HPG80 - Knowledge (XXG)

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and the Michigan Gastrointestinal Peptide Research Center, Ann Arbor, MI 48109, USA Division of Gastroenterology, Department of Pediatrics, VA Medical Center and University of Michigan, and the Michigan Gastrointestinal Peptide Research Center, Ann Arbor, MI 48109, USA Division of Gastroenterology, Department of Internal Medicine, VA Medical Center and University of Michigan, and the Michigan Gastrointestinal Peptide Research Center, Ann Arbor, MI 48109, USA Kochman, Michael Lee DelValle, John Dickinson, Chris John Boland, C. Richard (2006-04-10).

516:(c-Src) is activated in colon cancer cells and leads to increased amounts of hPG80. This means that hPG80 production, which occurs during early tumorigenesis, could play a role in this activation, which is known as an early event in colon tumorigenesis. The PI3K/Akt pathway, which is particularly involved in proliferation, is also activated by hPG80. NF-kappaB is another important signaling messenger regulated by hPG80. Its involvement in mechanisms responsible for the anti-apoptotic effect of hPG80 has been demonstrated in 626:. Thus, several types of tumors express the unmatured peptide. hPG80 can be detected and quantified in the blood of cancer patients. A first demonstration has been made in colorectal cancer showing an increase of hPG80 and non-amide gastrin levels in plasma in these patients compared to a control series (healthy individuals). In addition, an hPG80 increase has been observed in patients with adenomatous polyps. hPG80 is therefore expressed at all stages by the tumor, from early stages to metastasis. 635: 504:, respectively, and abrogated by inhibition of PI3K. Thus, constitutive activation of the Wnt pathway, considered to be at the onset of tumorigenesis in the colon, and the K-Ras oncogene, present in 50% of human colorectal tumors, synergistically stimulate the production of hPG80, a tumorigenesis promoter. Tumorigenesis induced by activation of the Wnt pathway is partially dependent on hPG80. 22: 565:

binding of progastrin to certain cell lines (IEC-6, IEC-18, HT-29, COLO320) was also detected. A specificity of binding was confirmed by competition with cold, unlabelled hPG80, but not with carboxy-terminal glycine-containing gastrin or amidated gastrin-17. Binding was not influenced by the presence of the classical CCK-2 receptor.

590:, those from GPCR56-deficient mice (GPCR56-/-) are resistant to hPG80. However, although hPG80 has been shown to bind to cells expressing GPCR56, authors did not provide direct evidence of a hPG80 bound to GPCR56 itself. GPCR56 is a good candidate, but evidence that it is hPG80 receptor is to this day not established. 1639:

Division of Gastroenterology, Department of Internal Medicine, VA Medical Center and University of Michigan, and the Michigan Gastrointestinal Peptide Research Center, Ann Arbor, MI 48109, USA Division of Gastroenterology, Department of Internal Medicine, VA Medical Center and University of Michigan,

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It is clear from these two studies that there is a binding site/receptor for hPG80 that is distinct from binding to gastrin-17 amidated and to gastrin 17 with carboxy-terminal glycine (G17-Gly). The sequence of hPG80 interacting with this receptor is likely located in the last 26 amino acid residues

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expression, the hypothesis of a possible cooperation between these two pathways to regulate hPG80 expression was investigated. Chakadar and al. found significant synergistic stimulation of the GAST gene promoter (by a factor of 25–40) by a combination of oncogenic β-catenin and K-Ras overexpression.

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High affinity binding sites have been described for the first time in intestinal epithelial cells using recombinant human progastrin iodine. Affinity was in the range of 0.5-1 nM, which is receptor compatible. When biotinylated progastrin binding was evaluated by flow cytometry, strong and specific

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An identification of the hPG80 receptor has been the subject of several studies in recent years. However, hPG80 receptor identity remains a real issue in the scientific community. The receptor can activate a number of signaling pathways, either directly or indirectly, which is rather unusual for a

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In addition, earlier detection of small lesions and monitoring of recurrence can be improved by measuring hPG80 levels as a complementary blood biomarker in a cohort of patients with hepatocellular carcinoma treated with local or systemic therapies (Fig. 3). Measured hPG80 levels are relevant in

419:(CSCs) constitute a small proportion of the tumor, usually between 1 and 5%. But they are essential for tumor survival because they act as a "reactor". Giraud and al. have demonstrated the major role played by hPG80 in CSCs. These authors have shown that hPG80 expression is strongly increased in 187:

The name hPG80 was thus proposed in the publication resulting from the work of Professor Benoît You under the management of Dominique Joubert and Alexandre Prieur in order to remove ambiguities between the intracellular version of the protein (in the function of digestion) and its extracellular

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cells. In addition, annexin A2 may be involved in progastrin-dependent clathrin endocytosis. However, progastrin affinity for Annexin A2 is not what would be expected for a specific receptor. And, although Annexin A2 plays a role in progastrin functions, it does not fit a receptor function.

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cells implanted mice are treated in vivo with such an antibody, CSCs frequency is decreased in the same proportions. These two scientific articles clearly show that hPG80 is a survival factor for CSCs. Moreover, hPG80 inhibition would induce CSC differentiation, opening the possibility of a

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gene or neutralization of hPG80 resulted in a decrease in the number of tumors in mice with a tumor predisposition (mutation on the APC gene). Conversely, a significant increase in tumor formation was observed in mice overexpressing progastrin and treated with azoxymethane (AOM), a chemical

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Ottewell, P. D.; Varro, A.; Dockray, G. J.; Kirton, C. M.; Watson, A. J. M.; Wang, T. C.; Dimaline, R.; Pritchard, D. M. (2005). "COOH-terminal 26-amino acid residues of progastrin are sufficient for stimulation of mitosis in murine colonic epithelium in vivo".

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Caplin, M.E.; Savage, K.; Khan, K.; Rode, J.; Brett, B.; Varro, A.; Michaeli, D.; Pounder, R.E.; Dhillon, A.P. (1998). "Expression and processing of gastrin in patients with hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma".

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Chakladar, Abhijit; Dubeykovskiy, Alexander; Wojtukiewicz, Lindsay J.; Pratap, Jitesh; Lei, Shi; Wang, Timothy C. (October 2005). "Synergistic activation of the murine gastrin promoter by oncogenic Ras and β-catenin involves SMAD recruitment".

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receptor. This could indicate a peculiarity of this receptor and why it is difficult to identify it. The unidentified hPG80 receptor transduces a progastrin signal via various intracellular intermediates known to be involved in tumorigenesis.

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is secreted by tumor cells and found in the plasma of cancer patients from early stages. It then has functions that are independent of digestion and totally different from progastrin and its only role as an intracellular precursor of

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Singh, Pomila; Velasco, Marco; Given, Randall; Wargovich, Michael; Varro, Andrea; Wang, Timothy C. (2000-03-01). "Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM".

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under conditions where CSCs are enriched. They then showed that hPG80 was able to regulate CSCs frequency (survival and self-renewal) in vitro and in vivo. Subsequently, Prieur and al. demonstrated that when a neutralizing

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In addition, You and al. observed a decrease in hPG80 levels after surgery in a patients cohort with gastrointestinal cancers with peritoneal involvement treated with post-operative chemotherapy and cytoreductive surgery.

309:. This work showed that hPG80 measurement more accurately reflected tumor than the conventional measurement of amide gastrin. Indeed, hPG80 is more than 700 times more abundant than amide gastrin in colorectal tumors. 1578:

Prieur, Alexandre; Cappellini, Monica; Habif, Guillaume; Lefranc, Marie-Paule; Mazard, Thibault; Morency, Eric; Pascussi, Jean-Marc; Flacelière, Maud; Cahuzac, Nathalie; Vire, Bérengère; Dubuc, Benjamin (2017-06-09).

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function of hPG80 in tumor cells. Generally, it has been shown that hPG80 does not mature properly in cancer cells, particularly in colorectal cancer, because maturation enzymes are either absent or non-functional.

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2020: hPG80 is detected in the plasma of patients with 11 different types of cancer. An association between longitudinal variations in hPG80 levels and the efficacy of anti-cancer treatments has been demonstrated.

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Wu, Hai; Owlia, Azarmidokht; Singh, Pomila (December 2003). "Precursor peptide progastrin1-80 reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP".

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Pannequin, Julie; Delaunay, Nathalie; Buchert, Michael; Surrel, Fanny; Bourgaux, Jean–François; Ryan, Joanne; Boireau, Stéphanie; Coelho, Jessica; Pélegrin, André; Singh, Pomila; Shulkes, Arthur (November 2007).

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Paterson, Adrienne C; Macrae, Finlay A; Pizzey, Cathy; Baldwin, Graham S; Shulkes, Arthur (2014-02-19). "Circulating gastrin concentrations in patients at increased risk of developing colorectal carcinoma".

724:(AFP) is below 20 ng/ml, an established threshold in clinical practice. Depending on disease management, patients in remission have lower levels of hPG80 than those in whom the cancer is still active. 585:

Another candidate is the G protein-coupled receptor 56 (GPCR56), expressed on both colon stem cells and cancer cells. While human recombinant hPG80 promotes in vitro growth and survival of wild mice colon

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One candidate is Annexin A2, identified as being able of binding progastrin and derived peptides. Annexin A2 is a partial mediator of the effect of progastrin/gastrins. In particular, Annexin A2 mediates

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Singh, P.; Lu, X.; Cobb, S.; Miller, B. T.; Tarasova, N.; Varro, A.; Owlia, A. (2003-02-01). "Progastrin1–80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites".

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as a model. Bardram was the first to hypothesize the presence of hPG80 in the early stages of the disease. He evaluated the presence of hPG80 and its maturation products in the serum of patients with

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In the early 90s, it was shown that hPG80 was not fully matured in human colon cancer cell lines and, more importantly, that it was secreted by in vitro cells. These observations led to the study of

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allows restoration of membrane localization of tight and adherent junctions constituent proteins in a human colorectal carcinoma cell line DLD-1. hPG80 thus plays a role on cell contacts integrity.

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You, Benoit; Mercier, Frédéric; Assenat, Eric; Langlois-Jacques, Carole; Glehen, Olivier; Soulé, Julien; Payen, Léa; Kepenekian, Vahan; Dupuy, Marie; Belouin, Fanny; Morency, Eric (January 2020).

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Westwood, David A; Patel, Oneel; Christophi, Christopher; Shulkes, Arthur; Baldwin, Graham S (2017-04-21). "Progastrin: a potential predictive marker of liver metastasis in colorectal cancer".

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Singh, P.; Xu, Z.; Dai, B.; Rajaraman, S.; Rubin, N.; Dhruva, B. (1994-03-01). "Incomplete processing of progastrin expressed by human colon cancer cells: role of noncarboxyamidated gastrins".

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Activation of the GAST gene promoter was also shown to be dependent on other signalling signals: enhanced or suppressed by co-expression of wild-type SMAD4 or by a dominant negative mutant of

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Ferrand, Audrey; Bertrand, Claudine; Portolan, Ghislaine; Cui, Guanglin; Carlson, Jane; Pradayrol, Lucien; Fourmy, Daniel; Dufresne, Marlene; Wang, Timothy C.; Seva, Catherine (2005-04-01).

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Singh, P.; Owlia, A.; Varro, A.; Dai, B.; Rajaraman, S.; Wood, T. (1996-09-15). "Gastrin gene expression is required for the proliferation and tumorigenicity of human colon cancer cells".

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Through a variety of mechanisms, all crucial for tumor growth and survival, research has demonstrated the major role that hPG80 plays in tumor initiation and progression, generally using

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hPG80 through various mechanisms can be considered as a major promoter of tumorigenesis. hPG80 is found in the plasma of cancer patients and its neutralization induces tumor reversion.

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Cell migration is based on their ability to become independent of adjacent cells. Intercellular contacts integrity is essential for electrolyte uptake regulation as well as for tumor

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hPG80 is found in different tumor types and secreted in vitro by certain cancer cells. A study has shown its presence in the blood of patients with 11 different types of cancer:

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Kowalski-Chauvel, Aline; Gouaze-Andersson, Valerie; Vignolle-Vidoni, Alix; Delmas, Caroline; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth; Seva, Catherine (2017-04-20).

2711:"Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells" 741:, appears to be a promising approach. The use of anti-hPG80 antibodies has also been discussed as a potential treatment in colorectal cancer patients with a mutation in the 2226: 1663: 1520:

Giraud, J.; Failla, L. M.; Pascussi, J.-M.; Lagerqvist, E. L.; Ollier, J.; Finetti, P.; Bertucci, F.; Ya, C.; Gasmi, I.; Bourgaux, J.-F.; Prudhomme, M. (2016-05-04).

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Ramanathan, Vigneshwaran; Jin, Guangchun; Westphalen, Christoph Benedikt; Whelan, Ashley; Dubeykovskiy, Alexander; Takaishi, Shigeo; Wang, Timothy C. (2012-04-05).

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The first event leading to colon cancer is in 80 to 90% of cases a constitutive activation of the Wnt/β-catenin oncogenic pathway induced by mutations in the APC (

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Figure 3 - Longitudinal changes in hPG80 and AFP levels during hepatocellular carcinoma management (inclusion; remission; progression) in a representative patient

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Caplin, M.; Savage, K.; Khan, K.; Brett, B.; Rode, J.; Varro, A.; Dhillon, A. (2000-08-01). "Expression and processing of gastrin in pancreatic adenocarcinoma".

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A link between this protein and cancer has been known for more than 30 years. hPG80 is involved in most of the biological functions that ensure the existence of

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gene. JAK2 (Janus-activated kinase 2), STAT3 and kinases increases regulated by extracellular signals have also been observed in the colon mucosa of hGAS mice.

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This has recently been confirmed for ovarian, breast, esophageal, liver and gastric cancers making this therapeutic antibody a potential multi-cancer drug.

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Jin, Guangchun; Sakitani, Kosuke; Wang, Hongshan; Jin, Ying; Dubeykovskiy, Alexander; Worthley, Daniel L.; Tailor, Yagnesh; Wang, Timothy C. (2017-03-23).

440:, which probably explains why this peptide can be considered as a potential predictive marker for the presence of liver metastasis in colorectal cancer. 1581:"Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer" 380:

activation and a decrease in DNA fragmentation. Therefore, the effect of hPG80 on cell survival results from both increased proliferation and decreased

1914:"Intestinal expression of mutant and wild-type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice" 2307:

Kondo, Jumpei; Powell, Anne E.; Coffey, Robert J. (2016). "466 Escape From BMP4-Mediated Growth Suppression Is an Early Event in Colonic Neoplasia".

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3. decreased tumor burden and increased cell differentiation in the remaining tumors in transgenic mice developing Wnt-induced intestinal neoplasia.

2445:"Activation of NF-κB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo" 771:

factor that can be targeted to sensitize rectum radiation-resistant cancers. hPG80 decreased expression increases sensitivity to irradiation in

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Do, Catherine; Bertrand, Claudine; Palasse, Julien; Delisle, Marie-Bernadette; Cohen-Jonathan-Moyal, Elizabeth; Seva, Catherine (2013-11-08).

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gene is repressed, inducing inactivation of the Notch pathway which plays a major role in the acquisition of a differentiated cell phenotype.

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of the topic and provide significant coverage of it beyond a mere trivial mention. If notability cannot be shown, the article is likely to be

2994: 2825:"The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis" 569:

of hPG80 carboxy-terminal end, which have been shown to be sufficient for its function. However, this putative receptor identity is unknown.

1246:"pp60c-Src Kinase Mediates Growth Effects of the Full-Length Precursor Progastrin1–80 Peptide on Rat Intestinal Epithelial Cells, in Vitro" 247:

2003: hPG80 is involved in the dissociation regulation of adherent and tight junctions. Src mediates the effects of hPG80 on cell growth.

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differentiation therapy rather than a classical anti-proliferative therapy. Its main function is to help CSCs survive and spread to form

1186:"Plasma levels of progastrin but not amidated gastrin or glycine extended gastrin are elevated in patients with colorectal carcinoma" 117: 536:

cells which do not express hPG80 return to a "normal" state. This is due to the fact that when the Wnt pathway is inactivated, the

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Pre- and post-operative plasma assays of hPG80 in colorectal cancer patients show that hPG80 presence reflects tumor production.

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prevention. In 2003, it was demonstrated that blocking hPG80 secretion by an antisense construction directed against progastrin

43: 137:. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention ' 3061:

Do, C.; Bertrand, C.; Palasse, J.; Delisle, M.-B.; Shulkes, A.; Cohen-Jonathan-Moyal, E.; Ferrand, A.; Seva, C. (2012-02-24).

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2. prolongation of in vitro and in vivo chemosensitivity and delayed relapse after treatment of T84 xenografted mouse cells;

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2000 - 2001: The GAST gene is a target of the β-catenin/Tcf4 pathway. The presence of hPG80 is demonstrated in the plasma of

820:"The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients" 457:) coding gene or the β-catenin coding gene. Mutations induction into normal intestinal stem cells is sufficient to trigger 2768:"Annexin A2 Mediates Up-regulation of NF-κB, β-catenin, and Stem Cell in Response to Progastrin in Mice and HEK-293 Cells" 2396:"Antiapoptotic Effects of Progastrin on Pancreatic Cancer Cells Are Mediated by Sustained Activation of Nuclear Factor- B" 663: 196: 488:

expression are produced by activation of the Raf-MEK-ERK signal transduction pathway, final step being activation of the

39: 32: 55: 1350:"β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors" 348:

When a tumor develops, its need for oxygen and nutrients causes creation of new blood vessels. This process is called

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For more clarity, the remainder of this article uses exclusively the name hPG80 to refer to extracellular progastrin.

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Van Solinge, Wouter W.; Nielsen, Finn C.; Friis-Hansen, Lennart; Falkmer, Ursula G.; Rehfeld, Jens F. (April 1993).

98: 2502:"The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells" 454: 2178:"Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR" 552:

gene mutation was shown to increase hPG80-dependent colon cells proliferation and colon cancer formation in mice.

70: 2347:"Signaling Pathways Associated with Colonic Mucosa Hyperproliferation in Mice Overexpressing Gastrin Precursors" 882:"Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells" 188:

version of the protein (in the case of cancer patients) which is no longer, despite its name, the precursor of

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gene expression is required for human colon cancer cell tumorigenesis. 60 to 80% of colon cancers express the

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Pannequin, J.; Bonnans, C.; Delaunay, N.; Ryan, J.; Bourgaux, J.-F.; Joubert, D.; Hollande, F. (2009-07-21).

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van Solinge, W. W.; Odum, L.; Rehfeld, J. F. (1993-04-15). "Ovarian cancers express and process progastrin".

77: 1402:"P53 Gene Mutation Increases Progastrin Dependent Colonic Proliferation and Colon Cancer Formation in Mice" 2176:

Hori, Hiroyuki Nakata, Hirohisa Iguchi, Genzo Yamada, Hajime Chihara, Kazuo Baba, Hisamitsu (2010-04-01).

1522:"Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells" 1130:

Koh, Theodore J; Chen, Duan (September 2000). "Gastrin as a growth factor in the gastrointestinal tract".

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It has been observed that hPG80 concentrations are increased in patients at risk of developing colorectal

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Cobb, Stephanie; Wood, Thomas; Ceci, Jeffrey; Varro, Andrea; Velasco, Marco; Singh, Pomila (2004-03-15).

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To date, no drug is able to target CSCs. Humanized anti-hPG80 antibodies, alone or in combination with

84: 51: 3063:"A New Biomarker That Predicts Colonic Neoplasia Outcome in Patients with Hyperplastic Colonic Polyps" 2253: 945: 278:

2016: Autocrine secretion of hPG80 promotes survival and self-renewal of stem cells in colon cancer.

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Dubeykovskiy, Alexander; Nguyen, Thomas; Dubeykovskaya, Zinaida; Lei, Shi; Wang, Timothy C. (2008).

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Sarkar, Shubhashish; Swiercz, Rafal; Kantara, Carla; Hajjar, Katherine A.; Singh, Pomila (2011).

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Najib, S; Kowalski-Chauvel, A; Do, C; Roche, S; Cohen-Jonathan-Moyal, E; Seva, C (2014-08-11).

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In the name hPG80, the "h" describes the human species: human; "PG" is a common script for the

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is not the only type of cancer to express hPG80. Its expression has also been demonstrated in

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Ciccotosto, Giuseppe D.; McLeish, Andrew; Hardy, Kenneth J.; Shulkes, Arthur (October 1995).

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Demonstration of the link between hPG80 and an oncogenic pathway has been described for

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oncogenic pathway. It is a downstream target of the β-catenin/Tcf-4 signaling pathway.

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Treatment of intestinal epithelial cells with hPG80 results in a significant loss of

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gene mutation increases hPG80-dependent colonic proliferation and cancer formation.

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gene. Targeting of hPG80 with the humanized anti-hPG80 antibody has been shown:

619: 1310: 3243: 2841: 2081: 437: 393: 200: 181: 177: 138: 134: 3251: 3228:"Targeting progastrin enhances radiosensitization of colorectal cancer cells" 3204: 3145: 3136: 3088: 3031: 2947: 2912: 2850: 2791: 2736: 2679: 2671: 2625: 2570: 2562: 2527: 2468: 2421: 2372: 2328: 2275: 2204: 2144: 2089: 2043: 2035: 1991: 1939: 1880: 1841: 1800: 1757: 1708: 1683:"Expression but incomplete maturation of progastrin in colorectal carcinomas" 1649: 1606: 1547: 1487: 1425: 1375: 1318: 1271: 1209: 1151: 1103: 1065: 1017: 967: 843: 1642:

Post-translational processing of gastrin in neoplastic human colonic tissues

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2005: Ras and β-catenin/Tcf4 pathways induce synergistic activation of the

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1996 - 1997: hPG80 is identified as necessary for the proliferation and

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Nemeth, J; Taylor, B; Pauwels, S; Varro, A; Dockray, G J (1993-01-01).

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Imdahl, A.; Eggstein, S.; Baldwin, G.S.; Farthmann, E.H. (April 1995).

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1. a decrease in the self-renewal capacity of CSCs of various origins;

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