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Sun R, Wang D, Song Y, Li Q, Su P, Pang Y. Granulin as an important immune molecule involved in lamprey tissue repair and regeneration by promoting cell proliferation and migration. Cell Mol Biol Lett 2022; 27:64. [PMID: 35907821 PMCID: PMC9338584 DOI: 10.1186/s11658-022-00360-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/30/2022] [Indexed: 01/17/2023] Open
Abstract
Progranulin (PGRN) is an autocrine growth factor that regulates cell proliferation, migration, wound healing, and tissue repair in mammals. Lamprey is the most primitive of the extant vertebrates and is regarded as the survivor of a once flourishing group of paleozoic vertebrates, with a history of more than 500 million years. To date, the evolutionary dynamics and the underlying function of the PGRNs remain largely unclear in lamprey. Here, we screened four genes encoding PGRNs from the genomes of Lethenteron reissneri and Petromyzon marinus, including one long form (named Lr-PGRN-L) and three short forms (named Lr-PGRN-S1, Lr-PGRN-S2, and Lr-PGRN-S3), and performed phylogenetic tree, functional domain, and synteny analyses to identify the evolutionary history of the four Lr-PGRNs. In addition, the expressions of the four Lr-pgrn family genes and the immune response against various pathogenic challenges were also investigated. We found that these genes were widely distributed in various tissues of lamprey and performed a variety of functions. Moreover, our results suggest that Lr-PGRN-S1 induces cell migration and proliferation, and is involved in repair after skin and spinal cord injury under appropriate conditions. Our findings are valuable because they improve the understanding of the evolutionary relationship of vertebrate pgrn genes, as well as providing new insights into the diverse and important roles of Lr-PGRNs.
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Affiliation(s)
- Ruixiang Sun
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China.,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Dong Wang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China.,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Yuxuan Song
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China.,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Qingwei Li
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China.,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Peng Su
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China. .,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China. .,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China.
| | - Yue Pang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China. .,Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China. .,Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China.
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2
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Lubián López DM. Management of genitourinary syndrome of menopause in breast cancer survivors: An update. World J Clin Oncol 2022; 13:71-100. [PMID: 35316932 PMCID: PMC8894268 DOI: 10.5306/wjco.v13.i2.71] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 09/19/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
There is increasing attention about managing the adverse effects of adjuvant therapy (Chemotherapy and anti-estrogen treatment) for breast cancer survivors (BCSs). Vulvovaginal atrophy (VVA), caused by decreased levels of circulating estrogen to urogenital receptors, is commonly experienced by this patients. Women receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM), that it can in turn lead to pain, discomfort, impairment of sexual function and negatively impact on multiple domains of quality of life (QoL). The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly. The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Systemic estrogen treatment is contraindicated in BCSs. In these patients, GSM may be prevented, reduced and managed in most cases but this requires early recognition and appropriate treatment, but it is normally undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy (VET) because of unknown levels of systemic absorption of estradiol. Lifestyle modifications and nonhormonal treatments (vaginal moisturizers, lubricants, and gels) are the first-line treatment for GSM both in healthy women as BCSs, but when these are not effective for symptom relief, other options can be considered, such as VET, ospemifene, local androgens, intravaginal dehydroepiandrosterone (prasterone), or laser therapy (erbium or CO2 Laser). The present data suggest that these therapies are effective for VVA in BCSs; however, safety remains controversial and a there is a major concern with all of these treatments. We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. We include recommendations for an approach to the management of GSM in women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease.
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Affiliation(s)
- Daniel María Lubián López
- Department of Mother and Child Health and Radiology, Faculty of Medicine, University of Cadiz, Cádiz 11100, Spain
- Department of Obstetrics and Gynecology Service, University Hospital of Jerez de la Frontera, Jerez de la Frontera 11407, Spain
- Department of Obstetrics and Gynecology, Hospital Viamed Bahía de Cádiz, Chiclana de la Frontera 11130, Cádiz, a Spain
- Department of Obstetrics and Gynecology, Hospital Quirónsalud Campo de Gibraltar, Los Barrios 11379, Cádiz, Spain
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3
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Callizot N, Estrella C, Burlet S, Henriques A, Brantis C, Barrier M, Campanari ML, Verwaerde P. AZP2006, a new promising treatment for Alzheimer's and related diseases. Sci Rep 2021; 11:16806. [PMID: 34413330 PMCID: PMC8376949 DOI: 10.1038/s41598-021-94708-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023] Open
Abstract
Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.
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Affiliation(s)
- N Callizot
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France.
- Neuro-Sys, 410 Chemin Départemental 60, 13120, Gardanne, France.
| | - C Estrella
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France
| | - S Burlet
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France
| | - A Henriques
- Neuro-Sys, 410 Chemin Départemental 60, 13120, Gardanne, France
| | - C Brantis
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France
| | - M Barrier
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France
| | - M L Campanari
- Neuro-Sys, 410 Chemin Départemental 60, 13120, Gardanne, France
| | - P Verwaerde
- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France
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4
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Granulin: An Invasive and Survival-Determining Marker in Colorectal Cancer Patients. Int J Mol Sci 2021; 22:ijms22126436. [PMID: 34208547 PMCID: PMC8235441 DOI: 10.3390/ijms22126436] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/25/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we wanted to assess the expression of granulin in colorectal cancer patients to evaluate its potential as a prognostic biomarker. Methods: Expressional differences of granulin in colorectal carcinoma tissue (n = 94) and corresponding healthy colon mucosa were assessed using qRT-PCR. Immunohistochemistry was performed in colorectal cancer specimens (n = 97), corresponding healthy mucosa (n = 47) and colorectal adenomas (n = 19). Subsequently, the results were correlated with histopathological and clinical patients’ data. HCT-116 cells were transfected with siRNA for invasion and migration assays. Results: Immunohistochemistry and qRT-PCR revealed tumoral over expression of granulin in colorectal cancer specimens compared to corresponding healthy colon mucosa and adenomas. Tumoral overexpression of granulin was associated with a significantly impaired overall survival. Moreover, downregulation of granulin by siRNA significantly diminished the invasive capacities of HCT-116 cells in vitro. Conclusion: Expression of granulin differs in colorectal cancer tissue, adenomas and healthy colon mucosa. Furthermore, granulin features invasive and migrative capabilities and overexpression of granulin correlates with a dismal prognosis. This reveals its potential as a prognostic biomarker and granulin could be a worthwhile molecular target for individualized anticancer therapy.
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5
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Guha R, Yue B, Dong J, Banerjee A, Serrero G. Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration. Breast Cancer Res Treat 2021; 186:637-653. [PMID: 33616772 DOI: 10.1007/s10549-021-06120-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/27/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC. METHODS The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo. RESULTS Inhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo. CONCLUSION PGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.
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Affiliation(s)
- Rupa Guha
- A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA.,Graduate Program in Life Sciences, University of Maryland School of Medicine, 655 W. Baltimore St, Baltimore, MD, 21201, USA
| | - Binbin Yue
- A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA
| | - Jianping Dong
- A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA
| | - Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, 655 W. Baltimore St, Baltimore, MD, 21201, USA
| | - Ginette Serrero
- A&G Pharmaceutical Inc, 9130 Red Branch Rd Suite X, Columbia, MD, 21045, USA. .,University of Maryland Greenebaum Comprehensive Cancer Center, 22 S. Greene St, Baltimore, MD, 21201, USA.
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6
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Campbell CA, Fursova O, Cheng X, Snella E, McCune A, Li L, Solchenberger B, Schmid B, Sahoo D, Morton M, Traver D, Espín-Palazón R. A zebrafish model of granulin deficiency reveals essential roles in myeloid cell differentiation. Blood Adv 2021; 5:796-811. [PMID: 33560393 PMCID: PMC7876888 DOI: 10.1182/bloodadvances.2020003096] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 12/01/2020] [Indexed: 12/22/2022] Open
Abstract
Granulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.
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Affiliation(s)
- Clyde A Campbell
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
| | - Oksana Fursova
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
| | - Xiaoyi Cheng
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
| | - Elizabeth Snella
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
| | - Abbigail McCune
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
| | - Liangdao Li
- Section of Cell and Developmental Biology, University of California at San Diego, San Diego, CA
| | | | - Bettina Schmid
- German Center for Neurodegenerative Diseases, Munich, Germany
| | - Debashis Sahoo
- Department of Computer Science and Engineering, University of California at San Diego, San Diego, CA; and
| | - Mark Morton
- College of Veterinary Medicine, Iowa State University, Ames, IA
| | - David Traver
- Section of Cell and Developmental Biology, University of California at San Diego, San Diego, CA
| | - Raquel Espín-Palazón
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA
- Section of Cell and Developmental Biology, University of California at San Diego, San Diego, CA
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7
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Yabe K, Yamamoto Y, Takemura M, Hara T, Tsurumi H, Serrero G, Nabeshima T, Saito K. Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells. Heliyon 2021; 7:e05849. [PMID: 33490663 PMCID: PMC7809376 DOI: 10.1016/j.heliyon.2020.e05849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/27/2020] [Accepted: 12/22/2020] [Indexed: 11/30/2022] Open
Abstract
Progranulin is an autocrine growth factor that promotes proliferation, migration, invasion, and chemoresistance of various cancer cells. These mechanisms mainly depend on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Recent studies have shown that patients with hematopoietic cancer have elevated serum progranulin levels. Thus, the current study aimed to investigate the role of progranulin in hematopoietic cancer cells and how it modulates their proliferation. Both knockdown of progranulin and progranulin neutralizing antibody treatment inhibited proliferation in several human hematopoietic cancer cell lines. Moreover, progranulin depletion not only decreases the phosphorylation level of the Akt/mTOR pathway but also, surprisingly, increases the expression of transforming growth factor-beta (TGF-β) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-β receptor type I/II kinase, and TGF-β neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-β axis and progranulin could be a new therapeutic target for hematopoietic cancers.
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Affiliation(s)
- Kuniaki Yabe
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.,A&T corporation, Kanagawa, Japan
| | - Yasuko Yamamoto
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan
| | - Masao Takemura
- Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan
| | - Takeshi Hara
- Department of Hematology, Matsunami General Hospital, Gifu, Japan
| | - Hisashi Tsurumi
- Department of Hematology, Matsunami General Hospital, Gifu, Japan
| | - Ginette Serrero
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.,A&G Pharmaceutical, Inc., Columbia, MD, USA
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan.,Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan
| | - Kuniaki Saito
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.,Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan.,Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan.,Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
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Zhou X, Kukar T, Rademakers R. Lysosomal Dysfunction and Other Pathomechanisms in FTLD: Evidence from Progranulin Genetics and Biology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1281:219-242. [PMID: 33433878 DOI: 10.1007/978-3-030-51140-1_14] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
It has been more than a decade since heterozygous loss-of-function mutations in the progranulin gene (GRN) were first identified as an important genetic cause of frontotemporal lobar degeneration (FTLD). Due to the highly diverse biological functions of the progranulin (PGRN) protein, encoded by GRN, multiple possible disease mechanisms have been proposed. Early work focused on the neurotrophic properties of PGRN and its role in the inflammatory response. However, since the discovery of homozygous GRN mutations in patients with a lysosomal storage disorder, investigation into the possible roles of PGRN and its proteolytic cleavage products granulins, in lysosomal function and dysfunction, has taken center stage. In this chapter, we summarize the GRN mutational spectrum and its associated phenotypes followed by an in-depth discussion on the possible disease mechanisms implicated in FTLD-GRN. We conclude with key outstanding questions which urgently require answers to ensure safe and successful therapy development for GRN mutation carriers.
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Affiliation(s)
- Xiaolai Zhou
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Thomas Kukar
- Department of Pharmacology and Chemical Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
| | - Rosa Rademakers
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
- VIB Center for Molecular Neurology, University of Antwerp-CDE, Antwerp, Belgium.
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9
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MicroRNA-107 enhances radiosensitivity by suppressing granulin in PC-3 prostate cancer cells. Sci Rep 2020; 10:14584. [PMID: 32883962 PMCID: PMC7471693 DOI: 10.1038/s41598-020-71128-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 07/30/2020] [Indexed: 11/20/2022] Open
Abstract
Prostate cancer is the second leading cause of cancer-related death worldwide. Radiotherapy is often applied for the treatment, but radioresistance is a challenge in some patients. MicroRNAs have been reported to be involved in the DNA damage response induced by ionizing radiation and recent studies have reported microRNA-mediated radiosensitivity. In the present study, we found microRNA-107 (miR-107) enhanced radiosensitivity by regulating granulin (GRN) in prostate cancer (PC-3) cells. MiR-107 was downregulated and GRN was upregulated in response to ionizing radiation in PC-3 cells. Overexpression of miR-107 and knockdown of GRN promoted the sensitivity of PC3 cells to ionizing radiation. By rescue experiments of GRN, we revealed that radiosensitivity enhanced by miR-107 can be attenuated by GRN overexpression in PC-3 cells. Furthermore, we showed miR-107 enhanced radiation-induced G1/S phase arrest and G2/M phase transit, and identify delayed apoptosis by suppressing p21 and phosphorylation of CHK2. Collectively, these results highlight an unrecognized mechanism of miR-107-mediated GRN regulation in response to ionizing radiation and may advance therapeutic strategies for the treatment of prostate cancer.
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10
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Tkaczuk KHR, Hawkins D, Yue B, Hicks D, Tait N, Serrero G. Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer. Clin Breast Cancer 2020; 20:220-227. [PMID: 31928925 PMCID: PMC8284563 DOI: 10.1016/j.clbc.2019.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/15/2019] [Accepted: 11/28/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Progranulin (GP88) is a critical player in breast tumorigenesis. GP88 tumor expression is associated with increased recurrence and mortality, whereas GP88 circulating levels are elevated in patients with breast cancer compared with healthy individuals. We examined here the correlation between serum GP88 levels in patients with metastatic breast cancer (MBC) with overall survival and disease status determined as response to therapy or progression of disease. PATIENTS AND METHODS An institutional review board (IRB)-approved study prospectively enrolled 101 patients with MBC at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. GP88 serum levels were correlated with patients' disease status determined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and survival outcomes by Kaplan-Meier analysis and log rank statistics. RESULTS Patients' survival was stratified by serum GP88 level. Patients with serum GP88 < 55 ng/mL had a 4-fold increased survival compared with patients with GP88 > 55 ng/mL. Examination of GP88 serum levels in association with disease status showed a statistically significant association between serum GP88 levels and disease progression or response to therapy while CA15-3 level was only associated to progression. CONCLUSION The association of serum GP88 level with survival and disease status suggests the potential of using the serum GP88 test for monitoring disease status in patients with MBC. Measurement of serum GP88 levels in patients with MBC may have clinical value as a cost-effective adjunct to the management of patients with MBC with imaging.
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Affiliation(s)
- Katherine H R Tkaczuk
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD
| | - Douglas Hawkins
- Department of Statistics, University of Minnesota, Minneapolis, MN
| | | | | | - Nancy Tait
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD
| | - Ginette Serrero
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD; A&G Pharmaceutical, Inc, Columbia, MD.
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11
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Voshtani R, Song M, Wang H, Li X, Zhang W, Tavallaie MS, Yan W, Sun J, Wei F, Ma X. Progranulin promotes melanoma progression by inhibiting natural killer cell recruitment to the tumor microenvironment. Cancer Lett 2019; 465:24-35. [PMID: 31491449 DOI: 10.1016/j.canlet.2019.08.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/23/2019] [Accepted: 08/30/2019] [Indexed: 12/20/2022]
Abstract
Progranulin (PGRN) is a growth factor with significant biological effects in different types of cancer. However, its role in melanoma progression has not been explored. In this study, we first analyze clinical datasets and show that high PGRN expression levels are correlated with poor prognosis of melanoma patients. Further, we demonstrate in a transplanted murine melanoma model in which the endogenous Grn gene encoding PGRN has been deleted that tumor-derived, not host-derived PGRN, promotes melanoma growth and metastasis. Immunological analyses reveal an enhanced infiltration of natural killer cells, but not T lymphocytes, into PGRN-deficient tumors compared to the wild type control. Antibody-mediated depletion confirms the critical role of NK cells in controlling B16 tumor growth. RNA-seq analysis reveals that several chemokines including CCL5 are strongly upregulated in PGRN-deficient tumor. Silencing CCL5 expression in PGRN-deficient tumor reduces NK cell recruitment and restores tumor growth to the control level. Lastly, we show that PGRN inhibits Ccl5 gene expression at the transcriptional level. This study highlights a novel and critical role of PGRN in melanoma growth and metastasis and suggests that it may represent a potential therapeutic target.
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Affiliation(s)
- Ramouna Voshtani
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Mei Song
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, USA
| | - Huan Wang
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Xiaoqi Li
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Wei Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mojdeh S Tavallaie
- Department of Pharmaceutical Sciences, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Wenjun Yan
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Joseph Sun
- Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - Fang Wei
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China.
| | - Xiaojing Ma
- State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, USA.
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12
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Li Y, Li S, Li Y, Xia H, Mao Q. Generation of a novel HEK293 luciferase reporter cell line by CRISPR/Cas9-mediated site-specific integration in the genome to explore the transcriptional regulation of the PGRN gene. Bioengineered 2019; 10:98-107. [PMID: 31023186 PMCID: PMC6527057 DOI: 10.1080/21655979.2019.1607126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Progranulin has multiple functions in several physiological and pathological processes, including embryonic development, wound repair, tumorigenesis, inflammation and neurodegeneration. To investigate the transcriptional regulation of the PGRN gene, a luciferase knock-in reporter system was established in HEK293 cells by integrating luciferase gene in the genome controlled by the endogenous PGRN promoter using CRISPR/Cas9. PCR results demonstrated the site-specific integration of the exogenous luciferase gene into the genome. To validate the novel luciferase knock-in system, a CRISPR/Cas9 transcription activation/repression system for the PGRN gene was constructed and applied to the knock-in system. In addition, phorbol ester (phorbol 12-myristate, 13-acetate), previously reported as activating the expression of PGRN, was applied to the system. The results indicated that luciferase activity was directly correlated with the activity of the PGRN endogenous promoter. This novel system will be a useful tool for investigating the transcriptional regulation of PGRN, and it has great potential in screening the drugs targeting PGRN.
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Affiliation(s)
- Yanqing Li
- a Laboratory of Gene Therapy, Department of Biochemistry , College of Life Sciences, Shaanxi Normal University , Xi'an , Shaanxi , P.R. China
| | - Sai Li
- a Laboratory of Gene Therapy, Department of Biochemistry , College of Life Sciences, Shaanxi Normal University , Xi'an , Shaanxi , P.R. China
| | - Yan Li
- a Laboratory of Gene Therapy, Department of Biochemistry , College of Life Sciences, Shaanxi Normal University , Xi'an , Shaanxi , P.R. China
| | - Haibin Xia
- a Laboratory of Gene Therapy, Department of Biochemistry , College of Life Sciences, Shaanxi Normal University , Xi'an , Shaanxi , P.R. China
| | - Qinwen Mao
- b Department of Pathology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA
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Determination and analysis of agonist and antagonist potential of naturally occurring flavonoids for estrogen receptor (ERα) by various parameters and molecular modelling approach. Sci Rep 2019; 9:7450. [PMID: 31092862 PMCID: PMC6520524 DOI: 10.1038/s41598-019-43768-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 04/17/2019] [Indexed: 12/29/2022] Open
Abstract
Most estrogen receptor α (ERα) ligands target the ligand binding domain (LBD). Agonist 17β-estradiol (E2) and tamoxifen (TM, known SERM), bind to the same site within the LBD. However, structures of ligand-bound complexes show that E2 and TM induce different conformations of helix 12 (H12). During the molecular modelling studies of some naturally occurring flavonoids such as quercetin, luteolin, myricetin, kaempferol, naringin, hesperidin, galangin, baicalein and epicatechin with human ERα (3ERT and 1GWR), we observed that most of the ligands bound to the active site pocket of both 3ERT and 1GWR. The docking scores, interaction analyses, and conformation of H12 provided the data to support for the estrogenic or antiestrogenic potential of these flavonoids to a limited degree. Explicit molecular dynamics for 50 ns was performed to identify the stability and compatibility pattern of protein-ligand complex and RMSD were obtained. Baicalein, epicatechin, and kaempferol with 1GWR complex showed similar RMSD trend with minor deviations in the protein backbone RMSD against 1GWR-E2 complex that provided clear indications that ligands were stable throughout the explicit molecular simulations in the protein and outcome of naringin-3ERT complex had an upward trend but stable throughout the simulations and all molecular dynamics showed stability with less than overall 1 Å deviation throughout the simulations. To examine their estrogenic or antiestrogenic potential, we studied the effect of the flavonoids on viability, progesterone receptor expression and 3xERE/3XERRE-driven reporter gene expression in ERα positive and estrogen responsive MCF-7 breast cancer cells. Epicatechin, myricetin, and kaempferol showed estrogenic potential at 5 µM concentration.
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14
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The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 2018; 136:1-17. [PMID: 29744576 DOI: 10.1007/s00401-018-1861-8] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 12/12/2022]
Abstract
Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its mechanistic relationship to FTLD remain unclear. However, growing evidence suggests a role for PGRN in the lysosome-most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease. Since this discovery, several links between PGRN and the lysosome have been established, including the existence of two independent lysosomal trafficking pathways, intralysosomal processing of PGRN into discrete functional peptides, and direct and indirect regulation of lysosomal hydrolases. Here, we summarize the cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases, with a particular focus dedicated to recent lysosome-related mechanistic developments.
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Abstract
Cancer cells have defects in regulatory mechanisms that usually control cell proliferation and homeostasis. Different cancer cells share crucial alterations in cell physiology, which lead to malignant growth. Tumorigenesis or tumor growth requires a series of events that include constant cell proliferation, promotion of metastasis and invasion, stimulation of angiogenesis, evasion of tumor suppressor factors, and avoidance of cell death pathways. All these events in tumor progression may be regulated by growth factors produced by normal or malignant cells. The growth factor progranulin has significant biological effects in different types of cancer. This protein is a regulator of tumorigenesis because it stimulates cell proliferation, migration, invasion, angiogenesis, malignant transformation, resistance to anticancer drugs, and immune evasion. This review focuses on the biological effects of progranulin in several cancer models and provides evidence that this growth factor should be considered as a potential biomarker and target in cancer treatment.
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16
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Li YW, Chiang KY, Li YH, Wu SY, Liu W, Lin CR, Wu JL. MiR-145 mediates zebrafish hepatic outgrowth through progranulin A signaling. PLoS One 2017; 12:e0177887. [PMID: 28531199 PMCID: PMC5439702 DOI: 10.1371/journal.pone.0177887] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/04/2017] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRs) are mRNA-regulatory molecules that fine-tune gene expression and modulate both processes of development and tumorigenesis. Our previous studies identified progranulin A (GrnA) as a growth factor which induces zebrafish hepatic outgrowth through MET signaling. We also found that miR-145 is one of potential fine-tuning regulators of GrnA involved in embryonic hepatic outgrowth. The low level of miR-145 seen in hepatocarinogenesis has been shown to promote pathological liver growth. However, little is known about the regulatory mechanism of miR-145 in embryonic liver development. In this study, we demonstrate a significant decrease in miR-145 expression during hepatogenesis. We modulate miR-145 expression in zebrafish embryos by injection with a miR-145 mimic or a miR-145 hairpin inhibitor. Altered embryonic liver outgrowth is observed in response to miR-145 expression modulation. We also confirm a critical role of miR-145 in hepatic outgrowth by using whole-mount in situ hybridization. Loss of miR-145 expression in embryos results in hepatic cell proliferation, and vice versa. Furthermore, we demonstrate that GrnA is a target of miR-145 and GrnA-induced MET signaling is also regulated by miR-145 as determined by luciferase reporter assay and gene expression analysis, respectively. In addition, co-injection of GrnA mRNA with miR-145 mimic or MO-GrnA with miR-145 inhibitor restores the liver defects caused by dysregulation of miR-145 expression. In conclusion, our findings suggest an important role of miR-145 in regulating GrnA-dependent hepatic outgrowth in zebrafish embryonic development.
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Affiliation(s)
- Ya-Wen Li
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Keng-Yu Chiang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- Department of Life science, National Taiwan University, Taipei, Taiwan
| | - Yen-Hsing Li
- Department of Chemistry, Purdue University, West Lafayette, Indiana, United States of America
| | - Sung-Yu Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Wangta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Ray Lin
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Jen-Leih Wu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- * E-mail:
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17
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Sousa MS, Peate M, Jarvis S, Hickey M, Friedlander M. A clinical guide to the management of genitourinary symptoms in breast cancer survivors on endocrine therapy. Ther Adv Med Oncol 2017; 9:269-285. [PMID: 28491147 PMCID: PMC5405994 DOI: 10.1177/1758834016687260] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/16/2016] [Indexed: 12/19/2022] Open
Abstract
There is increasing attention and concern about managing the adverse effects of adjuvant endocrine therapy for women with early breast cancer as the side effects of therapy influence compliance and can impair quality of life (QoL). Most side effects associated with tamoxifen (TAM) and aromatase inhibitors (AIs) are directly related to estrogen deprivation, and the symptoms are similar to those experienced during natural menopause but appear to be more severe than that seen in the general population. Prolonged estrogen deprivation may lead to atrophy of the vulva, vagina, lower urinary tract and supporting pelvic structures, resulting in a range of genitourinary symptoms that can in turn lead to pain, discomfort, impairment of sexual function and negatively impact on multiple domains of QoL. The genitourinary side effects may be prevented, reduced and managed in most cases but this requires early recognition and appropriate treatment. We provide an overview of practical clinical approaches to understanding the pathophysiology and the management of genitourinary symptoms in postmenopausal women receiving adjuvant endocrine therapy for breast cancer.
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Affiliation(s)
- Mariana S. Sousa
- School of Nursing and Midwifery, Western Sydney University, Centre for Applied Nursing Research, South Western Sydney Local Health District, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
Prince of Wales Clinical School, University of New South Wales Australia Sydney, New South Wales, Australia
| | - Michelle Peate
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Parkville, Victoria, Australia
| | - Sherin Jarvis
- Pelvic Floor Physiotherapy, Women’s Health & Research Institute of Australia, New South Wales, Australia
| | - Martha Hickey
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Parkville, Victoria, Australia
| | - Michael Friedlander
- Prince of Wales Clinical School, University of New South Wales Australia, Sydney, New South Wales, Australia
Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia
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Kim WE, Yue B, Serrero G. Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2016; 9:71-7. [PMID: 27168723 PMCID: PMC4859449 DOI: 10.4137/bcbcr.s29371] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/08/2016] [Accepted: 03/06/2016] [Indexed: 12/16/2022]
Abstract
Her2 is a receptor tyrosine kinase overexpressed in 25% of breast tumors. We have shown that the 88 kDa autocrine growth and survival factor GP88 (progranulin) stimulated Her2 phosphorylation and proliferation and conferred Herceptin resistance in Her2-overexpressing cells. Herein, we report that GP88 stimulates c-myc phosphorylation and upregulates c-myc levels in Her2-overexpressing cells. c-myc phosphorylation and upregulation by GP88 were not observed in non-Her2-overexpressing breast cancer cells. c-myc activation was inhibited upon treatment with ERK, PI3 kinase, and c-src pathway inhibitors, U0126, LY294002, and PP2. GP88 also stimulated c-src phosphorylation, a known upstream regulator of c-myc. Thus, we describe here a signaling pathway for GP88 in Her2-overexpressing cells, with GP88 stimulating Src phosphorylation, followed by phosphorylation and upregulation of c-myc. These data would suggest that targeting GP88 could provide a novel treatment approach in breast cancer.
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Affiliation(s)
- Wes E Kim
- A&G Pharmaceutical Inc., Columbia, MD, USA
| | - Binbin Yue
- A&G Pharmaceutical Inc., Columbia, MD, USA
| | - Ginette Serrero
- A&G Pharmaceutical Inc., Columbia, MD, USA.; Member of the Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA
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19
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Botelho MC, Alves H, Richter J. Wound healing and cancer progression in Opisthorchis viverrini associated cholangiocarcinoma. Parasitol Res 2016; 115:2913-4. [PMID: 27130317 DOI: 10.1007/s00436-016-5090-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 04/21/2016] [Indexed: 11/25/2022]
Abstract
Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). It was shown previously that O. viverrini-secreted proteins accelerate wound resolution in human cholangiocytes. Recombinant Ov-GRN-1 (O. viverrini-derived gene encoding granulin-like growth factor) induced angiogenesis and accelerated mouse wound healing. Given the striking similarities of wound healing and cancer progression, here we discuss the major implications of this finding for an infection-induced cancer of major public health significance in the developing world.
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Affiliation(s)
- Monica C Botelho
- INSA-National Institute of Health Dr. Ricardo Jorge, Rua Alexandre Herculano, 321, 4000-055, Porto, Portugal.
- I3S, Instituto de Investigação e Inovação da Universidade do Porto, Porto, Portugal.
| | - Helena Alves
- INSA-National Institute of Health Dr. Ricardo Jorge, Rua Alexandre Herculano, 321, 4000-055, Porto, Portugal
| | - Joachim Richter
- Tropical Medicine Unit, Department for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
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20
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Tanimoto R, Lu KG, Xu SQ, Buraschi S, Belfiore A, Iozzo RV, Morrione A. Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers. Front Endocrinol (Lausanne) 2016; 7:100. [PMID: 27512385 PMCID: PMC4961702 DOI: 10.3389/fendo.2016.00100] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 07/08/2016] [Indexed: 11/13/2022] Open
Abstract
The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.
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Affiliation(s)
- Ryuta Tanimoto
- Biology of Prostate Cancer Program, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Kuojung G. Lu
- Biology of Prostate Cancer Program, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Shi-Qiong Xu
- Biology of Prostate Cancer Program, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Simone Buraschi
- Cancer Cell Biology and Signaling Program, Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Antonino Belfiore
- Department of Health Sciences, Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Renato V. Iozzo
- Cancer Cell Biology and Signaling Program, Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Andrea Morrione
- Biology of Prostate Cancer Program, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
- *Correspondence: Andrea Morrione,
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21
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Yamamoto Y, Takemura M, Serrero G, Hayashi J, Yue B, Tsuboi A, Kubo H, Mitsuhashi T, Mannami K, Sato M, Matsunami H, Matuo Y, Saito K. Increased serum GP88 (Progranulin) concentrations in rheumatoid arthritis. Inflammation 2015; 37:1806-13. [PMID: 24803297 DOI: 10.1007/s10753-014-9911-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
GP88 (Progranulin; PGRN) is a secreted glycosylated protein with important functions in several processes, including immune response and cancer growth. Recent reports have shown that PGRN is a therapeutic target for rheumatoid arthritis (RA) because of its capability to bind with tumor necrosis factor receptor (TNFR). However, the serum PGRN level in RA patients has not been investigated. We used enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of PGRN in 417 healthy subjects, 56 patients with RA and 31 patients with osteoarthritis (OA). In RA patients, we also measured the serum TNF-α and sTNFR concentration. Immunohistochemical staining of PGRN was performed using synovectomy tissue of RA patients. The serum PGRN normal range was established as 40.1 ± 8.7 ng/ml. PGRN levels were not influenced by sex or age. A significant increase in serum PGRN levels was observed in RA (50.2 ± 11.1 ng/ml) and OA (45.4 ± 6.6 ng/ml) groups compared to those in age-matched healthy controls (40.4 ± 9.9 ng/ml) (p<0.05, Tukey). Further, PGRN levels in the synovial fluid of RA patients (68.4 ± 3.4 ng/ml) were found to be significantly higher than those in OA patients (35.9 ± 16.8 ng/ml). Immunohistochemical staining of PGRN revealed that the highest positive signal was detected in macrophages. Circulating PGRN in RA patients was weakly associated with TNF-α and sTNFR 2 concentration. Furthermore, PGRN/TNF-α ratio was correlated the stage of the disease in RA patients. The concentrations of serum PGRN in RA were found to be significantly higher than those in age-matched healthy controls, although it remains to be clarified how blood PGRN is related to the pathogenesis of RA. Our results showed that the serum PGRN may be a useful approach to monitor the disease activity in RA patients.
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Affiliation(s)
- Yasuko Yamamoto
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 606-8507, Japan,
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22
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Belkaid A, Duguay SR, Ouellette RJ, Surette ME. 17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells. BMC Cancer 2015; 15:440. [PMID: 26022099 PMCID: PMC4446951 DOI: 10.1186/s12885-015-1452-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 05/19/2015] [Indexed: 12/16/2022] Open
Abstract
Background To sustain cell growth, cancer cells exhibit an altered metabolism characterized by increased lipogenesis. Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the production of monounsaturated fatty acids that are essential for membrane biogenesis, and is required for cell proliferation in many cancer cell types. Although estrogen is required for the proliferation of many estrogen-sensitive breast carcinoma cells, it is also a repressor of SCD-1 expression in liver and adipose. The current study addresses this apparent paradox by investigating the impact of estrogen on SCD-1 expression in estrogen receptor-α-positive breast carcinoma cell lines. Methods MCF-7 and T47D mammary carcinomas cells and immortalized MCF-10A mammary epithelial cells were hormone-starved then treated or not with 17β-estradiol. SCD-1 activity was assessed by measuring cellular monounsaturated/saturated fatty acid (MUFA/SFA) ratios, and SCD-1 expression was measured by qPCR, immunoblot, and immunofluorescence analyses. The role of SCD-1 in cell proliferation was measured following treatment with the SCD-1 inhibitor A959372 and following SCD-1 silencing using siRNA. The involvement of IGF-1R on SCD-1 expression was measured using the IGF-1R antagonist AG1024. The expression of SREBP-1c, a transcription factor that regulates SCD-1, was measured by qPCR, and by immunoblot analyses. Results 17β-estradiol significantly induced cell proliferation and SCD-1 activity in MCF-7 and T47D cells but not MCF-10A cells. Accordingly, 17β-estradiol significantly increased SCD-1 mRNA and protein expression in MCF-7 and T47D cells compared to untreated cells. Treatment of MCF-7 cells with 4-OH tamoxifen or siRNA silencing of estrogen receptor-α largely prevented 17β-estradiol-induced SCD-1 expression. 17β-estradiol increased SREBP-1c expression and induced the mature active 60 kDa form of SREBP-1. The selective SCD-1 inhibitor or siRNA silencing of SCD-1 blocked the 17β-estradiol-induced cell proliferation and increase in cellular MUFA/SFA ratios. IGF-1 also induced SCD-1 expression, but to a lesser extent than 17β-estradiol. The IGF-1R antagonist partially blocked 17β-estradiol-induced cell proliferation and SCD-1 expression, suggesting the impact of 17β-estradiol on SCD-1 expression is partially mediated though IGF-1R signaling. Conclusions This study illustrates for the first time that, in contrast to hepatic and adipose tissue, estrogen induces SCD-1 expression and activity in breast carcinoma cells. These results support SCD-1 as a therapeutic target in estrogen-sensitive breast cancer.
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Affiliation(s)
- Anissa Belkaid
- Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine Maillet Ave, Moncton, NB, E1A 3E9, Canada. .,Atlantic Cancer Research Institute, Moncton, NB, Canada.
| | - Sabrina R Duguay
- Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine Maillet Ave, Moncton, NB, E1A 3E9, Canada.
| | | | - Marc E Surette
- Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine Maillet Ave, Moncton, NB, E1A 3E9, Canada.
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23
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Yeh JE, Kreimer S, Walker SR, Emori MM, Krystal H, Richardson A, Ivanov AR, Frank DA. Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer. Genes Cancer 2015; 6:153-68. [PMID: 26000098 PMCID: PMC4426952 DOI: 10.18632/genesandcancer.58] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 04/14/2015] [Indexed: 11/25/2022] Open
Abstract
Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer.
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Affiliation(s)
- Jennifer E Yeh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Simion Kreimer
- Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA
| | - Sarah R Walker
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA ; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Megan M Emori
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Hannah Krystal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Andrea Richardson
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Alexander R Ivanov
- Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA ; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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24
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Edelman MJ, Feliciano J, Yue B, Bejarano P, Ioffe O, Reisman D, Hawkins D, Gai Q, Hicks D, Serrero G. GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma. Hum Pathol 2014; 45:1893-9. [PMID: 25033727 DOI: 10.1016/j.humpath.2014.05.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 05/16/2014] [Accepted: 05/21/2014] [Indexed: 11/29/2022]
Abstract
GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non-small cell lung carcinoma (NSCLC) patients, 85 with localized (stage I-II), and 40 with locally advanced disease (stage IIIa) and correlated with clinical outcome. Serum GP88 levels from stage IIIb/IV patients, quantified by enzyme immunoassay were compared with GP88 levels from patients with chronic obstructive pulmonary disease and healthy individuals. GP88 was expressed in more than 80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 immunohistochemistry score, 3+ versus < 3+) with survival for patients with localized resected NSCLC with hazard ratio (HR) = 2.28 (P = .0076) for disease-free survival and HR = 2.17 (P = .014) for overall survival. A statistically significant decrease in progression-free survival (HR = 2.9; P = .022) for GP88 scores of 3+ versus less than 3+ was observed for stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in stage IIIb/IV NSCLC compared with control subjects (49.9 ng/mL versus 28.4 ng/mL; P < .0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics.
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Affiliation(s)
- Martin J Edelman
- Department of Medicine, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, MD 21201
| | - Josephine Feliciano
- Department of Medicine, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, MD 21201
| | | | - Pablo Bejarano
- Department of Pathology, Cleveland Clinic Florida, Weston, FL 33331
| | - Olga Ioffe
- Department of Pathology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore MD 21201
| | - David Reisman
- Department of Medicine, University of Florida, Gainesville, FL 32610
| | - Douglas Hawkins
- School of Statistics University of Minnesota, Minneapolis, MN 55455
| | - Qiwei Gai
- Department of Medicine, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, MD 21201
| | | | - Ginette Serrero
- A&G Pharmaceutical, Columbia MD 21045; University of Maryland, Greenebaum Cancer Center, Baltimore, MD 21201.
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Romanello M, Piatkowska E, Antoniali G, Cesaratto L, Vascotto C, Iozzo RV, Delneri D, Brancia FL. Osteoblastic cell secretome: a novel role for progranulin during risedronate treatment. Bone 2014; 58:81-91. [PMID: 24120669 PMCID: PMC5072534 DOI: 10.1016/j.bone.2013.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 09/19/2013] [Accepted: 10/01/2013] [Indexed: 11/25/2022]
Abstract
It is well established that osteoblasts, the key cells involved in bone formation during development and in adult life, secrete a number of glycoproteins harboring autocrine and paracrine functions. Thus, investigating the osteoblastic secretome could yield important information for the pathophysiology of bone. In the present study, we characterized for the first time the secretome of human Hobit osteoblastic cells. We discovered that the secretome comprised 89 protein species including the powerful growth factor progranulin. Recombinant human progranulin (6nM) induced phosphorylation of mitogen-activated protein kinase in both Hobit and osteocytic cells and induced cell proliferation and survival. Notably, risedronate, a nitrogen-containing bisphosphonate widely used in the treatment of osteoporosis, induced the expression and secretion of progranulin in the Hobit secretome. In addition, our proteomic study of the Hobit secretome revealed that risedronate induced the expression of ERp57, HSP60 and HSC70, three proteins already shown to be associated with the prevention of bone loss in osteoporosis. Collectively, our findings unveil novel targets of risedronate-evoked biological effects on osteoblast-like cells and further our understanding of the mechanisms of action of this currently used compound.
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Affiliation(s)
- Milena Romanello
- Laboratory of Regional Centre for Rare Diseases, University Hospital, Santa Maria della Misericordia, 33100 Udine, Italy.
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Hwang HJ, Jung TW, Hong HC, Choi HY, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH, Yoo HJ. Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways. PLoS One 2013; 8:e76679. [PMID: 24098801 PMCID: PMC3786912 DOI: 10.1371/journal.pone.0076679] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 08/25/2013] [Indexed: 12/22/2022] Open
Abstract
Objective Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Method and Results Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Conclusion Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis.
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Affiliation(s)
- Hwan-Jin Hwang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Tae Woo Jung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Ho Cheol Hong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Hae Yoon Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Ji-A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Sin Gon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Dong Seop Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Sei Hyun Baik
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Hye Jin Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea
- * E-mail:
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Carlson AM, Maurer MJ, Goergen KM, Kalli KR, Erskine CL, Behrens MD, Knutson KL, Block MS. Utility of progranulin and serum leukocyte protease inhibitor as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Epidemiol Biomarkers Prev 2013; 22:1730-5. [PMID: 23878295 DOI: 10.1158/1055-9965.epi-12-1368] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related death in females and leading gynecologic cause of cancer-related death. Despite the identification of a number of serum biomarkers, methods to identify early-stage disease and predict prognosis remain scarce. We have evaluated two biologically connected serum biomarkers, serum leukocyte protease inhibitor (SLPI) and progranulin (PGRN). METHODS Two-hundred frozen plasma samples were acquired from the Mayo Clinic Biospecimen Repository for Ovarian Cancer Research. Samples were obtained from 50 patients with benign conditions, 50 with American Joint Committee on Cancer (AJCC) stage I and II EOC, and 100 with AJCC stage III and IV EOC. Samples were obtained before surgical resection of a mass and were analyzed for absolute levels of SLPI and PGRN using ELISA assays. Receiver-operator characteristic curves were generated for SLPI and PGRN. Median follow-up was 48 months. RESULTS Absolute levels of SLPI were significantly elevated in patients with EOC compared with benign disease and predicted the presence of EOC (AUC of 0.812; P = 0.04); SLPI remained elevated in the subset of patients with normal CA-125. PGRN levels were not significantly increased in patients with early-stage or late-stage EOC as a whole, but an increase in PGRN levels was associated with decreased overall survival in advanced EOC. CONCLUSIONS SLPI levels are elevated in EOC, and SLPI shows promise as a diagnostic biomarker for patients with both elevated and normal CA-125 levels. An increase in PGRN is associated with decreased overall survival. IMPACT SLPI is elevated in EOC and warrants investigation in a screening study in women at risk for EOC.
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Affiliation(s)
- Aaron M Carlson
- Authors' Affiliations: Mayo Medical School, Biomedical Statistics and Informatics, and Departments of Medical Oncology and Immunology, Mayo Clinic, Rochester, Minnesota
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Kleinberger G, Capell A, Haass C, Van Broeckhoven C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol 2012; 47:337-60. [PMID: 23239020 PMCID: PMC3538123 DOI: 10.1007/s12035-012-8380-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 11/14/2012] [Indexed: 12/12/2022]
Abstract
The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a “loss-of-function” mechanism, encouraging researchers to develop a growing number of cellular and animal models for GRN deficiency. GRN is a multifunctional secreted growth factor, and loss of its function can affect different cellular processes. Besides loss-of-function (i.e., mostly premature termination codons) mutations, which cause GRN haploinsufficiency through reduction of GRN expression, FTD-associated GRN missense mutations have also been identified. Several of these missense mutations are predicted to increase the risk of developing neurodegenerative diseases through altering various key biological properties of GRN-like protein secretion, proteolytic processing, and neurite outgrowth. With the use of cellular and animal models for GRN deficiency, the portfolio of GRN functions has recently been extended to include functions in important biological processes like energy and protein homeostasis, inflammation as well as neuronal survival, neurite outgrowth, and branching. Furthermore, GRN-deficient animal models have been established and they are believed to be promising disease models as they show accelerated aging and recapitulate at least some neuropathological features of FTD. In this review, we summarize the current knowledge on the molecular mechanisms leading to GRN deficiency and the lessons we learned from the established cellular and animal models. Furthermore, we discuss how these insights might help in developing therapeutic strategies for GRN-associated FTD.
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Affiliation(s)
- Gernot Kleinberger
- Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, Antwerp, 2610, Belgium
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Steinman RA, Brufsky AM, Oesterreich S. Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment? Breast Cancer Res 2012; 14:213. [PMID: 23014660 PMCID: PMC4053096 DOI: 10.1186/bcr3223] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Zoledronic acid (ZA) is an imidazole-containing bisphosphonate that has been extensively studied as an osteoclast inhibitor. ZA decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti-cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anti-cancer effects of ZA are limited to estrogen-poor environments. This review explores possible mechanisms compatible with differences in ZA activity in premenopausal women compared with postmenopausal (or hormone-suppressed) women.
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Lam HM, Babu CS, Wang J, Yuan Y, Lam YW, Ho SM, Leung YK. Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion. Mol Cell Endocrinol 2012; 358:27-35. [PMID: 22370157 PMCID: PMC3348253 DOI: 10.1016/j.mce.2012.02.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 01/20/2012] [Accepted: 02/10/2012] [Indexed: 12/30/2022]
Abstract
Multiple phosphorylation sites on the human estrogen receptor (hER)α were identified and shown to influence mammary carcinogenesis. In contrast, functional phosphorylation sites of hERβ have yet to be experimentally identified and validated. Here, using mass spectrometry, we uncovered three serines (S75, S87, and S105) in the N-terminus of hERβ as targets of ERK1/2 and p38 kinases. We raised a specific antibody against phosphorylated S105 (pS105) and demonstrated that this site was endogenously phosphorylated in MDA-MB-231 and BT-474 cells. A phospho-mimetic mutant generated from hERβ1 was found to exhibit higher transactivation activity than hERβ1. Ectopic expression of this mutant inhibited cell migration and invasion, but did not affect cell growth and cell-cycle progression in these cell models. In breast cancer specimens, pS105-hERβ immunoreactivity was detected with a higher prevalence and intensity than that of hERβ1. These results underscore the functional importance of the first experimentally identified hERβ-phosphorylation site in breast cancer.
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Affiliation(s)
- Hung-Ming Lam
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
| | - C.V. Suresh Babu
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
| | - Jiang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267
| | - Yong Yuan
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
| | - Ying-Wai Lam
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267
| | - Shuk-Mei Ho
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Cincinnati Cancer Center, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Cincinnati Veteran Affairs Medical Center, Cincinnati, OH 45220
- To whom correspondence should be addressed (co-corresponding authors): Yuet-Kin Leung, Ph.D., Division of Environmental Genetics and Molecular Toxicology, Kettering Complex, Room 331, 3223 Eden Avenue, Department of Environmental Health, College of Medicine, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267, Tel: 513- 558-5181, Fax: 513-558-5155, , Shuk-Mei Ho, Ph.D., Kettering Complex, Room 128, 3223 Eden Avenue, Department of Environmental Health, College of Medicine, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267, Tel: 513- 558-5701, Fax: 513-558-5155,
| | - Yuet-Kin Leung
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267
- Cincinnati Cancer Center, University of Cincinnati Medical Center, Cincinnati, OH 45267
- To whom correspondence should be addressed (co-corresponding authors): Yuet-Kin Leung, Ph.D., Division of Environmental Genetics and Molecular Toxicology, Kettering Complex, Room 331, 3223 Eden Avenue, Department of Environmental Health, College of Medicine, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267, Tel: 513- 558-5181, Fax: 513-558-5155, , Shuk-Mei Ho, Ph.D., Kettering Complex, Room 128, 3223 Eden Avenue, Department of Environmental Health, College of Medicine, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267, Tel: 513- 558-5701, Fax: 513-558-5155,
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Huang K, Huang C, Shan K, Chen J, Li H. Significance of PC cell-derived growth factor and cyclin D1 expression in cutaneous squamous cell carcinoma. Clin Exp Dermatol 2012; 37:411-7. [PMID: 22420613 DOI: 10.1111/j.1365-2230.2011.04275.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND PC cell-derived growth factor (PCDGF) is an autocrine growth factor originally purified from the highly tumorigenic teratoma PC cell line. It participates in tumorigenesis and tumour progression through upregulation of cyclin D1. To date, there has been no report on the role of PCDGF in skin cancer, to our knowledge. AIM To investigate the expression of PCDGF and cyclin D1 in basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and seborrhoeic keratosis (SK), and their relationship with the clinicopathological parameters of SCC. METHODS Immunohistochemical expression of PCDGF and cyclin D1 was examined in 42 SCC, 30 BCC and 20 SK tissues. RESULTS PCDGF and cyclin D1 were overexpressed in SCC or BCC tissues compared with normal skin or SK, and their expressions were significantly higher in SCC than in BCC. Moreover, positive expression of PCDGF and cyclin D1 was significantly correlated with depth of invasion and metastasis of SCC. There was significant correlation between PCDGF and cyclin D1 expression in SCC. CONCLUSIONS Expression of PCDGF and cyclin D1 plays an important role in the tumorigenesis of BCC and SCC. Abnormal expression of PCDGF and Cyclin D1 may be related to invasion and metastasis of SCC.
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Affiliation(s)
- K Huang
- Department of Dermatology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Serrero G, Hawkins DM, Yue B, Ioffe O, Bejarano P, Phillips JT, Head JF, Elliott RL, Tkaczuk KR, Godwin AK, Weaver J, Kim WE. Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma. Breast Cancer Res 2012; 14:R26. [PMID: 22316048 PMCID: PMC3496144 DOI: 10.1186/bcr3111] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 01/16/2012] [Accepted: 02/08/2012] [Indexed: 01/10/2023] Open
Abstract
Introduction GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients. Methods Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis. Results GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments. Conclusions The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.
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Affiliation(s)
- Ginette Serrero
- A&G Pharmaceutical Inc,, 9130 Red Branch Rd,, Columbia, MD 21045, USA.
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Abstract
BACKGROUND AND OBJECTIVES Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. METHODS The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. RESULTS Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. CONCLUSIONS Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies.
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Frampton G, Invernizzi P, Bernuzzi F, Pae HY, Quinn M, Horvat D, Galindo C, Huang L, McMillin M, Cooper B, Rimassa L, DeMorrow S. Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut 2012; 61:268-77. [PMID: 22068162 PMCID: PMC4498955 DOI: 10.1136/gutjnl-2011-300643] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVES Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. METHODS The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. RESULTS Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. CONCLUSIONS Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies.
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Affiliation(s)
- Gabriel Frampton
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Francesca Bernuzzi
- Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy,Department of Translational Medicine, Università degli studi di Milano, Rozzano, Italy
| | - Hae Yong Pae
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | - Matthew Quinn
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | - Darijana Horvat
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | - Cheryl Galindo
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | - Li Huang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Matthew McMillin
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
| | | | - Lorenza Rimassa
- UO Oncologia medica e ematologia, Humanitas Cancer Center, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Sharon DeMorrow
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA,Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA,Research Service, Central Texas Veterans Health Care System, Temple, Texas USA
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Xu J, Xilouri M, Bruban J, Shioi J, Shao Z, Papazoglou I, Vekrellis K, Robakis NK. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 2011; 32:2326.e5-16. [PMID: 21820214 PMCID: PMC3375317 DOI: 10.1016/j.neurobiolaging.2011.06.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 06/08/2011] [Accepted: 06/18/2011] [Indexed: 11/23/2022]
Abstract
To reduce damage from toxic insults such as glutamate excitotoxicity and oxidative stresses, neurons may deploy an array of neuroprotective mechanisms. Recent reports show that progranulin (PGRN) gene null or missense mutations leading to inactive protein, are linked to frontotemporal lobar degeneration (FTLD), suggesting that survival of certain neuronal populations needs full expression of functional PGRN. Here we show that extracellular PGRN stimulates phosphorylation/activation of the neuronal MEK/extracellular regulated kinase (ERK)/p90 ribosomal S6 kinase (p90RSK) and phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stress. Pharmacological inhibition of MEK/ERK/p90RSK signaling blocks the PGRN-induced phosphorylation and neuroprotection against glutamate toxicity while inhibition of either MEK/ERK/p90RSK or PI3K/Akt blocks PGRN protection against neurotoxin MPP(+). Inhibition of both pathways had synergistic effects on PGRN-dependent neuroprotection against MPP(+) toxicity suggesting both pathways contribute to the neuroprotective activities of PGRN. Extracellular PGRN is remarkably stable in neuronal cultures indicating neuroprotective activities are associated with full-length protein. Together, our data show that extracellular PGRN acts as a neuroprotective factor and support the hypothesis that in FTLD reduction of functional brain PGRN results in reduced survival signaling and decreased neuronal protection against excitotoxicity and oxidative stress leading to accelerated neuronal cell death. That extracellular PGRN has neuroprotective functions against toxic insults suggests that in vitro preparations of this protein may be used therapeutically.
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Affiliation(s)
- Jindong Xu
- Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA 10029
| | - Maria Xilouri
- Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece 11527
| | - Julien Bruban
- Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA 10029
| | - Junichi Shioi
- Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA 10029
| | - Zhiping Shao
- Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA 10029
| | - Ioannis Papazoglou
- Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece 11527
| | - Kostas Vekrellis
- Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece 11527
| | - Nikolaos K. Robakis
- Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA 10029
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Liu CJ, Bosch X. Progranulin: a growth factor, a novel TNFR ligand and a drug target. Pharmacol Ther 2011; 133:124-32. [PMID: 22008260 DOI: 10.1016/j.pharmthera.2011.10.003] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Accepted: 09/21/2011] [Indexed: 01/05/2023]
Abstract
Progranulin (PGRN) is abundantly expressed in epithelial cells, immune cells, neurons, and chondrocytes, and reportedly contributes to tumorigenesis. PGRN is a crucial mediator of wound healing and tissue repair. PGRN also functions as a neurotrophic factor and mutations in the PGRN gene resulting in partial loss of the PGRN protein cause frontotemporal dementia. PGRN has been found to be a novel chondrogenic growth factor and to play an important role in cartilage development and inflammatory arthritis. Although research has shown that PGRN exhibits anti-inflammatory properties, the details about the exact molecular pathway of such effects, and, in particular, the PGRN binding receptor, have not been identified so far. Recently, researchers have shown that PGRN binds to tumor necrosis factor (TNF)-receptors (TNFR), interfering with the interaction between TNFα and TNFR. They further demonstrated that mice deficient in PGRN are susceptible to collagen-induced arthritis, an experimental model of rheumatoid arthritis, and that administration of PGRN reversed the arthritic process. An engineered protein made of three PGRN fragments (Atsttrin), displayed selective TNFR binding and was more active than natural PGRN. Both PGRN and Atsttrin prevented inflammation in various arthritis mouse models and inhibited TNFα-induced intracellular signaling pathways. Thus, PGRN is a key regulator of inflammation and it may mediate its anti-inflammatory effects, at least in part, by blocking TNF binding to its receptors. As we discuss here, TNFR-based interventions may both stimulate and suppress the growth of cancer cells, and the same may be true in analogy for Atsttrin as a new player.
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Affiliation(s)
- Chuan-ju Liu
- Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, United States
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Tkaczuk KR, Yue B, Zhan M, Tait N, Yarlagadda L, Dai H, Serrero G. Increased Circulating Level of the Survival Factor GP88 (Progranulin) in the Serum of Breast Cancer Patients When Compared to Healthy Subjects. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2011; 5:155-62. [PMID: 21792312 PMCID: PMC3140268 DOI: 10.4137/bcbcr.s7224] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Introduction: GP88 (PC-Cell Derived Growth Factor, progranulin) is a glycoprotein overexpressed in breast tumors and involved in their proliferation and survival. Since GP88 is secreted, an exploratory study was established to compare serum GP88 level between breast cancer patients (BC) and healthy volunteers (HV). Methods: An IRB approved prospective study enrolled 189 stage 1–4 BC patients and 18 HV. GP88 serum concentration was determined by immunoassay. Results: Serum GP88 level was 28.7 + 5.8 ng/ml in HV and increased to 40.7 + 16.0 ng/ml (P = 0.007) for stage 1–3 and 45.3 + 23.3 ng/ml (P = 0.0007) for stage 4 BC patients. There was no correlation between the GP88 level and BC characteristics such as age, race, tumor grade, ER, PR and HER-2 expression. Conclusion: These data suggest that serial testing of serum GP88 levels may have value as a circulating biomarker for detection, monitoring and follow up of BC.
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Affiliation(s)
- Katherine Rak Tkaczuk
- University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA
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Structure, function, and mechanism of progranulin; the brain and beyond. J Mol Neurosci 2011; 45:538-48. [PMID: 21691802 DOI: 10.1007/s12031-011-9569-4] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 05/31/2011] [Indexed: 12/13/2022]
Abstract
Mutation of human GRN, the gene encoding the secreted glycoprotein progranulin, results in a form of frontotemporal lobar degeneration that is characterized by the presence of ubiquitinated inclusions containing phosphorylated and cleaved fragments of the transactivation response element DNA-binding protein-43. This has stimulated interest in understanding the role of progranulin in the central nervous system, and in particular, how this relates to neurodegeneration. Progranulin has many roles outside the brain, including regulation of cellular proliferation, survival, and migration, in cancer, including cancers of the brain, in wound repair, and inflammation. It often acts through the extracellular signal-regulated kinase and phopshatidylinositol-3-kinases pathways. The neurobiology of progranulin has followed a similar pattern with proposed roles for progranulin (PGRN) in the central nervous system as a neuroprotective agent and in neuroinflammation. Here we review the structure, biology, and mechanism of progranulin action. By understanding PGRN in a wider context, we may be better able to delineate its roles in the normal brain and in neurodegenerative disease.
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Abrhale T, Brodie A, Sabnis G, Macedo L, Tian C, Yue B, Serrero G. GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells. BMC Cancer 2011; 11:231. [PMID: 21658239 PMCID: PMC3129588 DOI: 10.1186/1471-2407-11-231] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 06/09/2011] [Indexed: 01/13/2023] Open
Abstract
Background Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells Methods We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined. Results GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. Conclusion Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.
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Affiliation(s)
- Tesfom Abrhale
- A&G Pharmaceutical Inc, 9130 Red Branch Rd, Columbia, MD, USA
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40
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Cellular effects of progranulin in health and disease. J Mol Neurosci 2011; 45:549-60. [PMID: 21611805 DOI: 10.1007/s12031-011-9553-z] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 05/10/2011] [Indexed: 12/12/2022]
Abstract
Progranulin is a fascinating multifunctional protein, which has been implicated in cell growth, wound repair, tumorigenesis, inflammation, neurodevelopment, and more recently in neurodegeneration. The mechanism of action of this protein is still largely unknown, but the knowledge about the cellular effects on various cell types is expanding. In the current review, we will summarize what is known about the cell biology of progranulin. A better understanding of the biology of progranulin will impact diverse areas of research.
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Wu S, Zang W, Li X, Sun H. Proepithelin stimulates growth plate chondrogenesis via nuclear factor-kappaB-p65-dependent mechanisms. J Biol Chem 2011; 286:24057-67. [PMID: 21566130 DOI: 10.1074/jbc.m110.201368] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Proepithelin, a previously unrecognized growth factor in cartilage, has recently emerged as an important regulator for cartilage formation and function. In the present study, we provide several lines of evidences in proepithelin-mediated induction of cell proliferation, differentiation, and apoptosis in the metatarsal growth plate. Proepithelin-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by pyrrolidine dithiocarbamate, a known NF-κB inhibitor. In rat growth plate chondrocytes, proepithelin induced NF-κB-p65 nuclear translocation, and nuclear NF-κB-p65 initiated its target gene cyclin D1 to regulate chondrocyte functions. The inhibition of NF-κB-p65 expression and activity (by p65 short interfering RNA (siRNA) and pyrrolidine dithiocarbamate, respectively) in chondrocytes reversed the proepithelin-mediated induction of cell proliferation and differentiation and the proepithelin-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of proepithelin on NF-κB activation. Finally, using siRNA and antisense strategies, we demonstrated that endogenously produced proepithelin by chondrocytes is important for chondrocyte growth in serum-deprived conditions. These results support the hypothesis that the induction of NF-κB activity of in growth plate chondrocytes is critical in proepithelin-mediated growth plate chondrogenesis and longitudinal bone growth.
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Affiliation(s)
- Shufang Wu
- First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, 710061 China.
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Smout MJ, Sripa B, Laha T, Mulvenna J, Gasser RB, Young ND, Bethony JM, Brindley PJ, Loukas A. Infection with the carcinogenic human liver fluke, Opisthorchis viverrini. MOLECULAR BIOSYSTEMS 2011; 7:1367-75. [PMID: 21311794 PMCID: PMC3739706 DOI: 10.1039/c0mb00295j] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Throughout Southeast Asia there is a strikingly high incidence of cholangiocarcinoma (CCA--hepatic cancer of the bile duct epithelium), particularly in people from rural settings in Laos and Northeast Thailand who are infected with the liver fluke, Opisthorchis viverrini, one of only three carcinogenic eukaryotic pathogens. More ubiquitous carcinogenic microbes, such as Helicobacter pylori, induce cancer in less than 1% of infected people, while as many as one-sixth of people with opisthorchiasis will develop CCA. The mechanisms by which O. viverrini causes cancer are multi-factorial, involving mechanical irritation from the activities and movements of the flukes, immunopathology, dietary nitrosamines and the secretion of parasite proteins that promote a tumourigenic environment. Genomic and proteomic studies of the liver fluke secretome have accelerated the discovery of parasite proteins with known/potential roles in pathogenesis and tumourigenesis, establishing a framework towards understanding, and ultimately preventing, the morbidity and mortality attributed to this highly carcinogenic parasite.
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Affiliation(s)
- Michael J Smout
- Queensland Tropical Health Alliance, James Cook University, Cairns, QLD, Australia
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Cheung ST, Cheung PFY, Cheng CKC, Wong NCL, Fan ST. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance. Gastroenterology 2011; 140:344-55. [PMID: 20682318 DOI: 10.1053/j.gastro.2010.07.049] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 06/23/2010] [Accepted: 07/29/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chemotherapy is used to treat unresectable liver cancer with marginal efficacy; this might result from hepatic cancer cells with stem cell and chemoresistant features. Gene expression profiling studies have shown that hepatic cancer cells express granulin-epithelin precursor (GEP); we investigated its role in hepatic cancer stem cell functions and chemoresistance. METHODS The effects of GEP and drug transporter signaling on chemoresistance were investigated in hepatic cancer stem cells. We analyzed the expression patterns of 142 clinical samples from liver tumors, adjacent nontumorous liver tissue, and liver tissue from patients who did not have cancer. RESULTS GEP regulated the expression of the adenosine triphosphate-dependent binding cassette (ABC)B5 drug transporter in liver cancer cells. Chemoresistant cells that expressed GEP had increased levels of ABCB5; suppression of ABCB5 sensitized the cells to doxorubicin uptake and apoptosis. Most cells that expressed GEP and ABCB5 also expressed the hepatic cancer stem cell markers CD133 and EpCAM; blocking ABCB5 reduced their expression. Expression levels of GEP and ABCB5 were correlated in human liver tumor samples. ABCB5 levels were increased in liver cancer cells compared with nontumor liver tissue from patients with cirrhosis or hepatitis, or normal liver tissue. ABCB5 expression was associated with the recurrence of hepatocellular carcinoma after partial hepatectomy. CONCLUSIONS Expression of GEP and ABCB5 in liver cancer stem cells is associated with chemoresistance and reduced survival times of patients with hepatocellular carcinoma. Reagents designed to target these proteins might be developed as therapeutics and given in combination with chemotherapy to patients with liver cancer.
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Affiliation(s)
- Siu Tim Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China.
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Duarte RA, Mello ER, Araki C, Bolzani VDS, Siqueira e Silva DH, Regasini LO, Silva TGA, de Morais MCC, Ximenes VF, Soares CP. Alkaloids extracted from Pterogyne nitens induce apoptosis in malignant breast cell line. Tumour Biol 2010; 31:513-22. [PMID: 20700682 DOI: 10.1007/s13277-010-0064-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Accepted: 05/31/2010] [Indexed: 11/26/2022] Open
Abstract
In the present study, two alkaloids isolated from Pterogyne nitens, a plant native to Brazil, have been shown to induce apoptosis in human breast cancer cells. These compounds, pterogynine (PGN) and pterogynidine (PGD), were tested for their effect on a human infiltrating ductal carcinoma cell line (ZR-7531). The cell line was treated with each alkaloid at several concentrations. Time-dependence (with or without recuperation time) and concentration-dependence (in the range 0.25-10 mM) were investigated in cytotoxicity and apoptosis assays. The annexin assay indicated an apparently higher percentage of death by necrosis of malignant cells after 24 h exposure to both P. nitens extracts than the Hoechst assay. Thus, our results in the two tests demonstrated that the Hoechst assay can discriminate between late apoptotic cells and necrosis, whereas the flow cytometry-based annexin V assay cannot. We concluded that PGN and PGD have effective antineoplastic activity against human breast cancer cells in vitro, by inducing programmed cell death.
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Affiliation(s)
- Roberta Aparecida Duarte
- School of Pharmaceutical Sciences, University of São Paulo State -UNESP, Rua Expedicionários do Brasil, 1621, Zip code 14801-902, Araraquara, Sao Paulo, Brazil
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Ryan CL, Baranowski DC, Chitramuthu BP, Malik S, Li Z, Cao M, Minotti S, Durham HD, Kay DG, Shaw CA, Bennett HPJ, Bateman A. Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci 2009; 10:130. [PMID: 19860916 PMCID: PMC2779192 DOI: 10.1186/1471-2202-10-130] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Accepted: 10/27/2009] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival. RESULTS In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival. CONCLUSION Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.
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Affiliation(s)
- Cara L Ryan
- Royal Victoria Hospital and Department of Medicine, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
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Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, Brindley PJ, Loukas A. A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells. PLoS Pathog 2009; 5:e1000611. [PMID: 19816559 PMCID: PMC2749447 DOI: 10.1371/journal.ppat.1000611] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Accepted: 09/10/2009] [Indexed: 01/02/2023] Open
Abstract
The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov-GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma.
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Affiliation(s)
- Michael J. Smout
- Division of Infectious Diseases, Queensland Institute of Medical Research, Queensland, Australia, and School of Population Health, The University of Queensland, Queensland, Australia
| | - Thewarach Laha
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
| | - Jason Mulvenna
- Division of Infectious Diseases, Queensland Institute of Medical Research, Queensland, Australia, and School of Population Health, The University of Queensland, Queensland, Australia
| | - Banchob Sripa
- Department of Pathology, Khon Kaen University, Khon Kaen, Thailand
| | - Sutas Suttiprapa
- Department of Pathology, Khon Kaen University, Khon Kaen, Thailand
| | - Alun Jones
- Institute for Molecular Biosciences, The University of Queensland, Queensland, Australia
| | - Paul J. Brindley
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, D. C., United States of America
| | - Alex Loukas
- Division of Infectious Diseases, Queensland Institute of Medical Research, Queensland, Australia, and School of Population Health, The University of Queensland, Queensland, Australia
- * E-mail:
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Suzuki M, Lee HC, Kayasuga Y, Chiba S, Nedachi T, Matsuwaki T, Yamanouchi K, Nishihara M. Roles of progranulin in sexual differentiation of the developing brain and adult neurogenesis. J Reprod Dev 2009; 55:351-5. [PMID: 19721334 DOI: 10.1262/jrd.20249] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Progranulin (PGRN) is a growth modulating factor released by a variety of cells. This molecule has gained the attention of the neuroscience community with recent discoveries of multifunctional roles of PGRN in normal brain and neurodegenerative disorders. We focus on novel roles of PGRN as a sex steroid-responsible gene in the developing and adult rodent brain. While the developing brain is feminine by default, hormone exposure, including androgen and estrogen, induces masculinization during the critical period. We have shown that PGRN is a sex steroid-responsible gene that may be involved in masculinization of the perinatal rat brain. We also found that in adult rats PGRN gene expression was up-regulated by estrogen in the hippocampus, suggesting that PGRN may mediate the mitogenic effects of estrogen in the active area of neurogenesis. Since it has been recently reported that mutations in PGRN gene are responsible for a type of frontotemporal lobar degeneration in humans, PGRN appears to be also involved in modulating neurodegeneration. Together, PGRN gene expression is induced by estrogen in both developing and adult brains, and it may play multifunctional roles in the organization of functional masculinization in the developing brain and the maintenance of adult brain function.
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Affiliation(s)
- Masatoshi Suzuki
- The Waisman Center, The Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705-2280, USA
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Lovat F, Bitto A, Xu SQ, Fassan M, Goldoni S, Metalli D, Wubah V, McCue P, Serrero G, Gomella LG, Baffa R, Iozzo RV, Morrione A. Proepithelin is an autocrine growth factor for bladder cancer. Carcinogenesis 2009; 30:861-868. [PMID: 19237611 PMCID: PMC2675649 DOI: 10.1093/carcin/bgp050] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Revised: 01/28/2009] [Accepted: 02/14/2009] [Indexed: 12/23/2022] Open
Abstract
The growth factor proepithelin functions as an important regulator of proliferation and motility. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian and renal cancer, as well as glioblastomas. Using recombinant proepithelin on 5637 transitional cell carcinoma-derived cells, we have shown previously that proepithelin plays a critical role in bladder cancer by promoting motility of bladder cancer cells. In this study, we used the ONCOMINE database and gene microarray analysis tool to analyze proepithelin expression in several bladder cancer microarray studies. We found a statistically significant increase in proepithelin messenger RNA expression in bladder cancers vis-à-vis non-neoplastic tissues, and this was associated with pathologic and prognostic parameters. Targeted downregulation of proepithelin in T24 transitional carcinoma cells with small hairpin RNA inhibited both Akt and mitogen-activated protein kinase pathways, severely reduced the ability of T24 cells to proliferate in the absence of serum and inhibited migration, invasion and wound healing. In support of these in vitro results, we discovered that proepithelin expression was significantly upregulated in invasive bladder cancer tissues compared with normal urothelium. In addition, proepithelin was secreted in the urine, where it was detectable by immunoblotting and enzyme-linked immunosorbent assay. Collectively, these results support the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and progression of bladder cancer and suggest that proepithelin may prove a novel biomarker for the diagnosis and prognosis of bladder neoplasms.
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Affiliation(s)
| | | | | | | | - Silvia Goldoni
- Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | | | | | - Peter McCue
- Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Ginette Serrero
- A&G Pharmaceutical Inc., Columbia, MD 21045, USA
- Program in Oncology, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
| | | | - Raffaele Baffa
- Department of Urology
- Present address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878, USA
| | - Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Andrea Morrione
- Department of Urology
- Endocrine Mechanisms and Hormone Action Program
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Monami G, Emiliozzi V, Bitto A, Lovat F, Xu SQ, Goldoni S, Fassan M, Serrero G, Gomella LG, Baffa R, Iozzo RV, Morrione A. Proepithelin regulates prostate cancer cell biology by promoting cell growth, migration, and anchorage-independent growth. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1037-1047. [PMID: 19179604 PMCID: PMC2665763 DOI: 10.2353/ajpath.2009.080735] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/01/2008] [Indexed: 11/20/2022]
Abstract
The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors.
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Affiliation(s)
- Giada Monami
- Department of Urology, Thomas Jefferson University, 233 South 10th St., BLSB Room 620, Philadelphia, PA 19107, USA
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Desmarais JA, Cao M, Bateman A, Murphy BD. Spatiotemporal expression pattern of progranulin in embryo implantation and placenta formation suggests a role in cell proliferation, remodeling, and angiogenesis. Reproduction 2008; 136:247-57. [DOI: 10.1530/rep-08-0044] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Embryo implantation in the mink is preceded by a variable but obligate period of delay in development. Under the influence of progesterone and unknown luteal factors, the mink embryo implants 11–13 days following its exit from diapause. Recent work suggests that progranulin, a growth factor and secreted glycoprotein, is involved in trophoblast proliferation, placental development and endometrial differentiation in the mouse. Using the mink model of delayed implantation and endotheliochorial placentation, we examined the spatiotemporal distribution of progranulin in trophoblast and endometrium during pre- and early post-implantation gestationin vivo. A partial sequence of the mink progranulin gene was cloned and sequenced. Comparative sequence analysis revealed that exons 1 and 2 of mink progranulin share 86.6, 82.4, and 94.9% of nucleic acid sequence identity with the human, mouse, and dog sequences respectively, and indicated that the invariable residues of the cysteine-rich motifs of progranulin are well conserved in the mink sequence. Byin situhybridization, we show that mink progranulin transcript is present in the cytotrophoblast and in epithelial and stromal endometrial cells at the site of implantation and during early placental formation. Immunohistochemistry revealed the progranulin protein to be strongly expressed in endometrial luminal and glandular epithelium around the time of implantation. In the incipient labyrinth, progranulin expression is localized to cytotrophoblasts and fetal capillaries, as well as to the hypertrophied maternal endothelial cells. This study demonstrates that high levels of progranulin expression correspond to active cell proliferation, remodeling, and angiogenesis occurring during the establishment of the placenta in the mink.
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