• Humans
• Dinoprostone/metabolism
• Tumor Microenvironment
• Animals
• Receptors, Prostaglandin E, EP2 Subtype/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/immunology
• Neoplasms/pathology
• Receptors, Prostaglandin E, EP4 Subtype/metabolism
• Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors
• Signal Transduction

• Alzheimer's disease
• CNS
• EP1 receptor
• Parkinson's disease
• neurodegeneration

• Receptors, Prostaglandin E, EP1 Subtype/genetics
• Signal Transduction/physiology
• Protein Kinase C/metabolism

• COX-2
• Cancer survival
• EP1
• PGE2
• Prognosis
• Vulvar carcinoma

• Female
• Humans
• Cyclooxygenase 2/metabolism
• Dinoprostone
• Vulvar Neoplasms
• Receptors, Prostaglandin E, EP1 Subtype/metabolism
• Carcinogenesis

• Universitätsklinik München (6933)

Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3β, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.

• National Major Science and Technology Projects of China
• Science and Technology Program of Zhejiang Province

•

PGE2 enhanced β1- integrin expression via EP1 receptor, PKC, MEK and NfҡB.

Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.

• Breast cancer
• E2F1
• FOXC2
• NF-ҡB
• Prostaglandin E2
• β1-integrin

• cancer stemness
• chemoresistance
• cyclooxygenase-2
• head and neck cancer
• hypopharyngeal carcinoma
• prostaglandin E receptor 2

While prostaglandins (PGs), short-range lipid signals, regulate single cell migration, their roles in collective migration remain unclear. To address this, we use Drosophila border cell migration, an invasive, collective migration that occurs during Stage 9 of oogenesis. Pxt is the Drosophila cyclooxygenase-like enzyme responsible for PG synthesis. Loss of Pxt results in both delayed border cell migration and elongated clusters, whereas somatic Pxt knockdown causes delayed migration and compacted clusters. These findings suggest PGs act in both the border cells and nurse cells, the substrate on which the border cells migrate. As PGs regulate the actin bundler Fascin, and Fascin is required for on-time migration, we assessed whether PGs regulate Fascin to promote border cell migration. Coreduction of Pxt and Fascin results in delayed migration and elongated clusters. The latter may be due to altered cell adhesion, as loss of Pxt or Fascin, or coreduction of both, decreases integrin levels on the border cell membranes. Conversely, integrin localization is unaffected by somatic knockdown of Pxt. Together these data lead to the model that PG signaling controls Fascin in the border cells to promote migration and in the nurse cells to maintain cluster cohesion.

To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP₁) contribute to disease and whether they help predict prognosis.

We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP₁ receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.

Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP₁ receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP₁. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP₁ receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001).

COX-2 expression appears to be linked to early HCC events (initiation), while EP₁ receptor expression may participate in tumor progression and predict survival.

• Cyclooxygenase-2
• Hepatocellular carcinoma
• Liver resection
• Prognosis
• Prostaglandin E1 receptor

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/mortality
• Cyclooxygenase 2/biosynthesis
• Cyclooxygenase 2/metabolism
• Disease Progression
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/enzymology
• Liver Neoplasms/mortality
• Male
• Middle Aged
• Prognosis
• Receptors, Prostaglandin E, EP1 Subtype/metabolism
• Retrospective Studies
• Treatment Outcome

Cyclooxygenase-2 (COX-2) has been implicated in cell invasion in non-small-cell lung cancer (NSCLC). However, the mechanism is unclear. The present study investigated the effect of COX-2 on β1-integrin expression and cell invasion in NSCLC. COX-2 and β1-integrin were co-expressed in NSCLC tissues. COX-2 overexpression or Prostaglandin E2 (PGE2) treatment increased β1-integrin expression in NSCLC cell lines. β1-integrin silencing suppressed COX-2-mediated tumour growth and cancer cell invasion in vivo and in vitro. Prostaglandin E Receptor EP1 transfection or treatment with EP1 agonist mimicked the effect of PGE₂ treatment. EP1 siRNA blocked PGE₂-mediated β1-integrin expression. EP1 agonist treatment promoted Erk1/2, p38 phosphorylation and E2F-1 expression. MEK1/2 and p38 inhibitors suppressed EP1-mediated β1-integrin expression. E2F-1 silencing suppressed EP1-mediated FoxC2 and β1-integrin upregulation. ChIP and Luciferase Reporter assays identified that EP1 agonist treatment induced E2F-1 binding to FoxC2 promotor directly and improved FoxC2 transcription. FoxC2 siRNA suppressed β1-integrin expression and EP1-mediated cell invasion. Immunohistochemistry showed E2F-1, FoxC2, and EP1R were all highly expressed in the NSCLC cases. This study suggested that COX-2 upregulates β1-integrin expression and cell invasion in NSCLC by activating the MAPK/E2F-1 signalling pathway. Targeting the COX-2/EP1/PKC/MAPK/E2F-1/FoxC2/β1-integrin pathway might represent a new therapeutic strategy for the prevention and treatment of this cancer.

Prostaglandin E₂ (PGE₂) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE₂ exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1–4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE₂ (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE₂ increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE₂ mimicked the effect of PGE₂ treatment. EP1 siRNA blocked PGE₂-mediated β1-integrin expression. 17-PT-PGE₂ treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE₂-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE₂. NF-κB inhibitor suppressed 17-PT-PGE₂-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE₂ upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE₂/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.

We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.

Expression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.

Our data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.

The results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for HCC. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the carcinogenesis of HCC. HBx is a multifunctional regulator that plays a key role in the occurrence, development, invasion and metastasis of cancers. Due to its important roles in the development of HCC, the research on the HBx protein has become a hot topic in recent years. This review describes the latest advances in understanding the role of the HBx protein in hepatocarcinogenesis.

• Hepatitis B virus
• Hepatitis B virus X protein
• Hepatocellular carcinoma