Tumor LXR Expression is a Prognostic Marker for Patients with Hepatocellular Carcinoma

Long, Houyong; Guo, Xiaomao; Qiao, S; Huang, Qingxing

doi:10.1007/s12253-017-0249-8

Cited by 25 publications

(21 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In summary, we found that LXR agonists can enhance the activity of sorafenib in killing HCC. This result stems from our in vivo data demonstrating that Nr1h3 cDNA (encoding LXR) is incompatible with the growth of MYC-driven tumors in the presence of sorafenib, and fits well with a recent study noting a correlation between LXR expression and improved HCC survival 31 . Furthermore, another publication compared the expression patterns of sorafenib-sensitive and resistant human HCC cell lines, 38 and their data showed a significantly decreased level of LXRα expression in sorafenib-resistant cells (p < 0.01).…”

Section: Discussionsupporting

confidence: 91%

“…A potential concern with using LXR agonists is increased fatty acid synthesis and hepatic steatosis upon LXR activation 30 . However, HCC patients with increased LXR expression have better prognosis than those with lower expression 31 , suggesting that activating LXR with an agonist is a plausible treatment option. LXR expression has been found to be upregulated in various adenocarcinomas, as compared to squamous cell carcinomas from the same tissues of origin 32 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

et al. 2019

Preprint

View full text Add to dashboard Cite

Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah−/−) mice, which led to highly penetrant HCC. We then treated mice with vehicle or sorafenib to discover genetic determinants of sensitivity and resistance. Liver X Receptor alpha (LXRα) emerged as a potential target. To examine LXRα agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRα agonist drugs to HCC cell lines. We performed transcriptomic analysis to elucidate the mechanisms of HCC death. Fah−/− mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRα, suggesting that LXRα activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. The combination of sorafenib and LXR agonism led to enhanced cell death as compared to monotherapy in multiple HCC cell lines, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Our novel in vivo screen led to the discovery that LXR agonist drugs potentiate the efficacy of sorafenib in treating HCC.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In this study, we for the first time revealed that LXR downregulated HULC by repressing its gene promoter activity, leading to the growth inhibition of HCC cells. Besides HCC, LXR and HULC are also associated with other cancers such as breast cancer, prostate cancer, ovarian cancer and colorectal cancer [11][12][13][14][15][16][28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that LXR plays important roles in regulating the metabolisms of glucose, lipid and cholesterol by binding to LXR response elements (LXREs) of its targeting genes [9,10]. Interestingly, the recent studies have revealed that LXR exerts anti-tumor effects on various cancers such as HCC, breast cancer, prostate cancer, ovarian cancer, and colorectal cancer [11][12][13][14][15][16], suggesting that LXR is a potential target in cancer treatment. However, it is not well known about the mechanisms by which LXR plays its anti-tumor function, especially, it is unclear whether the anti-HCC effect of LXR is involved in the regulation of HULC.…”

mentioning

confidence: 99%

Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis

Teng

et al. 2020

Cellular Signalling

View full text Add to dashboard Cite

Background Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA (lncRNA) in human hepatocellular carcinoma (HCC), can promote the growth and metastasis of HCC cells. Therefore, it will be benefit to HCC treatment by effectively downregulating HULC. Liver X receptor (LXR), a member of nuclear receptor superfamily, exerts anti-tumor effects on various human malignancies including HCC. However, it is unclear whether the anti-HCC function of LXR is involved in the regulation of HULC. Methods Quantitative real-time PCR and Western blot were used to separately examine RNA and protein levels in HCC cells. Cell counting kit-8 assay was used to detect the growth of HCC cells in vitro. Dual-luciferase reporter assays were performed to analyze the regulation of forkhead box M1 (FOXM1) by miR-134-5p and the regulation of miR-134-5p by HULC. Xenograft models were engaged to evaluate the growth of HCC cells in vivo. Results In this study, we found that activation of LXR could inhibit the growth of HCC cells by downregulating HULC. Mechanistically, LXR decreased HULC via suppressing its gene promoter activity. Moreover, HULC and FOXM1 were highly expressed while miR-134-5p was lowly expressed in HCC tissues, and the level of HULC was positively correlated with that of FOXM1 while negatively correlated with that of miR-134-5p. Additionally, miR-134-5p downregulated FOXM1 by targeting 3′untranslated region (UTR) of its mRNA, and HULC upregulated FOXM1 and its downstream target molecule cyclin D1 through sequestrating miR-134-5p. Furthermore, activation of LXR increased miR-134-5p while decreased FOXM1 by reducing HULC in HCC cells. The in vivo experiments showed that activation of LXR repressed the growth of HCC xenografts, and decreased HULC, FOXM1 and cyclin D1 while increased miR-134-5p in the xenografts. Conclusions Our results for the first time reveal that LXR can inhibit the growth of HCC cells by regulating HULC/miR-134-5p/FOXM1 axis. The novel pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a promising target in HCC treatment. Background Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNAs with longer than 200

show abstract

“… 17 - 19 Recently, accumulating evidence demonstrated that LXR was a potential prognostic marker and exerted significant anti-tumor effect in HCC. 20 , 21 Furthermore, many genes related with cell proliferation (FOXM1, SOCS3), invasion, and migration in HCC are directly regulated by LXR. 22 - 24 However, limited knowledge is available concerning whether LXR affects the proliferation of HCC cells by modulating miR-124-3p, which needs to be studied further.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-124-3p by Liver X Receptor Inhibits the Growth of Hepatocellular Carcinoma Cells Via Suppressing Cyclin D1 and CDK6

Zhong

Lyu

et al. 2020

Technol Cancer Res Treat

View full text Add to dashboard Cite

MiR-124-3p has been identified as a novel tumor suppressor and a potential therapeutic target in hepatocellular carcinoma (HCC) through regulating its target genes. However, the upstream regulatory mechanisms of mir-124-3p in HCC has not been fully understood. The transcription factor liver X receptor (LXR) plays a critical role in suppressing the proliferation of HCC cells, but it is unclear whether LXR is involved in the regulation of mir-124-3p. In the present study, we demonstrated that the expression of mir-124-3p was positively correlated with that of LXR in HCC, and the cell growth of HCC was significantly inhibited by LXR agonists. Moreover, activation of LXR with the agonists up-regulated the expression of mir-124-3p, and in turn down-regulated cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression, which are the target genes of mir-124-3p. Mechanistically, miR-124-3p mediates LXR induced inhibition of HCC cell growth and down-regulation of cyclin D1 and CDK6 expression. In vivo experiments also confirmed that LXR induced miR-124-3p expression inhibited the growth of HCC xenograft tumors, as well as cyclin D1 and CDK6 expression. Our findings revealed that miR-124-3p is a novel target gene of LXR, and regulation of the miR-124-3p-cyclin D1/CDK6 pathway by LXR plays a crucial role in the proliferation of HCC cells. LXR-miR-124-3p-cyclin D1/CDK6 pathway may be a novel potential therapeutic target for HCC treatment.

show abstract

Tumor LXR Expression is a Prognostic Marker for Patients with Hepatocellular Carcinoma

Cited by 25 publications

References 13 publications

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis

Upregulation of miR-124-3p by Liver X Receptor Inhibits the Growth of Hepatocellular Carcinoma Cells Via Suppressing Cyclin D1 and CDK6

Contact Info

Product

Resources

About