Pregnancy-Promoting Actions of HCG in Human Myometrium and Fetal Membranes

Ticconi, Carlo; Zicari, Alessandra; Belmonte, Alessia; Realacci, Massimo; Rao, Ch.V.; Piccione, Emilio

doi:10.1016/j.placenta.2007.01.002

Cited by 52 publications

(39 citation statements)

References 35 publications

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“…The 75-kDa band observed for NOS2A in transfected HCT116 cells (Figs. 1D and 3A) has been documented previously (Ticconi et al, 2007). NOS3 was not shown to catalyze PR-104A reduction in transfected HCT116 cells, but weak expression prevented interpretation of this finding (Fig.…”

Section: Discussionsupporting

confidence: 63%

Diflavin Oxidoreductases Activate the Bioreductive Prodrug PR-104A under Hypoxia

Guise¹,

Abbattista²,

Tipparaju³

et al. 2011

Mol Pharmacol

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The clinical agent PR-104 is converted systemically to PR-104A, a nitrogen mustard prodrug designed to target tumor hypoxia. Reductive activation of PR-104A is initiated by oneelectron oxidoreductases in a process reversed by oxygen. The identity of these oxidoreductases is unknown, with the exception of cytochrome P450 reductase (POR). To identify other hypoxia-selective PR-104A reductases, nine candidate oxidoreductases were expressed in HCT116 cells. Increased PR-104A-cytotoxicity was observed in cells expressing methionine synthase reductase (MTRR), novel diflavin oxidoreductase 1 (NDOR1), and inducible nitric-oxide synthase (NOS2A), in addition to POR. Plasmid-based expression of these diflavin oxidoreductases also enhanced bioreductive metabolism of PR-104A in an anoxia-specific manner. Diflavin oxidoreductase-dependent PR-104A metabolism was suppressed Ͼ90% by pan-flavoenzyme inhibition with diphenyliodonium chloride. Antibodies were used to quantify endogenous POR, MTRR, NDOR1, and NOS2A expression in 23 human tumor cell lines; however, only POR protein was detectable and its expression correlated with anoxic PR-104A reduction (r 2 ϭ 0.712). An anti-POR monoclonal antibody was used to probe expression using human tissue microarrays; 13 of 19 cancer types expressed detectable POR with 21% of cores (185 of 874) staining positive; this heterogeneity suggests that POR is a useful biomarker for PR-104A activation. Immunostaining for carbonic anhydrase 9 (CAIX), reportedly an endogenous marker of hypoxia, revealed only moderate coexpression (9.6%) of both CAIX and POR across a subset of five cancer types.

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Section: Discussionsupporting

confidence: 63%

Diflavin Oxidoreductases Activate the Bioreductive Prodrug PR-104A under Hypoxia

Guise¹,

Abbattista²,

Tipparaju³

et al. 2011

Mol Pharmacol

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“…Additionally, it also provides a base through which growing cytotrophoblast columns migrate outward to establish the rudiments of the placental villous tree. This early syncytium is also the major form of trophoblast present when the mother must respond to trophoblast signals to maintain her pregnancy, particularly the hormone hCG, which is required for continued corpus luteum support and avoidance of endometrial shedding and menstruation, which would normally occur after about 2 wk if pregnancy recognition had not ensued (39). Is it possible that the hESCderived STB represents this early syncytium?…”

Section: Discussionmentioning

confidence: 99%

Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas

Yabe

Alexenko

Amita

et al. 2016

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

149

148

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Human embryonic stem cells (ESCs) readily commit to the trophoblast lineage after exposure to bone morphogenetic protein-4 (BMP-4) and two small compounds, an activin A signaling inhibitor and a FGF2 signaling inhibitor (BMP4/A83-01/PD173074; BAP treatment). During differentiation, areas emerge within the colonies with the biochemical and morphological features of syncytiotrophoblast (STB). Relatively pure fractions of mononucleated cytotrophoblast (CTB) and larger syncytial sheets displaying the expected markers of STB can be obtained by differential filtration of dispersed colonies through nylon strainers. RNA-seq analysis of these fractions has allowed them to be compared with cytotrophoblasts isolated from term placentas before and after such cells had formed syncytia. Although it is clear from extensive gene marker analysis that both ESC-and placenta-derived syncytial cells are trophoblast, each with the potential to transport a wide range of solutes and synthesize placental hormones, their transcriptome profiles are sufficiently dissimilar to suggest that the two cell types have distinct pedigrees and represent functionally different kinds of STB. We propose that the STB generated from human ESCs represents the primitive syncytium encountered in early pregnancy soon after the human trophoblast invades into the uterine wall.is encountered during at least two stages of human placental development (1-3). The first coincides with early implantation when a multinucleated syncytium forms, presumably by cell fusion events, ahead of proliferating, mononucleated, cytotrophoblast (CTB) cells originating from polar trophectoderm (3,4). This invasive syncytium emerges either during or soon after the trophoblast passes through the breached uterine epithelium and into the decidualized stromal layer beneath and appears to be responsible for hollowing out regions within the stroma to form lacunae (5), which become filled with fluid and cells from maternal blood and uterine glands and presumably provide a source of nutrients for the conceptus (3, 6). By about 12 d of gestation, soon after the blastocyst has sunk below the endometrial surface, strands of cytotrophoblast begin to form and penetrate through the primitive syncytium to form primary chorionic villi, which are subsequently invaded by extraembryonic mesoderm to form secondary and tertiary villi (villous trees) (2-4). The cytotrophoblast cells associated with the villi continue to divide and provide a progenitor cell population for the villous STB, which is the cell layer that covers the outer surface of the villi and forms the definitive interface involved in exchange of gases, nutrients, and excretory materials between the fetal placenta and maternal blood. Villous STB is also the major site for production of placental hormones. Cytotrophoblast cells at the tips of the anchoring villi proliferate and colonize the endometrium, thus expanding the placental bed and simultaneously remodeling maternal spiral arteries. The extent to which extravillous trophoblast becom...

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“…However, there is evidence that hCG may affect the expression of iNOS (37,38) and activins (22). Additionally, it has been reported that activin-A, its type II receptors, and iNOS are involved in the immune response to C. trachomatis infection, and that their pathologic expression may lead to tubal damage and the development of EP (21).…”

Section: Moleculementioning

confidence: 99%

Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation

Refaat

Simpson

Britton

et al. 2012

Fertility and Sterility

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Pregnancy-Promoting Actions of HCG in Human Myometrium and Fetal Membranes

Cited by 52 publications

References 35 publications

Diflavin Oxidoreductases Activate the Bioreductive Prodrug PR-104A under Hypoxia

Diflavin Oxidoreductases Activate the Bioreductive Prodrug PR-104A under Hypoxia

Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas

Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation

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