Farnesoid X receptor, overexpressed in pancreatic cancer with lymph node metastasis promotes cell migration and invasion

Lee, J. Y.; Lee, K. T.; Lee, J. K.; Lee, K. H.; Jang, Kee–Taek; Heo, Jin Seok; Choi, Seong Hee; Kim, Y. I. I.; Rhee, Jong Chul

doi:10.1038/bjc.2011.37

Cited by 67 publications

(64 citation statements)

References 40 publications

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“…However, the expression of FXR and its role in the tumorigenesis remain controversial. Lee et al (11) reported that FXR overexpression in pancreatic cancer tissues with lymphatic metastasis was associated with poor patient survival, and downregulation of FXR was an effective approach for inhibition of pancreatic tumor progression. However, for other cancers, FXR was considered as a tumor suppressor rather than a tumor promoter.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

Liu

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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The nuclear receptor farnesoid X receptor (FXR) acts as a liver protector by regulating normal liver homeostasis. Spontaneously developed liver tumors have been found in FXR-null mice. However, the role of FXR in the tumorigenesis of human hepatocellular carcinoma (HCC) is still poorly understood. In this study, we measured the expression of FXR and its primary target gene, small heterodimer partner, and analyzed the clinical significance of FXR expression in HCC patients. A lentiviral vector that selectively overexpresses FXR was used to investigate the function of FXR in HCC cell proliferation both in vitro and in vivo. Our data showed that in human HCC, FXR expression was significantly reduced and was positively correlated with multiple malignant clinicopathological characteristics. Lentivirus-mediated exogenous FXR expression resulted in a marked increase of small heterodimer partner expression, significant repression of liver cancer cell proliferation, and tumor growth in nude mice. These results suggest that FXR may be of clinical and pharmacological importance as a promising biomarker of HCC. farnesoid X receptor; small heterodimer partner; tumor suppressor; proliferation HUMAN HEPATOCELLULAR CARCINOMA (HCC) is one of the most common human malignancies in the world and is prevalent in developing countries. In China, HCC has become the second highest cancer-related cause of death since the 1990s and accounts for 53% of all liver cancer deaths worldwide (12). The high mortality of HCC is due in large part to the lack of good biomarkers for early diagnosis and treatment assessment. Patients are often diagnosed at advanced stages, when most available therapies have only limited efficacy.The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is highly expressed in the liver. FXR controls the expression of various genes involved in bile acid, lipid, and glucose metabolism (21). In recent years, the understanding of the role of FXR in the liver has developed from that as a metabolic regulator to the novel function as a cell protector implicated in liver regeneration (9, 23) and hepatocarcinogenesis (22). In 2007, we first reported that in the absence of FXR, mice displayed spontaneous development of liver tumors (22). In parallel, Kim et al. (10) published very similar observations showing that aged FXR-null mice had a high incidence of liver tumors. However, limited information was available regarding the role of FXR in the development and progression of human HCC.The nuclear receptor small heterodimer partner (SHP) is an important modulator of metabolic signaling pathways (1,8,20) and is a primary FXR target gene. One of the well-characterized mechanisms by which FXR regulates gene expression in the liver is through the induction of SHP. Recent studies (24, 25) have revealed the role of SHP in the inhibition of cellular proliferation. However, combined loss of FXR and SHP expression in human HCC has not been previously reported.In this study...

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Section: Discussionmentioning

confidence: 99%

Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

Liu

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…14 In contrast, the inhibition of FXR promotes apoptosis in Barrett's esophageal-derived cells 15 and inhibits proliferation, migration and invasion in pancreatic cancer cells. 16 In our previous study, we have demonstrated that FXR is expressed in tissues of normal and tumor Fisher rat testis and in Leydig normal and tumor cell lines. 17 Particularly, in R2C rat Leydig tumor cells the FXR activators CDCA and GW4064 downregulate aromatase expression at both mRNA and protein levels, together with the inhibition of its enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy

Catalano

Panza

Malivindi

et al. 2012

Intl Journal of Cancer

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Leydig cell tumors (LCTs) are the most common tumors of the gonadal stroma and represent about 3% of all testicular neoplasms. In most cases, LCTs are benign; however, if the tumor is malignant, no effective treatments are currently available. We have recently reported that farnesoid X receptor (FXR) is expressed in R2C Leydig tumor cells, and it reduces the estrogen-dependent cell proliferation by negatively regulating aromatase expression. Here, we demonstrated that treatment with GW4064, a specific FXR agonist, markedly reduced Leydig tumor growth in vivo by inhibiting proliferation and inducing apoptosis. Indeed, the tumors from GW4064-treated mice exhibited a decrease in the expression of the proliferation marker Ki-67 and aromatase along with an increase in the apoptotic nuclei. FXR activation induced an enhanced poly(ADP-ribose) polymerase cleavage, a marked DNA fragmentation and a strong increase in TUNEL-positive R2C cells also in vitro. Moreover, in both in vivo and in vitro models, FXR ligands upregulated mRNA and protein levels of p53 and of its downstream effector p21 WAF1/Cip1 . Functional experiments showed that FXR ligands upregulated p53 promoter activity and this occurred through an increased binding of FXR/nuclear factor-kB (NF-kB) complex to the NF-kB site located within p53 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Taken together, results from our study show, for the first time, that treatment with FXR ligands induces Leydig tumor regression in vivo, suggesting that activation of FXR may represent a promising therapeutic strategy for LCTs.

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“…Previous genome-wide studies aimed at identifying the transcriptional mechanisms that underlie metastasis formation have primarily focused on comparisons between end-stage primary and metastatic tumors of mouse or human origin [20, 26], broad characterization of transcriptional changes [27], or between primary tumors of differing metastatic phenotypes [28–30]. In particular, experiments using in vivo selection of metastatic cell lines have yielded considerable insight into the transcriptional basis for metastatic localization [31–33].…”

Section: Discussionmentioning

confidence: 99%

Time-dependent transcriptional profiling links gene expression to mitogen-activated protein kinase kinase 4 (MKK4)-mediated suppression of omental metastatic colonization

Bainer

Veneris

Yamada

et al. 2012

Clin Exp Metastasis

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Although metastasis is the most lethal attribute of cancer, critical gaps in our knowledge of how cancer cells effectively colonize distant sites remain. For example, little is known about the cellular and molecular events that occur during the timecourse of metastatic colonization. To address this we are using the mitogen-activated protein kinase kinase 4 (MKK4) metastasis suppressor as a tool to identify these events. Specifically, we report a microarray expression-based strategy to identify genes whose transcription is altered in SKOV3ip.1 human ovarian cancer cells that express ectopic MKK4 throughout the course of in vivo metastatic colonization. The majority of genes identified fell into the categories of cytokinesis, cytoskeleton remodeling, and cell adhesion, and their expression was repressed in MKK4-expressing cells relative to vector controls. The greatest transcriptional divergence was concomitant with impaired proliferation at 14 days post injection (dpi). Specifically, 763 genes were differentially expressed (FDR < 0.05) between lesions that expressed ectopic MKK4 and paired controls. In contrast, only seven genes were differentially expressed at the experimental endpoint, when MKK4-expressing and control cells had formed macroscopic metastases. Application of our cohort of differentially expressed genes to three independent clinical datasets demonstrated a strong correlation between our findings and metastatic phenotypes in patient samples. Our results highlight the dynamic nature of metastatic colonization and reinforce the importance of examining both molecular and cellular phenotypes over time when studying metastasis formation.

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Farnesoid X receptor, overexpressed in pancreatic cancer with lymph node metastasis promotes cell migration and invasion

Cited by 67 publications

References 40 publications

Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy

Time-dependent transcriptional profiling links gene expression to mitogen-activated protein kinase kinase 4 (MKK4)-mediated suppression of omental metastatic colonization

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