cancer development. Gli1 over-expression and reduced SuFu expression were found to be typical events in gastric cancer tissues. Gli1 over-expression was found to correlate with a poorly differentiated histology, advanced clinical stage, membrane serosa infiltration and lymph node metastasis in patients with gastric cancer. Data obtained from multiple cell biological assays showed that human gastric cancer cells require active Hedgehog signaling for survival, proliferation, migration and colony formation. N-Shh treatment significantly enhanced the migration, invasion and colony formation of gastric cancer cells. Moreover, the results of cDNA microarray analyses indicated that after treatment with cyclopamine or GANT61 (inhibitors of Hedgehog signaling), differentially expressed genes in gastric cancer cells were enriched in the apoptosis and MAPK pathways. Inhibitors of the Hedgehog pathway were found to suppress gastric cancer cell growth via apoptosis induction. CONCLUSIONS Our findings indicate a vital role of the activated Hedgehog signaling pathway in promoting gastric initiation and progression. The Hedgehog signaling pathway may serve as a target for gastric cancer therapy.
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Affiliation(s)
- Runwei Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No.17 Yongwai street, Donghu district, Nanchang, 330006, China
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Carneiro P, Figueiredo J, Bordeira-Carriço R, Fernandes MS, Carvalho J, Oliveira C, Seruca R. Therapeutic targets associated to E-cadherin dysfunction in gastric cancer. Expert Opin Ther Targets 2013; 17:1187-201. [PMID: 23957294 DOI: 10.1517/14728222.2013.827174] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Epithelial cadherin (E-cadherin) plays a key role in epithelial cell-cell adhesion, contributing to tissue differentiation and homeostasis. Throughout the past decades, research has shed light on the molecular mechanisms underlying E-cadherin's role in tumor progression, namely in invasion and metastization. Emerging evidence established E-cadherin as a tumor suppressor and suggests that targeting E-cadherin or downstream signaling molecules may constitute effective cancer therapeutics. AREAS COVERED This review aims to cover E-cadherin-mediated signaling during cancer development and progression and highlight putative therapeutic targets. EXPERT OPINION Reconstitution of E-cadherin expression or targeting of E-cadherin downstream molecules holds promise in cancer therapies. Considering the high frequency of CDH1 promoter hypermethylation as a second hit in malignant lesions from hereditary diffuse gastric cancer patients, histone deacetylase inhibitors are potential therapeutic agents in combination with conventional chemotherapy, specifically in initial tumor stages. Concerning E-cadherin-mediated signaling, we propose that HER receptors (as epidermal growth factor receptor) and Notch downstream targets are clinically relevant and should be considered in gastric cancer therapeutics and control.
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Affiliation(s)
- Patrícia Carneiro
- IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto , Rua Dr. Roberto Frias s/n, 4200-465 Porto , Portugal +00351 225570700 ; +00351 225570799 ;
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48
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Merchant JL, Saqui-Salces M. Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Cancer Treat Rev 2013; 40:12-21. [PMID: 24007940 DOI: 10.1016/j.ctrv.2013.08.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 08/02/2013] [Accepted: 08/06/2013] [Indexed: 02/08/2023]
Abstract
This review summarizes emerging information regarding the Hedgehog (Hh) signaling pathway during neoplastic transformation in the gastrointestinal tract. Although there is a role for the well-established canonical pathway in which Hedgehog ligands interact with their receptor Patched, there is sufficient evidence that downstream components of the Hh pathway, e.g., Gli1, are hijacked by non-Hh signaling pathways to promote the conversion of the epithelium to dysplasia and carcinoma. We review the canonical pathway and involvement of primary cilia, and then focus on current evidence for Hh signaling in luminal bowel cancers as well as accessory organs, i.e., liver, pancreas and biliary ducts. We conclude that targeting the Hh pathway with small molecules, nutriceuticals and other mechanisms will likely require a combination of inhibitors that target Gli transcription factors in addition to canonical modulators such as Smoothened.
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Affiliation(s)
- Juanita L Merchant
- Departments of Internal Medicine and Molecular and Integrative Physiology, Division of Gastroenterology, University of Michigan, United States.
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49
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Abstract
Gastric cancer (GC) remains one of the most common cancers worldwide. Its prevalence is still on the rise in the developing countries due to the ageing population. The cancer stem cell (CSC) theory provides a new insight into the interpretation of tumor initiation, aggressive growth, recurrence, and metastasis of cancer, as well as the development of new strategies for cancer treatment. This review will focus on the progress of biomarkers and signaling pathways of CSCs, the complex crosstalk networks between the microenvironment and CSCs, and the development of therapeutic approaches against CSCs, predominantly focusing on GC.
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50
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Uppal DS, Powell SM. Genetics/genomics/proteomics of gastric adenocarcinoma. Gastroenterol Clin North Am 2013; 42:241-60. [PMID: 23639639 DOI: 10.1016/j.gtc.2013.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hereditary diffuse gastric cancer can be caused by epithelial cadherin mutations for which genetic testing is available. Inherited cancer predisposition syndromes including Lynch, Li-Fraumeni, and Peutz-Jeghers syndromes, can be associated with gastric cancer. Chromosomal and microsatellite instability occur in gastric cancers. Several consistent genetic and molecular alterations including chromosomal instability, microsatellite instability, and epigenetic alterations have been identified in gastric cancers. Biomarkers and molecular profiles are being discovered with potential for diagnostic, prognostic, and treatment guidance implications.
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Affiliation(s)
- Dushant S Uppal
- Division of Gastroenterology/Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA 22908-0708, USA
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