Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization

Sawai, Yoshiyuki; Tamura, Shinji; Fukui, Koji; Ito, Nobuyuki; Imanaka, Kazuho; Saeki, Ayuko; Sakuda, Shohei; Kiso, Shinichi; Matsuzawa, Yūji

doi:10.1016/s0168-8278(03)00498-7

Cited by 47 publications

(38 citation statements)

References 26 publications

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“…28 The Eph/Ephrins also can enhance angiogenesis during cancer progression. 29,30 In our study, we demonstrated that EphrinA2 could endow the HCC cells with resistance to both basal and cytokine-induced apoptosis, thus providing a growth advantage to cancer cells, which consequently enhanced the development and progression of HCC. Because the mechanism underlying the regulation of cell survival and apoptosis by Eph/Ephrins in cancer cells remains largely unknown, 31 our study provides novel insights into this mechanism.…”

Section: Discussionmentioning

confidence: 63%

Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway

Feng

Zhao

et al. 2009

Hepatology

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Eph/Ephrin family, one of the largest receptor tyrosine kinase families, has been extensively studied in morphogenesis and neural development. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, the role of Eph/Ephrins in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that the expression of EphrinA2 was significantly up-regulated in both established cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Forced expression of EphrinA2 in HCC cells significantly promoted in vivo tumorigenicity, whereas knockdown of this gene inhibited this oncogenic effect. We further found that suppression of apoptosis, rather than accelerating proliferation, was responsible for EphrinA2-enhanced tumorigenicity. In addition, EphrinA2 endowed cancer cells with resistance to tumor necrosis factor alpha (TNF-␣)-induced apoptosis, thus facilitating their survival. Furthermore, we disclosed a novel EphrinA2/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog ( H epatocellular carcinoma (HCC) is a major health problem worldwide, ranking as the fifth most common cancer in the world and the third most common cause of cancer-related death. 1 HCC shows great geographical variation, with a very high incidence in Asia and sub-Saharan Africa, but it is now becoming more common in the West. During the past 20 years in the United States, HCC has risen by 114%. 2 This paralleled an increase in the incidence of chronic hepatitis, which serves as a main risk factor for HCC. 3 At the initiation of hepatic oncogenesis, transformed hepatocytes must elude various cellular defense activities and acquire abnormal capabilities to survive and proliferate. 4 Aberrant signaling through receptor tyrosine kinases plays a pivotal role in the development and progression of HCC. 5 Eph receptors constitute one of the largest receptor tyrosine kinase families and have been reported to be involved in a variety of cancers. For example, up-regulation of EphA2 has been observed in many malignant tumors [6][7][8] and is associated with accelerated cell prolifera-

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Section: Discussionmentioning

confidence: 63%

Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway

Feng

Zhao

et al. 2009

Hepatology

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“…Previously published observations have highlighted strong ephrin-B1 expression found in multiple nonlymphoid malignancies, including hepatocarcinomas, gastric adenocarcinomas, ovarian carcinomas, and osteosarcomas (45)(46)(47)(48), whereas little is known about the functions of this protein in cancer cells. Our findings show that ephrin-B1 is strongly expressed by pediatric T-ALLs, suggesting a potentially important role for ephrin-B1 in malignant T-cell biology.…”

Section: Discussionmentioning

confidence: 99%

“…In agreement, ephrin-B2 was shown to enhance attachment and migration of melanoma cells, indirectly suggesting that ephrin-B proteins may control metastatic behavior of cancer cells (43). Ephrin-B3 is strongly expressed in invasive glioma cells (44), whereas ephrin-B1 is overexpressed in hepatocarcinomas and gastric adenocarcinomas, and is highly expressed in ovarian carcinomas (45)(46)(47). In osteosarcomas, overexpression of ephrin-B1 correlates with a poorer clinical prognosis (48).…”

Section: Introductionmentioning

confidence: 87%

“…Although in nonlymphoid malignancies ephrin-B1 is often overexpressed and this overexpression seems to correlate with a poorer patient survival (45)(46)(47)(48), the expression and exact functions of ephrin-B1 in malignant T lymphocytes have yet to be addressed. To examine the possibility that ephrin-B1 is also expressed by the human malignant T cells, we used a reverse transcription-PCR approach and analyzed expression of ephrin-B1 in pediatric T-ALLs.…”

Section: Ephrin-b1 Is Consistently Expressed By Pediatric T-all Cellsmentioning

confidence: 99%

“…One of the members of the ephrin-B subfamily, in particular ephrin-B1, has been shown to be expressed in T lymphocytes and to play a role in thymocyte differentiation (58,59), although the precise functions and the mechanism of action of ephrin-B1 in both normal or malignant T lymphocytes have yet to be described. As deregulation of ephrin-B1 expression seems to be associated with increased aggressiveness in solid tumors (45)(46)(47)(48)60), it is important to elucidate its role and mechanism of action in T-cell malignancies.…”

Section: Introductionmentioning

confidence: 99%

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In Human Leukemia Cells Ephrin-B–Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes

Jiang

Freywald

Webster

et al. 2008

Molecular Cancer Research

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Proteins of the ephrin-B group operate in nonlymphoid cells through the control of their migration and attachment, and are crucial for the development of the vascular, lymphatic, and nervous systems. Ephrin-B activity is deregulated in various nonlymphoid malignancies; however, their precise role in cancer has only started to be addressed. We show here that ephrin-B1, a member of the ephrin-B group, is expressed in pediatric T-cell leukemias, including leukemia cell line Jurkat. Treatment of Jurkat cells with ephrin-Bstimulating EphB3 enhances ephrin-B1 phosphorylation and induces its relocalization into lipid rafts. These events are mediated by the T lineage -specific kinase, Lck, as ephrin-B1 phosphorylation and lipid raft association are blocked in the Lck-deficient clone of Jurkat, JCAM1.6. Ephrin-B1 also induces colocalization of the CrkL and Rac1 cytoskeleton regulators and initiates in leukemic cells a strong repulsive response. The absence of Lck blocks ephrin-B1 -induced signaling and repulsion, confirming the essential role for Lck in ephrin-B1 -mediated responses. This shows a new role for ephrin-B1 in the regulation of leukemic cells through the Lck-dependent Rac1 colocalization with its signaling partner, CrkL, in lipid rafts. In agreement with its repulsive action, ephrin-B1 seems to support metastatic properties of leukemic cells, as suppression of ephrin-B1 signaling inhibits their invasiveness. Because ephrin-B1 -activating EphB proteins are ubiquitously expressed, our findings suggest that ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raftassociated signaling, adhesion, and invasive activity, and therefore may represent a novel target for cancer treatment. (Mol Cancer Res 2008;6(2):291 -305)

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Tumor Angiogenesis

Becker¹,

and²,

Schweigerer³

2006

Apoptosis and Cancer Therapy

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Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization

Cited by 47 publications

References 26 publications

Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway

Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway

In Human Leukemia Cells Ephrin-B–Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes

Tumor Angiogenesis

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