Expression of retinoic acid α and β receptor genes in liver and hepatocellular carcinoma

Sever, Cordelia E.; Locker, Joseph

doi:10.1002/mc.2940040209

Cited by 28 publications

(19 citation statements)

References 41 publications

(39 reference statements)

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“…2 and 10), and we propose that this type of defect may also reflect a common mechanism for loss of RAR␤ expression in some epitheliumderived carcinomas, since this same defect has also been described in HeLa cells (7). Loss of RAR␤ expression has also been reported in head and neck squamous carcinoma (43), hepatocellular carcinoma (109), and breast carcinoma (112). The molecular details underlying defective RAR␤ expression in these types of cancer, as well as in other lung cancer cells, remain to be further characterized.…”

Section: Calu1supporting

confidence: 56%

Evidence for Impaired Retinoic Acid Receptor-Thyroid Hormone Receptor AF-2 Cofactor Activity in Human Lung Cancer

Moghal

Neel

1995

Molecular and Cellular Biology

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Retinoic acid (RA) is required for normal airway epithelial cell growth and differentiation both in vivo and in vitro. One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR␤) mRNA. Previous work established that many lung cancer cell lines and primary tumors display abnormal RAR␤ mRNA expression, most often absence or weak expression of the RAR␤2 isoform, even after RA treatment. Restoration of RAR␤2 into RAR␤-negative lung cancer cell lines has been reported to inhibit tumorigenicity. Since RAR␤2 inactivation may contribute to lung cancer, we have investigated the molecular mechanism of defective RAR␤2 expression. Nuclear run-on assays and transient transfections with RAR␤2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE). These defects cannot be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting transcription from both types of RARE. Studies using chimeras between RAR␣, TR␣, and other transcription factors suggest the existence of novel RAR-thyroid hormone receptor AF-2-specific cofactors, which are necessary for high levels of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.

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Section: Calu1supporting

confidence: 56%

Evidence for Impaired Retinoic Acid Receptor-Thyroid Hormone Receptor AF-2 Cofactor Activity in Human Lung Cancer

Moghal

Neel

1995

Molecular and Cellular Biology

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“…2,7,[12][13][14][15][16][17][18] Eleven genes were identified in systems other than regenerating liver: butyrate response factor 1, Mdm2, AP endonuclease, Gadd45, glucose regulated protein 78, Fra-2, snoN, monocyte chemoattractant protein-3, membrane glycoprotein gp130, membrane type matrix metalloproteinase 1 and macrophage inflammatory protein. [19][20][21][22][23] An additional 3 genes not previously known to be induced in liver regeneration, were confirmed as IE genes by northern blot analyses: CD14 antigen/LPS receptor, Tristetraproline and A20 zinc finger protein.…”

Section: Resultsmentioning

confidence: 99%

Global changes in interleukin-6–dependent gene expression patterns in mouse livers after partial hepatectomy

2001

Hepatology

101

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Liver regeneration following 70% partial hepatectomy leads to rapid activation of genes in the remnant liver. Interleukin-6 deficient (IL-6 ؊/؊) mice have impaired liver regeneration and abnormalities in immediate early gene expression. In this study, the gene expression program in the IL-6 ؉/؉ and ؊/؊ livers at 2 hours posthepatectomy was examined with a cDNA array representing 588 highly regulated mouse genes. Thirty-six percent of the 103 immediate early genes were induced differently in IL-6 ؉/؉ compared with IL-6 ؊/؊ livers, implying regulation by IL-6. IL-6 treatment of the IL-6 ؊/؊ mice in the absence of hepatectomy induced a much smaller set of genes in the liver, suggesting that IL-6 cooperates with other hepatectomy-induced factors to activate the large number of genes. Northern blot analyses were used to verify gene expression data obtained from the arrays. The expression of urokinase type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), critical components of the urokinase plasminogen activator (uPA) system, was lower and delayed in IL-6 ؊/؊ livers. Despite the fact that active uPAR/uPA complex is critical for hepatocyte growth factor (HGF) activation, no differences were detected between the IL-6 ؉/؉ and ؊/؊ livers in HGF activation as measured by receptor phosphorylation. On the contrary, the mitogen-activated protein kinase (MAPK) pathway was activated in IL-6 ؉/؉ livers early during regeneration but remarkably delayed in IL-6 ؊/؊ livers. Defective liver regeneration may be explained by the large number of gene activation pathways altered in IL-6 ؊/؊ livers and further supports the finding that IL-6 is necessary for normal liver regeneration. The liver has the capacity to regenerate after partial hepatectomy or injury. Following a two-thirds partial hepatectomy, liver cells switch from a quiescent state into a proliferative state and re-enter the cell cycle. 1 During this process, a large number of immediate and delayed early genes, which are not normally expressed in quiescent liver, are activated. Understanding the gene expression profile at the early stage of regeneration is essential for understanding the mechanism underlying this physiologic process.Interleukin-6 is essential for normal liver regeneration. IL-6 deficient mice have blunted DNA synthesis and liver necrosis after 70% partial hepatectomy, and are prone to liver failure. 2 A single dose of IL-6 injection before hepatectomy can correct all the above defects. IL-6 Ϫ/Ϫ livers also have increased injury and fibrosis after CCl 4 and Phenobarbital treatment, as well as reduced mitotic response after the injury. 3 IL-6 functions in the cell by binding to the gp80 receptor and inducing the dimerization of the gp130 receptor, which then activates the associated Janus tyrosine kinase (Jak). Jak rapidly phosphorylates Stat3, which undergoes nuclear translocation and activates target genes. 4,5 Previous studies from our lab and other labs showed that IL-6 is capable of activating a wide range of genes at th...

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“…In mice, RAR␤ is highly expressed in the developing respiratory epithelium, and its expression coincides with the onset of cytodifferentiation (15). Loss of RAR␤ expression has been reported for a number of epithelial cell-derived malignancies (21,22,27,49,62,65); notably, it is one of the most frequent events observed in lung cancer (21,49), in which NHBE differentiation is aberrant. Moreover, defective RAR␤ expression is an early event in epithelial carcinogenesis (42).…”

Section: Resultsmentioning

confidence: 99%

Integration of Growth Factor, Extracellular Matrix, and Retinoid Signals during Bronchial Epithelial Cell Differentiation

Moghal

Neel

1998

Molecular and Cellular Biology

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Epithelial cell differentiation is regulated by specific combinations of growth factors, hormones, and extracellular matrix (ECM). How these divergent signals are integrated is largely unknown. We used primary cultures of normal human bronchial epithelial cells (NHBEs) to investigate mechanisms of signal integration. In defined, serum-free media, NHBEs undergo mucosecretory differentiation only when grown in the presence of retinoids and on the appropriate substratum (collagen gels). We identified the retinoic acid receptor ␤ (RAR␤) gene as an early marker of NHBE differentiation. In contrast to immortalized cell lines, in NHBEs strong retinoid-induced RAR␤ transcription occurs only when cells are grown on collagen gels, and it requires new protein synthesis and a cis-acting element that maps outside the known RAR␤ promoter elements. NHBEs grown on collagen gels exhibit reduced epidermal growth factor (EGF)-induced Raf, MEK, and mitogenactivated protein kinase (MAPK) activity. This correlates with a specific inability to achieve high levels of p66 SHC tyrosyl phosphorylation and association of p66 SHC with GRB2, despite high levels of EGF receptor (EGFR) autophosphorylation. Notably, inhibition of EGFR or MEK/MAPK activation replaces the ECM requirement for RAR␤ induction. Our results strongly suggest that a key mechanism by which specific ECMs facilitate retinoid-induced mucosecretory differentiation of NHBEs is by restricting the level of EGFR-dependent MEK/MAPK activation evoked by autocrine and/or paracrine EGFR ligands.Epithelial cell differentiation is a complex process that results from the integration of growth factor-, hormone-, and extracellular matrix (ECM)-derived signals (for reviews see references 17 and 38). The respiratory epithelium provides a good model system for the study of signal integration, since normal bronchial epithelial cell differentiation requires the correct combination of growth factors, retinoids, and ECM (73, 74). In vivo, the upper airways are populated with basal, ciliated, and mucosecretory (goblet) cells (reviewed in reference 24), which rest on a thin basement membrane and a thick lamina propria rich in ECM molecules such as collagens, laminin, fibronectin, and heparan sulfate proteoglycans. Vitamin A (retinol)-deficient animals develop lesions along their upper airways in which mucociliary cells are replaced with highly keratinized squamous epithelia (44, 72), indicating a critical role for retinoids in normal respiratory cell differentiation. When grown ex vivo on plastic dishes in defined serum-free media without retinoids, cultures of normal tracheal/bronchial epithelial cells undergo squamous metaplasia upon reaching confluence (30, 54). Although retinoid treatment inhibits expression of the squamous phenotype under these culture conditions (28, 30, 54), it does not stimulate mucociliary differentiation. For mucosecretory cell differentiation ex vivo, tracheal/ bronchial epithelial cells must be cultured on type I collagen gels in the presence of retinoids (29, 55, 73)...

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Expression of retinoic acid α and β receptor genes in liver and hepatocellular carcinoma

Cited by 28 publications

References 41 publications

Evidence for Impaired Retinoic Acid Receptor-Thyroid Hormone Receptor AF-2 Cofactor Activity in Human Lung Cancer

Evidence for Impaired Retinoic Acid Receptor-Thyroid Hormone Receptor AF-2 Cofactor Activity in Human Lung Cancer

Global changes in interleukin-6–dependent gene expression patterns in mouse livers after partial hepatectomy

Integration of Growth Factor, Extracellular Matrix, and Retinoid Signals during Bronchial Epithelial Cell Differentiation

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