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The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management. Int J Mol Sci 2020; 21:ijms21103494. [PMID: 32429087 PMCID: PMC7279011 DOI: 10.3390/ijms21103494] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.
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Zhuang K, Yan Y, Zhang X, Zhang J, Zhang L, Han K. Gastrin promotes the metastasis of gastric carcinoma through the β-catenin/TCF-4 pathway. Oncol Rep 2016; 36:1369-76. [PMID: 27430592 DOI: 10.3892/or.2016.4943] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 03/26/2016] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer is the most common epithelial malignancy and the second leading cause of cancer-related death worldwide; metastasis is a crucial factor in the progression of gastric cancer. The present study applied gastrin-17 amide (G-17) in SGC7901 cells. The results showed that G-17 promoted the cell cycle by accelerating the G0/G1 phase and by increasing the cell proliferation rate by binding to the gastrin receptor. The migratory and invasive abilities of the SGC7901 cells were increased by G-17. The expression levels of matrix metalloproteinase (MMP)-7, MMP-9 and vascular endothelial growth factor (VEGF) were enhanced by G-17 as well. Moreover, G-17 caused the overexpression of β-catenin and TCF-4. G-17 also caused a preferential cytoplasmic and nuclear localization of β-catenin with a high TOP-FLASH activity. Finally, axin reduced the migratory and invasive abilities of the SGC7901 cells, and inhibited the expression of β-catenin, TCF-4, MMP-7, MMP-9 and VEGF; these effects were counteracted by adding G-17. In summary, the present study confirmed the proliferation and metastasis-promoting role of G-17 via binding to the gastrin receptor, and the β-catenin/TCF-4 pathway was found to be essential for mediating G-17-induced metastasis in gastric cancer. These results may provide a novel gene target for the treatment of gastric cancer.
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Affiliation(s)
- Kun Zhuang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Yuan Yan
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Xin Zhang
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| | - Jun Zhang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Lingxia Zhang
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| | - Kun Han
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
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Beck IM, Drebert ZJ, Hoya-Arias R, Bahar AA, Devos M, Clarisse D, Desmet S, Bougarne N, Ruttens B, Gossye V, Denecker G, Lievens S, Bracke M, Tavernier J, Declercq W, Gevaert K, Vanden Berghe W, Haegeman G, De Bosscher K. Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. PLoS One 2013; 8:e69115. [PMID: 23935933 PMCID: PMC3728325 DOI: 10.1371/journal.pone.0069115] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 06/06/2013] [Indexed: 12/24/2022] Open
Abstract
Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA’s anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.
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Affiliation(s)
- Ilse M Beck
- Laboratory of Experimental Cancer Research (LECR), Department of Radiation Therapy & Experimental Cancer Research, Ghent University, Ghent, Belgium.
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Blocking gastrin and CCK-B autocrine loop affects cell proliferation and apoptosis in vitro. Mol Cell Biochem 2010; 343:133-41. [PMID: 20559691 DOI: 10.1007/s11010-010-0507-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Accepted: 06/02/2010] [Indexed: 01/15/2023]
Abstract
Gastrin and cholecystokinin-B receptor (CCK-B) were co-expressed in human gastric carcinoma tissues, suggesting that a functional autocrine loop, the gastrin and CCK-B receptor loop, may be presented in gastric cancer cells and play an important role in the pathogenesis and progression of gastric carcinomas. The present study was aimed at studying the effects of blocking the gastrin and CCK-B receptor loop on cell proliferation and apoptosis in gastric cancer cell line SGC-7901 cells (SGC-7901 cells). First, the expression of gastrin and CCK-B receptor mRNAs and gastrin protein in SGC-7901 cells were measured by RT-PCR and immunocytochemistry, respectively. Radioimmunoassay (RIA) was used to detect the concentrations of gastrin in culture medium. The gastrin-CCK-B receptor axis was blocked by using a specific neutralizing antibody against human gastrin and siRNA specifically targeting human CCK-B receptors, respectively. Flow cytometry was used to measure the cell cycle and apoptotic cells, and western blotting was used to measure the expression of CCK-B receptor, caspase-3, and matrix metalloproteinase-2 (MMP-2) in cells. The results showed that SGC-7901 cells not only coexpressed gastrin and CCK-B receptor mRNAs, but also endogenously secreted gastrin protein into the culture medium, thus forming gastrin-CCK-B receptor autocrine loop. Biologically, disrupting gastrin-CCK-B receptor autocrine loop by neutralizing the endogenous gastrin or by knocking down CCK-B receptor expression significantly inhibited the cell proliferation and decreased the percentage of cells residing in the S-phase of the cell cycle, and meanwhile promoted cell apoptosis and increased caspase-3 expression as well as decreased MMP-2 expression. An autocrine loop between endogenously secreted gastrin and CCK-B receptors may play a key role in the regulation of cell proliferation and apoptosis in SGC-7901 cells.
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Umar S, Sarkar S, Wang Y, Singh P. Functional cross-talk between beta-catenin and NFkappaB signaling pathways in colonic crypts of mice in response to progastrin. J Biol Chem 2009; 284:22274-22284. [PMID: 19497850 DOI: 10.1074/jbc.m109.020941] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We recently reported a critical role of NFkappaB in mediating hyperproliferative and anti-apoptotic effects of progastrin on proximal colonic crypts of transgenic mice overexpressing progastrin (Fabp-PG mice). We now report activation of beta-catenin in colonic crypts of mice in response to chronic (Fabp-PG mice) and acute (wild type FVB/N mice) progastrin stimulation. Significant increases were measured in relative levels of cellular and nuclear beta-catenin and pbeta-cat45 in proximal colonic crypts of Fabp-PG mice compared with that in wild type littermates. Distal colonic crypts were less responsive. Interestingly, beta-catenin activation was downstream of IKKalpha,beta/NFkappaB, because treatment of Fabp-PG mice with the NFkappaB essential modulator (NEMO) peptide (inhibitor of IKKalpha,beta/NFkappaB activation) significantly blocked increases in cellular/nuclear levels of total beta-catenin/pbeta-cat45/and pbeta-cat552 in proximal colons. Cellular levels of pbeta-cat33,37,41, however, increased in proximal colons in response to NEMO, probably because of a significant increase in pGSK-3betaTyr216, facilitating degradation of beta-catenin. NEMO peptide significantly blocked increases in cyclin D1 expression, thereby, abrogating hyperplasia of proximal crypts. Goblet cell hyperplasia in colonic crypts of Fabp-PG mice was abrogated by NEMO treatment, suggesting a cross-talk between the NFkappaB/beta-catenin and Notch pathways. Cellular proliferation and crypt lengths increased significantly in proximal but not distal crypts of FVB/N mice injected with 1 nM progastrin associated with a significant increase in cellular/nuclear levels of total beta-catenin and cyclin D1. Thus, intracellular signals, activated in response to acute and chronic stimulation with progastrin, were similar and specific to proximal colons. Our studies suggest a novel possibility that activation of beta-catenin, downstream to the IKKalpha,beta/NFkappaB pathway, may be integral to the hyperproliferative effects of progastrin on proximal colonic crypts.
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Affiliation(s)
- Shahid Umar
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104; Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555
| | - Shubhashish Sarkar
- the Departments of Neuroscience and Cell Biology, Galveston, Texas 77555
| | - Yu Wang
- the Departments of Neuroscience and Cell Biology, Galveston, Texas 77555
| | - Pomila Singh
- the Departments of Neuroscience and Cell Biology, Galveston, Texas 77555
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He H, Shulkes A, Baldwin GS. PAK1 interacts with β-catenin and is required for the regulation of the β-catenin signalling pathway by gastrins. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2008; 1783:1943-54. [DOI: 10.1016/j.bbamcr.2008.04.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2008] [Revised: 04/22/2008] [Accepted: 04/23/2008] [Indexed: 10/22/2022]
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He H, Baldwin GS. Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins. Int J Biochem Cell Biol 2008; 40:2018-22. [PMID: 18565785 DOI: 10.1016/j.biocel.2008.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Revised: 05/01/2008] [Accepted: 05/02/2008] [Indexed: 10/22/2022]
Abstract
Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), accelerate the growth of gastrointestinal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide and Ggly activate different G proteins of the Rho family of small GTPases. For example, Gamide signals Rac/Cdc42 to activate p21-activated kinase 1 while Ggly signals Rho to activate Rho-activated kinase. p21-activated kinase 1 and Rho-activated kinase induce changes in phosphorylation or expression, respectively, of proteins of the Bcl-2 family, which then affect the caspase cascade with consequent inhibition of apoptosis. In addition, interaction of p21-activated kinase 1 with beta-catenin results in phosphorylation of beta-catenin, which enhances its translocation in to the nucleus, activation of TCF4-dependent transcription, and proliferation and migration. The central role of the beta-catenin pathway in carcinogenesis suggests that specific inhibitors of p21-activated kinase 1 may in the future provide novel therapies for gastrointestinal malignancies.
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Affiliation(s)
- Hong He
- Department of Surgery, University of Melbourne, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia
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Grabowska AM, Watson SA. Role of gastrin peptides in carcinogenesis. Cancer Lett 2007; 257:1-15. [PMID: 17698287 DOI: 10.1016/j.canlet.2007.06.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2007] [Revised: 06/25/2007] [Accepted: 06/28/2007] [Indexed: 01/22/2023]
Abstract
Gastrin gene expression is upregulated in a number of pre-malignant conditions and established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical CCK-2R receptor, CCK-2R isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion. Here we review this network of events, highlighting the importance of cellular context for interpreting the role of gastrin peptides and a possible role for gastrin in supporting the early stage of carcinogenesis.
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Affiliation(s)
- Anna M Grabowska
- Division of Pre-Clinical Oncology, D Floor, West Block, Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK.
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Cao J, Yu JP, Liu CH, Zhou L, Yu HG. Effects of gastrin 17 on beta-catenin/Tcf-4 pathway in Colo320WT colon cancer cells. World J Gastroenterol 2006; 12:7482-7487. [PMID: 17167838 PMCID: PMC4087595 DOI: 10.3748/wjg.v12.i46.7482] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2006] [Revised: 10/25/2006] [Accepted: 11/03/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the effect of gastrin 17 (G17) on beta-catenin/T cell factor-4 (Tcf-4) signaling in colonic cancer cell line Colo320WT. METHODS The pCR3.1/GR plasmid, which expresses gastrin receptor, cholecystokinin-2 receptor (CCK-2R), was transfected into a colonic cancer cell line Colo320 by Lipofectamine (TM)2000 and the stably expressing CCK-2R clones were screened by G418. The expression levels of gastrin receptor in the Colo320 and the transfected Colo320WT cell line were assayed by RT-PCR. Colo320WT cells were treated with G17 in a time-dependent manner (0, 1, 6, 12, 24 and 48 h), then with L365,260 (Gastrin(17) receptor blocker) for 30 min, and with G17 again for 12 h or L365,260 for 12 h. Expression levels of beta-catenin in a TX-100 soluble fraction and TX-100 insoluble fraction of Colo320WT cells treated with G17 were detected by co-immuniprecipation and Western blot. Immunocytochemistry was used to examine the distribution of beta-catenin in CoLoWT320 cells. Expression levels of c-myc and cyclin D1 in Colo320WT cells treated with G17 were assayed by Western blot. RESULTS Expression levels of beta-catenin in the TX-100 solution fraction decreased apparently in a time-dependent fashion and reached the highest level after G17 treatment for 12 h, while expression levels of beta-catenin in the TX-100 insoluble fraction were just on the contrary. Immunocytochemistry showed that beta-catenin was translocated from the cell membranes into the cytoplasm and nucleus under G17 treatment. Expression levels of c-myc and cyclin D1 in the G17-treated Colo320WT cells were markedly higher compared to the untreated Colo320WT cells. In addition, the aforementioned G17-stimulated responses were blocked by L365,260. CONCLUSION Gastrin17 activates beta-catenin/Tcf-4 signaling in Colo320WT cells, thereby leading to over-expression of c-myc and cyclin D1.
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Affiliation(s)
- Jun Cao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, Hubei Province, China
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Watson SA, Grabowska AM, El-Zaatari M, Takhar A. Gastrin - active participant or bystander in gastric carcinogenesis? Nat Rev Cancer 2006; 6:936-46. [PMID: 17128210 DOI: 10.1038/nrc2014] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in acid secretion in the gastric mucosa and a long-standing association with malignant progression in transgenic mouse models. However, its exact role in human gastric malignancy requires further validation. Gastrin expression is tightly regulated by two closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of their interaction may be deregulated during progression to gastric adenocarcinoma. Furthermore, agonists and antagonists of the receptors for all three hormones have shown modest clinical efficacy against gastric adenocarcinoma, which might provide useful information on the future combined use of these agents.
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Affiliation(s)
- Susan A Watson
- Academic Unit of Cancer Studies, University of Nottingham, Nottingham, NG7 2UH, UK.
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