Temporal and spatial pattern of cellular myc oncogene expression during human placental development

Rydnert, Jan; Pfeifer-Ohlsson, Susan; Goustin, Anton Scott; Ohlsson, Rolf

doi:10.1016/0143-4004(87)90061-0

Cited by 17 publications

(11 citation statements)

References 7 publications

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“…In human placenta, c-Myc was observed to peak at 4 to 5 weeks of gestation and to be highly expressed in the proliferating cytotrophoblasts (38). In the present study, we detected relatively high levels of c-Myc mRNA and protein expression in freshly isolated cytotrophoblasts, which declined upon syncytiotrophoblast differentiation in culture (Fig.…”

Section: Discussionsupporting

confidence: 59%

“…c-Myc belongs to a family of helix-loop-helix/leucine zipper transcription factors and together with its obligatory binding partner, Max, regulates cell proliferation, transformation, growth, differentiation and apoptosis (37). Increased c-Myc expression is evident in the proliferative cytotrophoblasts of human placenta (38). Interestingly, studies have shown that c-Myc directly binds and activates expression of the miR-17ϳ92 cluster in immortalized B lymphocytes (P493-6 cells) stably expressing a tetracycline-regulated c-Myc transgene (39).…”

Section: Microarray Analysis Of Mirnas In Trophoblast Cells Reveals Dmentioning

confidence: 99%

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The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation

Kumar

Luo

Tudela

et al. 2013

Molecular and Cellular Biology

146

108

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cMononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse, and differentiate to form multinucleated syncytiotrophoblast with induction of aromatase (hCYP19A1) and chorionic gonadotropin (hCG␤) expression. Using microarray analysis, we identified members of the miR-17ϳ92 cluster and its paralogs, miR-106aϳ363 and miR-106bϳ25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted human GCM1 (hGCM1), a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these microRNAs (miRNAs) impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCG␤ expression, substantiating its important role in human trophoblast differentiation. Expression of the c-Myc proto-oncogene was increased in proliferating cytotrophoblasts compared to that in differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17ϳ92 and inhibited hCYP19A1 and hCG␤ expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17ϳ92 and miR-106aϳ363 clusters in cytotrophoblasts dramatically decreased upon syncytiotrophoblast differentiation. Intriguingly, we observed higher levels of miR-106a and -19b and lower aromatase and hGCM1 expression in placentas from preeclamptic women than in placentas from gestation-matched normotensive women. Our findings reveal that c-Myc-regulated members of the miR-17ϳ92 and miR106aϳ363 clusters inhibit trophoblast differentiation by repressing hGCM1 and hCYP19A1 and suggest that aberrant regulation of these miRNAs may contribute to the pathogenesis of preeclampsia.T he multinucleated syncytiotrophoblast of the human placenta is formed by fusion of underlying proliferating cytotrophoblasts. This multinucleated cell layer, which covers the chorionic villi, is bathed in maternal blood and performs several essential functions to ensure growth and survival of the developing embryo. These include transport of O 2 and nutrients and synthesis and secretion of syncytiotrophoblast-specific protein and steroid hormones, including estrogen and progesterone. Synthesis of estrogens from C 19 steroids is catalyzed by aromatase P450 (P450arom, product of the hCYP19A1 gene). The ability of the human placenta to synthesize estrogens is vastly increased after the ninth week of gestation (1), in association with cytotrophoblast invasion and enlargement of the uterine arterioles, increased blood flow, and O 2 availability to the floating chorionic villi (2, 3). Trophoblast stem cells and cytotrophoblasts do not express hCYP19A1/aromatase; however, when cytotrophoblasts fuse to form multinucleated syncytiotrophoblast, aromatase is markedly induced (4, 5). The exceptionally high levels of placental aromatase likely function to metabolize large amounts of C 19 steroids produced by the human fetal adrenals (e.g., dehydroepiandrosterone), thus preventing conversion of these steroids t...

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Section: Discussionsupporting

confidence: 59%

Section: Microarray Analysis Of Mirnas In Trophoblast Cells Reveals Dmentioning

confidence: 99%

The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation

Kumar

Luo

Tudela

et al. 2013

Molecular and Cellular Biology

146

108

View full text Add to dashboard Cite

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“…The production of such a cell preparation and the maintenance of these cells in culture should allow further investigation of the mechanisms (hormonal and/or the role of growth factors) involved in the differentiation of the cytotrophoblast into syncytiotrophoblast in the early development of human placenta. Indeed, hormonal secretion, such as hCG (Lachan and Lopata, 1988;Patillo et al, 1983), and the presence of growth and oncogenic factors (Adamson, 1987;Rydnert et al, 1987) (Vettenranta et al, 1986;Mac Queen et al, 1987 (Simpson and MacDonald, 1981;Hoshina et al, 1982;Hoshina et al, 1985). The time required in vitro, to observe the formation of aggregated cells and the formation of the syncytiotrophoblast was identical for either first trimester, or term placenta (Kliman et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Characterization and differentiation of human first trimester placenta trophoblastic cells in culture

Dodeur¹,

Malassiné²,

Bellet³

et al. 1989

Placenta

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Summary ― A preparation of highly enriched isolated cytotrophoblasts was obtained from first trimester placenta using dispase incubation of villous tissue at 4 °C, followed by a spontaneous cell release at 37 °C. After 24 h of culture, 90-95% of the cells were immunostained by anticytokeratin antibody, showing their epithelial characteristic. After 48 h of culture, these cells differentiated into syncytiotrophoblast, as shown by optic and electron microscopic study. The secretion of hCG, and of its free a and 13 subunits, and the secretion of hPL were studied as a function of cell culture time. While the level of secreted hCG and its free subunits was stable during 72 h of culture, the hPL level was undetectable during the first 48 h of culture, increasing continuously afterwards. Addition of dibutyryl cAMP from the start or after 96 h of cell culture induced an increase of hCG production and of its free subunits and also stimulated the secretion of hPL. This suggests that these cells maintained the capacity to respond to stimuli which increased intracellular cAMP level. Such a cell culture is of interest in further determining the mechanisms of early gestation involved in the differentiation and growth of placental cytotrophoblasts, and in the regulation of their endocrine functions.

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“…In this important step in development, healthy cells invade into another tissue. Tightly regulated programming must prevent an immune response, especially as the embryo-derived trophoblast is not “self.” MYC is highly expressed in the trophoblast [69], a highly proliferative tissue that even is described as “pseudomalignant” [70]. The trophoblast uses multiple pathways, including the repression of polymorphic human leukocyte antigens (HLA) molecules and the induction of PD-L1, to prevent an immune response from the mother [71].…”

Section: General Mechanistic and Therapeutic Implicationsmentioning

confidence: 99%

MYC: Master Regulator of Immune Privilege

Casey

Baylot

Felsher

2017

Trends in Immunology

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Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor suppressor genes. These events are also critical for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes, or loss of tumor suppressors, indeed induces the expression of immune checkpoints including PD-L1, which regulate the immune response. Here, we discuss how oncogenes, and in particular MYC, suppress immune surveillance and how oncogene-targeted therapies may restore the immune response against tumors.

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Temporal and spatial pattern of cellular myc oncogene expression during human placental development

Cited by 17 publications

References 7 publications

The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation

The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation

Characterization and differentiation of human first trimester placenta trophoblastic cells in culture

MYC: Master Regulator of Immune Privilege

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