Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer

Katsuta, Miwako; Miyashita, Masao; Makino, Hiroshi; Nomura, Tsutomu; Shinji, Seiichi; Yamashita, Kiyohiko; Tajiri, Takashi; Kudo, Mitsuhiro; Ishiwata, Toshiyuki; Naito, Zenya

doi:10.1016/j.yexmp.2004.11.002

Cited by 76 publications

(58 citation statements)

References 33 publications

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“…A highly significant correlation has recently been found between the expression of HIF-1␣ and lymphatic metastasis and VEGF-C expression in human esophageal cancer (Katsuta et al, 2005). Likewise, in lymph node-positive invasive breast cancer, a significant correlation has been found between the expression of HIF-1␣ and VEGF-C and between the expression of HIF-1␣ and peritumoral lymphangiogenesis (Schoppmann et al, 2006).…”

Section: Discussionmentioning

confidence: 96%

EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

Ji¹,

Chou²,

Xu³

et al. 2010

Mol Pharmacol

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The EP1 prostanoid receptor is one of four subtypes whose cognate physiological ligand is prostaglandin-E2 (PGE 2 ). It is in the family of G-protein-coupled receptors and is known to activate Ca 2ϩ signaling, although relatively little is known about other aspects of E-type prostanoid receptor (EP) 1 receptor signaling. In human embryonic kidney (HEK) cells expressing human EP1 receptors, we now show that PGE 2 stimulation of the EP1 receptor up-regulates the expression of hypoxia-inducible factor-1␣ (HIF-1␣), which can be completely blocked by pertussis toxin, indicating coupling to G i/o . This up-regulation of HIF-1␣ occurs under normoxic conditions and could be inhibited with wortmannin, Akt inhibitor, and rapamycin, consistent with the activation of a phosphoinositide-3 kinase/Akt/ mammalian target of rapamycin (mTOR) signaling pathway, respectively. In contrast to the hypoxia-induced up-regulation of HIF-1␣, which involves decreased protein degradation, the up-regulation of HIF-1␣ by the EP1 receptor was associated with the phosphorylation of ribosomal protein S6 (rpS6), suggesting activation of the ribosomal S6 kinases and increased translation. Stimulation of endogenous EP1 receptors in human HepG2 hepatocellular carcinoma cells recapitulated the normoxic up-regulation of HIF-1␣ observed in HEK cells, was sensitive to pertussis toxin, and involved the activation of mTOR signaling and phosphorylation of rpS6. In addition, treatment of HepG2 cells with sulprostone, an EP1-selective agonist, up-regulated the mRNA expression of vascular endothelial growth factor-C, a HIF-regulated gene. HIF-1␣ is known to promote tumor growth and metastasis and is often up-regulated in cancer. Our findings provide a potential mechanism by which increased PGE 2 biosynthesis could up-regulate the expression of HIF-1␣ and promote tumorigenesis. E-type prostanoid receptors (EP) are the receptors that mediate the actions of prostaglandin E 2 (PGE 2 ) and are members of the superfamily of G-protein coupled receptors.There are four primary subtypes of EP receptors, named EP1, EP2, EP3, and EP4. The EP1, EP2, and EP3 receptors were initially classified on the basis of their pharmacology and upon differences in their functional effects on various types of smooth muscle, as well as their activation of second-messenger signaling pathways (Coleman et al., 1994). Thus, PGE 2 stimulation of EP1 receptors produced contractile responses that could be selectively blocked with 8-chloro-dibenz [b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide (SC-19220) and were involved in the mobilization of intracellular Ca 2ϩ . PGE 2 stimulation of EP2

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Section: Discussionmentioning

confidence: 96%

EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

Ji¹,

Chou²,

Xu³

et al. 2010

Mol Pharmacol

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“…Recent studies have also shown that hypoxia, beside regulating neoangiogenesis, can modulate lymphangiogenesis (30,31). The expression of HIF-1a has been shown to correlate with lymph node metastasis (41,42), and genome wide analysis of LEC exposed to low oxygen conditions indicates that hypoxia is capable of increasing VEGF-C, VEGF-D, VEGF-A, and HIF-1a mRNA (30). In addition to the classic hypoxia-mediated induction of HIF-1a, different growth factors, including ET-1, have been shown to enhance HIF-1a accumulation in tumor cells (18,20,43,44).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

et al. 2009

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The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothelin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET-1, ET-3, and express the endothelin B receptor (ET B R). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ET B

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“…The expression of VEGF gene was regulated by a variety of cytokines, oncogenes, products of tumor suppressor genes and hypoxia [19,20] . Under hypoxic conditions, HIF-1 can bind to 5' enhancer region of VEGF and promote the transcription and expression of VEGF [21] , hence increasing angiogenesis and blood supply of hypoxia area.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Zhang²,

Ru³

et al. 2007

WJG

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of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression

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Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer

Cited by 76 publications

References 33 publications

EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

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Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer

Cited by 76 publications

References 33 publications

EP1 Prostanoid Receptor Coupling to Gi/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

EP1 Prostanoid Receptor Coupling to Gi/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

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Resources

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EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway