Emerging Roles of Angiopoietin-like 4 in Human Cancer

Tan, Ming; Teo, Ziqiang; Sng, Ming Keat; Zhu, Pengcheng; Tan, Nguan Soon

doi:10.1158/1541-7786.mcr-11-0519

Cited by 146 publications

(173 citation statements)

References 58 publications

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“…Three genes regulated by berberine only in MDA-MB-231 cell were selected for a detailed investigation of the mechanisms of growth inhibition of berberine on breast cancer ER -cell. Recent studies have revealed an important role for ANGPTL4 in cancer proliferation, anoikis resistance, angiogenesis, and metastasis (Tan et al, 2012), and our finding suggested that berberine inhibited ANGPTL4 represents a novel molecular mechanism of its anticancer activity on MDA-MB-231 cells. CSF1R, which implicated in the pathogenesis and progression of breast cancer (Koren et al, 2000), was markedly decreased in berberine-treated MCA-MB-231 cells as compared with control.…”

Section: 6089 Genomic Screening For Targets Regulated By Berberine Isupporting

confidence: 56%

Genomic Screening for Targets Regulated by Berberine in Breast Cancer Cells

Wen¹,

Wu²,

Fu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Berberine, a common isoquinoline alkaloid, has been shown to possess anti-cancer activities. However, the underlying molecular mechanisms are still not completely understood. In the current study, we investigated the effects of berberine on cell growth, colony formation, cell cycle distribution, and whether it improved the anticancer efficiency of cisplatin and doxorubicin in human breast cancer estrogen receptor positive (ER+) MCF-7 cells and estrogen receptor negative (ER-) MDA-MB-231 cells. Notably, berberine treatment significantly inhibited cell growth and colony formation in the two cell lines, berberine in combination with cisplatin exerting synergistic growth inhibitory effects. Accompanied by decreased growth, berberine induced G1 phase arrest in MCF-7 but not MDA-MB-231 cells. To provide a more detailed understanding of the mechanisms of action of berberine, we performed genome-wide expression profiling of berberine-treated cells using cDNA microarrays. This revealed that there were 3,397 and 2,706 genes regulated by berberine in MCF-7 and MDA-MB-231 cells, respectively. Fene oncology (GO) analysis identified that many of the target genes were involved in regulation of the cell cycle, cell migration, apoptosis, and drug responses. To confirm the microarray data, qPCR analysis was conducted for 10 selected genes based on previously reported associations with breast cancer and GO analysis. In conclusion, berberine exhibits inhibitory effects on breast cancer cells proliferation, which is likely mediated by alteration of gene expression profiles.

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Section: 6089 Genomic Screening For Targets Regulated By Berberine Isupporting

confidence: 56%

Genomic Screening for Targets Regulated by Berberine in Breast Cancer Cells

Wen¹,

Wu²,

Fu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…It is plausible that HB-EGF regulates the expression of VEGFA or ANGPTL4 and that the suppressed function of VEGFA or ANGPTL4 is compensated by upregulation of HB-EGF. ANGPTL4 is recognized as one of several key molecules regulating angiogenesis, functioning as a proangiogenic factor or as an antiangiogenic factor, depending on the cellular context (28)(29)(30)(31)(32)(33). In this study, ANGPLT4 expression, which was induced by HB-EGF, was involved in tumor development in our TNBC xenograft model.…”

Section: Discussionmentioning

confidence: 76%

Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

Yotsumoto

Tokunaga

Oki

et al. 2013

Molecular Cancer Research

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Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under twodimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1a and NF-kB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis. Mol Cancer Res; 11(5); 506-17.

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“…This protein is a circulating glycoprotein that is highly expressed within adipose tissue, the liver and the placenta (13)(14)(15)(16). The native full-length ANGPTL4 (flANGPTL4) is a fusion protein consisting of an N-terminal coiled-coil domain (nANGPTL4) and a large ANG/fibrinogen-like COOH-terminal domain (cANGPTL4) (17)(18)(19); these three domains have been shown to exhibit distinct biological functions (18). Furthermore, ANGPTL4 has been reported to exhibit diverse effects, including lipid metabolism, glucose metabolism, vascular permeability, angiogenesis, wound healing and tumorigenesis, in normal and malignant cells (17,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…The native full-length ANGPTL4 (flANGPTL4) is a fusion protein consisting of an N-terminal coiled-coil domain (nANGPTL4) and a large ANG/fibrinogen-like COOH-terminal domain (cANGPTL4) (17)(18)(19); these three domains have been shown to exhibit distinct biological functions (18). Furthermore, ANGPTL4 has been reported to exhibit diverse effects, including lipid metabolism, glucose metabolism, vascular permeability, angiogenesis, wound healing and tumorigenesis, in normal and malignant cells (17,(20)(21)(22)(23). Among these biological effects, recent studies have focused on the critical roles of ANGPTL4 in tumor progression in various cancers, including hepatocellular carcinoma (HCC) (24), colorectal cancer (25-27), breast cancer (28,29), prostate cancer (30), renal cell carcinoma (31,32) and Kaposi's sarcoma (33,34).…”

Section: Introductionmentioning

confidence: 99%

Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

et al. 2015

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Abstract. Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting a long survival time, whereas HIF-1α predicts a poor prognosis, in gastric cancer patients. The hypoxic environment independently induces ANGPTL4 and HIF-1α, which are believed to exhibit adverse effects on tumor progression.

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Emerging Roles of Angiopoietin-like 4 in Human Cancer

Cited by 146 publications

References 58 publications

Genomic Screening for Targets Regulated by Berberine in Breast Cancer Cells

Genomic Screening for Targets Regulated by Berberine in Breast Cancer Cells

Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

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