Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression

Miyanishi, Masanori; Mandai, Masaki; Matsumura, Noriomi; Yamaguchi, Ken; Hamanishi, Junzo; Higuchi, Toshihiro; Takakura, Kenji; Fujii, Shingo

doi:10.3892/or.17.2.329

Cited by 17 publications

(23 citation statements)

References 19 publications

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“…Progranulin has been reported to activate many of the typical cell proliferation signaling pathways, including ERK, PI3K, and Akt pathways (48,50,51), not only in tumor cells but also in neurons (52,53). Progranulin may be a prognostic marker (54) or a therapeutic target in cancer: progranulin overexpression confers an aggressive phenotype to adenocarcinoma (46), immortalized ovarian epithelial cells (55), breast cancer (49,56), and hepatocellular carcinoma (57), and anti-progranulin treatment reduces in vivo tumorigenicity of teratoma (58) and breast cancer cell lines (59). However, it should be emphasized that although these early studies strongly linked progranulin to cancer, no cell surface receptor has been shown to mediate these effects.…”

Section: What Does Progranulin Do?mentioning

confidence: 99%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

207

196

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GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

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Section: What Does Progranulin Do?mentioning

confidence: 99%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

207

196

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“…The potency of PGRN as a tumorigenic agent was demonstrated using primary human cells from ovarian epithelia (20) and uterine smooth muscle. (12) Human primary cells are difficult to transform by gene transfer in culture, (85) requiring at minimum the increased expression of telomerase activity, blockade of the retinoblastoma (Rb) tumor suppressor system, and a strong mitotic drive provided in most experiments by oncogenes such as mutant RAS.…”

Section: Progranulin In Cancermentioning

confidence: 99%

“…PGRN can substitute for RAS in the transformation process. The combination of telomerase (Tert) and SV40 T-antigen (to block the Rb and P53 tumor suppressors) immortalized, but did not transform primary human ovarian cells (20) or uterine smooth muscle cells, (12) but when GRN was included with Tert and SV40, the primary cells became very tumorigenic in mice. (12,20) It is interesting to speculate whether this is related to the unusual property of PGRN as a conjoint competence and progression factor, although at present experimental evidence neither supports nor refutes this hypothesis.…”

Section: Progranulin In Cancermentioning

confidence: 99%

“…(6,7) The role of PGRN in cancer has been repeatedly demonstrated. (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) PGRN has been invoked in early embryogenesis, (27) wound repair, and inflammation. (28)(29)(30) These are diverse roles, extending from control of embryonic development during the first days of life to the survival of long-lived post-mitotic neurons of the adult brain.…”

Section: Introductionmentioning

confidence: 99%

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The granulin gene family: from cancer to dementia

2009

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The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine-rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN.

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“…Epithelial GRN expression has been associated previously with advanced invasive cancers (9,10). In previous reports in mice, depleting GRN from cancer cells by mRNA targeting (11) or monoclonal antibody strategies (12) reduced their tumorigenicity, while overexpressing GRN in cells that are only weakly tumorigenic enhanced their malignant properties (13,14). Taken together, these data suggest a model in which GRN delivered to a tumor by GRN + Sca1 + cKit -CD45 + BMCs plays a key role in the early stages of tumor development, particularly in stromal formation (7), but as tumors progress, GRN expression is no longer restricted to these cells (7), as cancer epithelial cells acquire the ability to both express and respond to GRN.…”

Section: Progranulin In Human Breast Cancersmentioning

confidence: 99%

Growing a tumor stroma: a role for granulin and the bone marrow

Bateman

2011

J. Clin. Invest.

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Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression

Cited by 17 publications

References 19 publications

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

The granulin gene family: from cancer to dementia

Growing a tumor stroma: a role for granulin and the bone marrow

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