Progesterone induces the expression of lipocalin‐2 through Akt‐c‐Myc pathway during mouse decidualization

Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%), though only 30 differentially expressed genes (DEGs) (15 up-regulated, 12 down-regulated and 3 discordant) out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells (0.1%). Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated), DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated) and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated). The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10). Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206) or PI3K (LY294002) further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively) correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6). Finally, we made use of Ingenuity Pathway Analysis (IPA) to investigate the relevant BioFunctions enriched by the costitutive activation of AKT1-, PI3K- or PTEN-dependent signalling in lung epithelial cells. Expectedly, the analysis of the DEGs common to all three alterations highlighted a group of BioFunctions that included Cell Proliferation of tumor cell lines (14 DEGs), Invasion of cells (10 DEGs) and Migration of tumour cell lines (10 DEGs), with a common core of 5 genes (ATF3, CDKN1A, GDF15, HBEGF and LCN2) that likely represent downstream effectors of the pro-oncogenic activities of PI3K/AKT signalling. Conversely, IPA analysis of exclusive DEGs led to the identification of different downstream effectors that are modulated by mutant AKT1 (TGFBR2, CTSZ, EMP1), mutant PIK3CA (CCND2, CDK2, IGFBP2, TRIB1) and PTEN loss (ASNS, FHL2).These findings not only shed light on the molecular mechanisms that are activated by aberrant signalling through the PI3K/AKT pathway in lung epithelial cells, but also contribute to the identification of previously unrecognised molecules whose regulation takes part in the development of lung cancer.

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“…Elevated LCN2 expression has been associated with increased tumor cell motility, invasion and survival [80–83]. …”

Section: Resultsmentioning

confidence: 99%

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

et al. 2017

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“…Additional studies, such as single-cell approaches that address the tissue cell heterogeneity, are therefore needed to determine which cell types express these genes in order to identify their role in BAT and whether these genes are directly regulated by sex steroids. Based on the literature, progesterone might regulate the expression of our identified genes, such as Cdh1, Cfd, and Lcn2, because these have been reported to show progesterone-dependent regulation in the endometrium, a tissue that becomes highly vascularized during the preimplantation stage (Yao et al 2003, Jeong et al 2005, Jha et al 2006, Liu et al 2016.…”

Section: Discussionmentioning

confidence: 99%

Sex difference in the mouse BAT transcriptome reveals a role of progesterone

Kaikaew

Grefhorst

Steenbergen

et al. 2021

Journal of Molecular Endocrinology

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Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, i.e., being generally more abundant and active in females than in males. Although sex steroids, particularly estrogens, have been shown to regulate BAT thermogenic function, the underlying molecular mechanisms contributing to sexual dimorphism in basal BAT activity have not been elucidated. Therefore, we assessed the transcriptome of interscapular BAT of male and female C57BL/6J mice by RNA sequencing and identified 295 genes showing ≥2-fold differential expression (adjusted P<0.05). In silico functional annotation clustering suggested an enrichment of genes encoding proteins involved in cell-cell contact, interaction, and adhesion. Ovariectomy reduced the expression of these genes in female BAT towards a male pattern whereas orchiectomy had marginal effects on the transcriptional pattern, indicating a prominent role of female gonadal hormones in this sex-differential expression pattern. Progesterone was identified as a possible upstream regulator of the sex-differentially expressed genes. Studying direct effects of progesterone in vitro in primary adipocytes showed that progesterone significantly altered the transcription of several of the identified genes, possibly via the glucocorticoid receptor. In conclusion, this study reveals a sexually dimorphic transcription profile in murine BAT at general housing conditions and demonstrates a role for progesterone in the regulation of the interscapular BAT transcriptome.

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“…Haneda et al [30] investigated the expression levels of NGAL in the gravid endometrium of mares, and found that endometrial NGAL could play a role in the transfer of small molecules from the mother to the fetus. A previous study demonstrated that NGAL-mediated LPS-induced inflammation in pregnant mice [31]. Moreover, Cao et al [13] reported higher levels of NGAL protein in placental tissues of patients with preeclampsia, compared with those noted in normal pregnancies.…”

Section: Discussionmentioning

confidence: 99%

Serum Levels and Placental Expression of NGAL in Gestational Diabetes Mellitus

Yin

Huo

Liu

et al. 2020

International Journal of Endocrinology

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Objectives. The aim was to investigate neutrophil gelatinase-associated lipocalin (NGAL) levels in the serum and term placentas and its potential role in gestational diabetes mellitus (GDM). Methods. A total of 49 GDM subjects and 39 age-matched women with normal pregnancies were recruited. We examined serum concentrations of NGAL and tumor necrosis factor-α (TNF-α) in maternal blood and cord blood and their expression levels in the term placentas and umbilical cord. Results. Serum NGAL levels were significantly higher in GDM patients than in normal pregnant controls both in the maternal blood (4.80 ± 1.99 vs. 3.66 ± 1.13, P=0.001) and the cord blood (4.70 ± 2.08 vs. 3.85 ± 1.44, P=0.027). Moreover, serum NGAL levels exhibited a positive correlation with various parameters of insulin resistance. Maternal serum NGAL levels positively correlated with the NGAL levels found in the cord blood of the control (r = 0.399, P=0.012) and the GDM subjects (r = 0.349, P=0.014). Finally, the expression of NGAL protein levels in the placenta (1.22 ± 0.39 vs. 0.65 ± 0.23, P<0.001) and umbilical cord (0.65 ± 0.23 vs. 0.25 ± 0.10, P<0.001) were higher in GDM women than those noted in the control subjects. In the GDM group, maternal serum NGAL levels exhibited a positive correlation with placental NGAL mRNA and protein levels (r = 0.848, P=0.008; r = 0.636, P=0.011, respectively). Conclusions. NGAL may be an important adipokine involved in GDM and fetal development. The oversecretion of NGAL from the placenta may contribute to the elevated levels of serum NGAL in gestational diabetes mellitus.

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Progesterone induces the expression of lipocalin‐2 through Akt‐c‐Myc pathway during mouse decidualization

Cited by 5 publications

References 23 publications

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

Sex difference in the mouse BAT transcriptome reveals a role of progesterone

Serum Levels and Placental Expression of NGAL in Gestational Diabetes Mellitus

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