Expression of the liver‐enriched transcription factors C/EBPα, C/EBPβ, HNF‐1, and HNF‐4 in preneoplastic nodules and hepatocellular carcinoma in rat liver

Flodby, Per; Liao, D. Joshua; Blanck, Agneta; Xanthopoulos, Kleanthis G.; Hällström, Inger Porsch

doi:10.1002/mc.2940120207

Cited by 48 publications

(26 citation statements)

References 46 publications

(12 reference statements)

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“…One of the central mediators in this regulatory network is HNF4α, which regulates not only the hepatocyte proliferation and differentiation but also the hepatic epithelial morphology (12). Previous studies clarified that the expression of HNF4α was decreased in rodent and human HCC in comparison with the adjacent noncancerous tissues (21)(22)(23). With this study, we reported the progressive reduction of HNF4α during hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma

et al. 2010

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Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma

et al. 2010

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“…[8][9][10] It has also been recognized that LETFs play important roles in liver differentiation, which is strictly controlled by the appropriate LETF expression pattern at each embryonic developmental stage.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, transcriptional alterations of these factors were observed between normal tissues and preneoplastic nodules or cancerous tissue taken from the same subject, both in clinical samples 8) and in chemically induced tumors of mice. 9,10) These reports suggest that changes of LETFs expression occur in hepatocarcinogenesis and their pattern and extent reflect the characteristics of HCCs, especially the differentiation grade. However, little is known about the correlation between histological differentiation and HNF-1α and HNF-1β, 11) and no study has as yet clarified the correlation between the expression of LETFs mRNAs and differentiation at the level of functional protein expression in HCCs.…”

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confidence: 97%

Expression of HNFs and C/EBPα is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes

et al. 2003

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Objective assessment of the differentiation grade of hepatocellular carcinomas (HCCs) is important for evaluation of the pathological diagnosis, prognosis and therapeutic treatment. Differentiation of hepatocytes is reflected by their expression of hepatic functional proteins in the mouse embryo, and liver‐enriched transcription factors (LETFs) have been shown to regulate hepatic functional genes strictly. Previous reports demonstrated that the level of LETF expression is altered in HCC or preneoplastic nodules compared with noncancerous tissues. Therefore, LETF expression levels might be useful as a measure of HCC maturation. In this study, to clarify the correlation between the expression of LETFs and the differentiation grade of HCCs, we performed a quantitative analysis of the mRNA expressions of HNFs and C/EBPα using real‐time reverse‐transcription PCR and immunocytochemical analysis for hepatic functional proteins in twelve cell lines. Furthermore, we examined orthotopic transplantations of the HCC cell lines in C.B‐17/Icrj‐scid/scid mice and characterized the histologic and cytologic differentiation of the tumors that developed. Our results showed that comprehensive expressions of HNF‐3β, HNF‐4α, HNF‐1α, and C/EBPα were specific to HCCs with well‐differentiated function and morphology. Furthermore, among these four transcription factors, HNF‐4α and HNF‐1α expressions showed synchronism and had a close relation with HCC differentiation. These in vitro results were confirmed in tumors developed in SCID mice in vivo. These findings suggested that HNF‐4α and HNF‐1α are useful markers to assess the degree of HCC differentiation, which we suggest could be evaluated objectively by the quantitative analysis of HNFs and C/EBPα in HCCs.

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“…Many studies have shown that C/EBP␣ can induce cell growth arrest in various cell types. For example, C/EBP␣ expression is reduced in preneoplastic nodules compared with the surrounding liver tissues (43). C/EBP␣ overexpression inhibits hepatocyte proliferation and also suppresses colony growth in mouse fibroblasts (44,45).…”

Section: C/ebp Isoforms Are Expressed Differentially and Bind To The mentioning

confidence: 99%

Transcriptional Regulation of Cyclooxygenase-2 in Mouse Skin Carcinoma Cells

Kim

Fischer

1998

Journal of Biological Chemistry

188

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Many studies have suggested that overexpression of cyclooxygenase-2 (COX-2) contributes to the development of tumors in several tissues. COX-2 expression tends to be up-regulated in various types of tumors and transformed cell lines, and the overexpression of COX-2 is caused by enhanced transcription of the gene. In an attempt to characterize the signaling pathway leading to the overexpression of COX-2 in the mouse skin carcinoma cell line JWF2, we investigated cis-and transacting factors required for COX-2 expression and demonstrated a molecular mechanism by which COX-2 is expressed differentially in normal and neoplastic tissues. Two regions of the COX-2 promoter containing an E-box and nuclear factor IL6 site were identified as the positive regulatory elements through transient transfections with luciferase reporter vectors containing the various 5-flanking regions of the promoter. Moreover, electrophoretic mobility shift assays and cotransfection experiments showed that upstream stimulatory factors and CCAAT/enhancer-binding proteins (C/EBPs) bind to the E-box and nuclear factor IL6 site, respectively, and functionally transactivate the COX-2 promoter. We also found that C/EBP isoforms are expressed differentially during mouse skin carcinogenesis, suggesting that overexpression of COX-2 in tumors may be caused by a change in C/EBP expression levels. Prostaglandins (PGs)1 are involved in many normal and pathophysiological responses (1). As a rate-limiting enzyme in the synthesis of PGs, cyclooxygenase (COX)

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Expression of the liver‐enriched transcription factors C/EBPα, C/EBPβ, HNF‐1, and HNF‐4 in preneoplastic nodules and hepatocellular carcinoma in rat liver

Cited by 48 publications

References 46 publications

Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma

Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma

Expression of HNFs and C/EBPα is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes

Transcriptional Regulation of Cyclooxygenase-2 in Mouse Skin Carcinoma Cells

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