PTTG1 Oncogene Promotes Tumor Malignancy via Epithelial to Mesenchymal Transition and Expansion of Cancer Stem Cell Population

Yoon, Changhwan; Kim, Min Jung; Lee, Hyejin; Kim, Rae Kwon; Lim, Eun Jung; Yoo, Kyoungkeun; Lee, Ga Haeng; Cui, Yan Hong; Oh, Yeong Seok; Gye, Myung Chan; Lee, Young Yiul; Park, In-Cheol; An, Sungkwan; Hwang, Sang‐Gu; Park, Myung Jin; Suh, Yongjoon; Lee, Su Jae

doi:10.1074/jbc.m111.337428

Cited by 90 publications

(91 citation statements)

References 41 publications

(41 reference statements)

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“…Whether EMT is (also) implicated in the growth-inhibitory effect of AMD3100 is not yet clear; the expression of the tested selection of EMT genes was not affected after long-term treatment in vivo (20 days) or short-term exposure in vitro (72 h). EMTassociated genes other than the ones analyzed in the present study may still be involved (as described for breast CSCs; Yoon et al 2012). Neither the activation of the TGFb pathway nor the inhibition of the Cxcr4 pathway significantly affected the proportion of SP cells, although the effects might be small, and the absence of an effect on proportion does not exclude a possible effect on the (molecular) activation status of the SP cells.…”

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confidence: 61%

“…Compared with the other cells in the tumor, the CSC subpopulation is considered to be more tumorigenic and more resistant to therapy, thereby surviving treatment and finally regrowing the (heterogeneous) tumor (Vankelecom & Gremeaux 2010, Clevers 2011, Vankelecom 2012, Vankelecom & Chen 2014. Recently, CSCs have been reported to display characteristics of epithelial-mesenchymal transition (EMT), which may drive these cells in their tumor expansion and invasive activity (Mani et al 2008, Morel et al 2008, Kong et al 2010, Pirozzi et al 2011, Yoon et al 2012. EMT represents a multi-step cell-conversion process during which epithelial cells gradually acquire mesenchymal features.…”

Section: Introductionmentioning

confidence: 99%

“…In general, EMT is known to play a key role in cancer pathogenesis, particularly during the growth, maintenance (including resistance to hostile conditions), and progression of the tumor with local invasion and/or metastasis (De Craene & Berx 2013). In several types of cancer, it has been shown that EMT markers are enriched in the CSC fraction, that the induction of EMT causes the upregulated expression of 'stemness' genes, and that EMT acts as a key driver in the generation and activity of the CSCs (Mani et al 2008, Morel et al 2008, Kong et al 2010, Pirozzi et al 2011, Yoon et al 2012.…”

Section: Introductionmentioning

confidence: 99%

“…In recent studies, CSCs and EMT have been linked, in that EMT has been shown to act as a major driver of CSC generation and activity (Mani et al 2008, Morel et al 2008, Kong et al 2010, Pirozzi et al 2011, Yoon et al 2012, De Craene & Berx 2013. In addition to being an argument in favor of the CSC(-like) phenotype of the pSP, the detection of EMT may also have implications for understanding of pituitary tumor behavior.…”

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confidence: 99%

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Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Mertens

Gremeaux

Chen

et al. 2015

Endocrine-Related Cancer

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Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express 'tumor stemness' markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self-renewing sphere-forming cells, considered to be a property of TSCs. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP 'main population'. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFb had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2 K/K ) mice that bear prolactinomas contain more pSP, Sox2C , and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. The present

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confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Mertens

Gremeaux

Chen

et al. 2015

Endocrine-Related Cancer

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“…We suggest that the AP-1 complex is activated in cholinergic amacrine cells, increasing Pttg1 expression and its downstream signaling required for maintaining the spacing between neighboring cells. Indeed, Pttg1 overexpression has been positively correlated with tumor invasiveness and the protein has been implicated in activation of other proteins intimately involved in cell motility, such as those of the Akt and Rho families (28)(29)(30)(31). While the molecular pathways involved remain to be determined, the expression of Pttg1 is clearly linked to the maintenance of orderly mosaics, regulating the spacing of homotypic neighbors.…”

Section: Discussionmentioning

confidence: 99%

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Keeley

Zhou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumortransforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing.L ike many other CNS structures, the retina is composed of recurring modular microcircuits. Distinct neuronal populations are each distributed across the tissue and establish stereotypic patterns of connectivity with one another. To ensure a complete functional coverage by these microcircuits, individual neuronal populations are arranged in regular arrays across the entire retina (1). The regularity of these arrays is achieved by the presence of a zone of exclusion surrounding each cell, minimizing proximity between like-type cells, and although several developmental mechanisms, such as selective cell death and tangential migration, have been shown to mediate formation of such exclusion zones (2), the molecular underpinnings of these processes have received little attention. Recently, however, the EGF-like transmembrane receptor Megf10, which is expressed in only two neuronal populations of the retina, has been shown to mediate recognition and repulsion between like-type cells (3). In another retinal neuronal population, the anti-and proapoptotic factors Bcl2 and Bax have been shown to modulate programmed cell death, a process that yields increased regularity of this mosaic (4, 5). Aside from these examples, relatively little is known about the genetic determinants that coordinate these retinal cell biological processes.In the pre...

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PTTG1 is involved in TNF‐α‐related hepatocellular carcinoma via the induction of c‐myc

et al. 2019

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Hepatocellular carcinoma (HCC) is a malignant disease caused by a variety of factors. However, the genomic and molecular aberrations in HCC are largely unknown. Herein, pituitary tumor transforming gene 1 (PTTG1) was discovered as a potential inflammation‐related oncogene in HCC, and its functions and molecular mechanisms were investigated. mRNA expression microarray, real‐time polymerase chain reaction (PCR), immunohistochemistry, and western blotting analyses revealed that PTTG1 is upregulated in HCC. Further in vitro and in vivo studies indicated that the proinflammatory cytokine tumor necrosis factor‐α (TNF‐α) induces PTTG1 expression, and PTTG1 was found to upregulate c‐myc, a well‐known oncogene. Downregulation of PTTG1 reduced c‐myc and proliferating cell nuclear antigen (PCNA) expression and inhibited cell proliferation. Interestingly, inhibition of c‐myc by 10058‐F4 did not affect PTTG1, which suggests that PTTG1 regulates c‐myc expression. Furthermore, PTTG1 expression levels are inversely correlated with HCC patient survival, indicating an independent prognostic biomarker for patients with HCC. Our data demonstrate that PTTG1 is involved in TNF‐α‐related HCC via c‐myc induction and that PTTG1 may be a potential therapeutic target for HCC.

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PTTG1 Oncogene Promotes Tumor Malignancy via Epithelial to Mesenchymal Transition and Expansion of Cancer Stem Cell Population

Cited by 90 publications

References 41 publications

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

PTTG1 is involved in TNF‐α‐related hepatocellular carcinoma via the induction of c‐myc

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