LRH-1在肿瘤及干细胞中的功能研究进展

核受体(nuclear receptors,NRs)是转录因子家族中最大的成员,多以配体依赖的方式特异性调节其靶基因的表达,参与机体代谢、发育和生殖功能的调控。LRH-1(liver receptor homolog-1),也称为NR5A2(nuclear receptor subfamily 5,group A,member 2),是核受体家族的成员,作为转录共激活子调控相关基因的表达。LRH-1调控多种重要的生理功能,包括调节脂肪酸和胆固醇的代谢,另外在胚胎发育和分化中也起了重要作用。LRH-1在促进多种癌症的发生过程中扮演重要的角色,如结肠癌、胰腺癌、卵巢癌和乳腺癌。随着对LRH-1研究的深入,其在疾病和胚胎干细胞中的功能作用已备受关注,这也使得LRH-1成为了许多疾病的潜在治疗靶点。     

LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis

The liver receptor homolog-1 (LRH-1; NR5A2) and steroidogenic factor-1 (SF-1; NR5A1) are two orphan members of the Ftz-F1 subfamily of nuclear receptors. LRH-1 is expressed in tissues derived from endoderm, including intestine, liver and exocrine pancreas, as well as in the ovary. In these tissues, LRH-1 plays a predominant role in development, reverse cholesterol transport, bile-acid homeostasis and steroidogenesis. SF-1 expression is confined to steroidogenic tissues and the hypothalamo-pituitary-adrenal axis, where it is involved in the control of development, differentiation, steroidogenesis and sexual determination. In this article, we will review data concerning the structure, regulation and function of LRH-1. These data highlight structural similarities between LRH-1 and other Ftz-F1 members but also underscore important functional differences, assigning to LRH-1 a unique position among nuclear receptors.     

From molecule to behavior: Brain aromatase (cyp19a1b) characterization,expression analysis and its relation with social status and male agonistic behavior in a Neotropical cichlid fish

The enzyme aromatase, responsible for the conversion of C19 androgens to C18 estrogens, exists as two paralogue copies in teleost fish: Cyp19a1a mostly expressed in the gonads, referred as gonadal aromatase, and Cyp19a1b, mostly expressed in the brain, accordingly known as brain aromatase. The neural localization of Cyp19a1b is greatly contained within the social behavior network and mesolimbic reward system in fish, suggesting a strong role of estrogen synthesis in the regulation of social behavior. In this work we aimed to analyze the variation in cyp19a1b expression in brain and pituitary of males of a highly social cichlid, Cichlasoma dimerus (locally known as chanchita), and its relation with inter-individual variability in agonistic behavior in a communal social environment. We first characterized chanchita's cyp19a1b mRNA and deduced amino acid sequence, which showed a high degree of conservation when compared to other teleost brain aromatase sequences, and its tissue expression patterns. Within the brain, Cyp19a1b was solely detected at putative radial glial cells of the forebrain, close to the brain ventricles. We then studied the relative expression levels of cyp19a1b by Real Time PCR in the brain and pituitary of males of different social status, territorial vs. non-territorial, and its relationship with an index of agonistic behavior. We found that even though, brain aromatase expression did not differ between types of males, pituitary cyp19a1b expression levels positively correlated with the index of agonistic behavior. This suggests a novel role of the pituitary in the regulation of social behavior by local estrogen synthesis.     

Real-time PCR analysis of ovary- and brain-type aromatase gene expression during Atlantic halibut (Hippoglossus hippoglossus) development

Two forms of cytochrome P450 aromatase, acting in both the brain and the ovary, have been implicated in controlling ovarian development in fish. To better understand the expression of these two enzymes during sexual differentiation in Atlantic halibut (Hippoglossus hippoglossus), real-time PCR was used to quantify the mRNA levels of ovary- (cyp19a) and brain-type cytochrome P450 aromatase (cyp19b) genes in the gonad and brain during gonadal development. Both enzymes showed high levels of expression in both tissues in developmental stages prior to histologically detectable ovarian differentiation (38 mm fork length), with increased expression occurring slightly earlier in the brain than the gonad. Cyp19a showed a second peak of expression in later stages (> 48 mm) in the gonad, but not the brain. Cyp19b expression was generally higher in the brain than the gonad. These results suggest that sexual differentiation may begin in the brain prior to gonadal differentiation, supporting the idea that steroid hormone expression in the brain is a key determinant of phenotypic sex in fish. In an examination of sexually immature adults, cyp19a was highly expressed in female gonad while cyp19b was very highly expressed in the pituitary of both sexes. The ratio of cyp19a to cyp19b expression was much higher in ovaries than in testes in the adult fish, so this ratio was analyzed in the developing gonads of juvenile halibut in an attempt to infer their sex. This was only partially successful, with about half the fish in later developmental stages showing apparently sex-specific differences in aromatase expression.     

Transcriptional regulation of aromatase in placenta and ovary

Our goal is to define the cellular and molecular mechanisms for tissue- and cell-specific, developmental and hormonal regulation of the human CYP19 (aromatase P450/P450arom) gene in estrogen-producing cells. In this article, we review studies using transgenic mice and transfected cells to identify genomic regions and response elements that mediate CYP19 expression in placenta and ovary, as well as to define the molecular mechanisms for O₂ regulation of differentiation and CYP19 gene expression in human trophoblast cells in culture. We also highlight recent findings regarding LRH-1 versus SF-1 mRNA expression and cellular localization in the mouse ovary during the estrous cycle and various stages of pregnancy. Spatial and temporal expression patterns of mRNAs encoding these orphan nuclear receptors in comparison to those of P450arom and 17-hydroxylase/17,20-lyase mRNAs, suggest an important role of LRH-1 together with SF-1 in ovarian steroidogenesis.