Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chem...Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.展开更多
AIM to determine whether cyclooxygenase-2(COX-2) and prostaglandin E1 receptor(EP1) contribute to disease and whether they help predict prognosis.METHODS We retrospectively reviewed the records of 116 patients with he...AIM to determine whether cyclooxygenase-2(COX-2) and prostaglandin E1 receptor(EP1) contribute to disease and whether they help predict prognosis.METHODS 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, paraffinembedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.RESULTS Factors associated with poor overall survival(OS) were alpha-fetoprotein > 400 ng/m L, 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).CONCLUSION COX-2 expression appears to be linked to early HCC events(initiation), while EP1 receptor expression may participate in tumor progression and predict survival.展开更多
BACKGROUND: Prostaglandin E2 (PGE2) can directly regulate toxic injury of hippocampal neurons through participation by its receptor. Increase of excitability of hippocampal membrane and long-term synaptic elasticity a...BACKGROUND: Prostaglandin E2 (PGE2) can directly regulate toxic injury of hippocampal neurons through participation by its receptor. Increase of excitability of hippocampal membrane and long-term synaptic elasticity are closely related to PGE2, PGD2 and PGF2A. This suggests that PGE2 may be a key molecule of neuronal signal passage and regulate the existence of neurons through its receptor. However, which isoforms of PGE2 receptor expressing in hippocampal neurons is still unclear. OBJECTIVE: To research the subtype expression of PGE2 receptor in hippocampus of rats through mRNA transcription and protein interpretation. DESIGN: Animal studies with random, control and operator and designer double-blind methods. SETTING: University of South Carolina, Animal Center. MATERIALS: Sprague-Dawley rats, aged 12 weeks, weighing 200 g, females 48 and males 48, were selected from Animal Center in South Carolina University. Tri ReagentTM kit was provided by Molecular Research Center, USA. METHODS: The experiment was carried out in Animal Center in South Carolina University from January to December 2005. The expression of the PGE2 receptors was profiled and compared in rat hippocampus using real-time RT-PCR and Western-blot techniques. MAIN OUTCOME MEASURES: Expression of PGE2 receptors in various isoforms of hippocampal neurons of rats. RESULTS: mRNAs of all four EP1-4 subtypes were detected in the hippocampus. Western-blot data showed consistently detectable bands at approximately Mr 50 000 of EP1, Mr 40 000 and Mr 52 000 of EP2, Mr 45 000, Mr 57 000 and Mr 105 000 of EP3, and Mr 46 000 of EP4. CONCLUSION: Identifying four subtypes of EPs heterogeneously expresses in the hippocampus.展开更多
AIM：To explore the role of prostaglandin F2α（PGF2α） on pacemaker activity in interstitial cells of Cajal（ICC）from mouse small intestine. METHODS：In this study,effects of PGF2αin the cultured ICC cells were in...AIM：To explore the role of prostaglandin F2α（PGF2α） on pacemaker activity in interstitial cells of Cajal（ICC）from mouse small intestine. METHODS：In this study,effects of PGF2αin the cultured ICC cells were investigated with patch clamp technology combined with Ca 2＋ image analysis. RESULTS：Externally applied PGF2α（10μmol/L）produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode.The application of flufenamic acid（a non-selective cation channel inhibitor）or niflumic acid（aCl channel inhibitor）abolished the generation of pacemaker currents but only flufenamic acid inhibited the PGF2α-induced tonic inward currents.In addition,the tonic inward currents induced by PGF2αwere not inhibited by intracellular application of 5’-[-thio]diphosphate trilithium salt.Pretreatment with Ca 2＋ free solution, U-73122,an active phospholipase C inhibitor,and thapsigargin,a Ca 2＋ -ATPase inhibitor in endoplasmic reticulum,abolished the generation of pacemaker currents and suppressed the PGF2α-induced tonic inward currents.However,chelerythrine or calphostin C,protein kinase C inhibitors,did not block the PGF2α-induced effects on pacemaker currents.When recording intracellular Ca 2＋ （[Ca 2＋ ]i）concentration using fluo-3/AM,PGF2α broadly increased the spontaneous[Ca 2＋ ]i oscillations. CONCLUSION：These results suggest that PGF2αcan modulate pacemaker activity of ICC by acting non-selective action channels through phospholipase C-dependent pathway via[Ca2＋]i regulation展开更多
Objective: To study the expression of activated epi-dermal growth factor receptor (EGFR) and transcrip-tion factor E2F (E2F) in Condyloma Accuminata(CA)patients. Methods: Immunofluorescent techniques were usedto inves...Objective: To study the expression of activated epi-dermal growth factor receptor (EGFR) and transcrip-tion factor E2F (E2F) in Condyloma Accuminata(CA)patients. Methods: Immunofluorescent techniques were usedto investigate the expression of activated EGFR andE2F in CA patients. Results: The expression of activated EGFR on themembrane of epithelial cells in CA lesions was sig-nificantly greater compared to expression levers inthe control group (P<0.01). Moreover, the co-expres-sion of activated EGFR and E2F was significantly in-creased compared to the control group (P<0.01). Conclusion: Our observations suggest that the in-crease in activated EGFR expression may stimulatehyperplasia in CA patients through the activation oftranscription factor E2F.展开更多
Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between t...Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases.展开更多
基金National Yang Ming Chiao Tung University Far Eastern Memorial Hospital Joint Research Programs(NYCU-FEMH 109DN03,110DN06,111DN04,112DN05).
文摘Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.
基金Supported by National Natural Science Foundation of China,No.81260331Key Laboratory for High-Incidence Tumor Prevention and Treatment,Ministry of Education,No.GKE2015-ZZ05
文摘AIM to determine whether cyclooxygenase-2(COX-2) and prostaglandin E1 receptor(EP1) contribute to disease and whether they help predict prognosis.METHODS 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, paraffinembedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.RESULTS Factors associated with poor overall survival(OS) were alpha-fetoprotein > 400 ng/m L, 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).CONCLUSION COX-2 expression appears to be linked to early HCC events(initiation), while EP1 receptor expression may participate in tumor progression and predict survival.
文摘BACKGROUND: Prostaglandin E2 (PGE2) can directly regulate toxic injury of hippocampal neurons through participation by its receptor. Increase of excitability of hippocampal membrane and long-term synaptic elasticity are closely related to PGE2, PGD2 and PGF2A. This suggests that PGE2 may be a key molecule of neuronal signal passage and regulate the existence of neurons through its receptor. However, which isoforms of PGE2 receptor expressing in hippocampal neurons is still unclear. OBJECTIVE: To research the subtype expression of PGE2 receptor in hippocampus of rats through mRNA transcription and protein interpretation. DESIGN: Animal studies with random, control and operator and designer double-blind methods. SETTING: University of South Carolina, Animal Center. MATERIALS: Sprague-Dawley rats, aged 12 weeks, weighing 200 g, females 48 and males 48, were selected from Animal Center in South Carolina University. Tri ReagentTM kit was provided by Molecular Research Center, USA. METHODS: The experiment was carried out in Animal Center in South Carolina University from January to December 2005. The expression of the PGE2 receptors was profiled and compared in rat hippocampus using real-time RT-PCR and Western-blot techniques. MAIN OUTCOME MEASURES: Expression of PGE2 receptors in various isoforms of hippocampal neurons of rats. RESULTS: mRNAs of all four EP1-4 subtypes were detected in the hippocampus. Western-blot data showed consistently detectable bands at approximately Mr 50 000 of EP1, Mr 40 000 and Mr 52 000 of EP2, Mr 45 000, Mr 57 000 and Mr 105 000 of EP3, and Mr 46 000 of EP4. CONCLUSION: Identifying four subtypes of EPs heterogeneously expresses in the hippocampus.
基金Supported by Research Fund from Chosun Hospital 2008
文摘AIM：To explore the role of prostaglandin F2α（PGF2α） on pacemaker activity in interstitial cells of Cajal（ICC）from mouse small intestine. METHODS：In this study,effects of PGF2αin the cultured ICC cells were investigated with patch clamp technology combined with Ca 2＋ image analysis. RESULTS：Externally applied PGF2α（10μmol/L）produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode.The application of flufenamic acid（a non-selective cation channel inhibitor）or niflumic acid（aCl channel inhibitor）abolished the generation of pacemaker currents but only flufenamic acid inhibited the PGF2α-induced tonic inward currents.In addition,the tonic inward currents induced by PGF2αwere not inhibited by intracellular application of 5’-[-thio]diphosphate trilithium salt.Pretreatment with Ca 2＋ free solution, U-73122,an active phospholipase C inhibitor,and thapsigargin,a Ca 2＋ -ATPase inhibitor in endoplasmic reticulum,abolished the generation of pacemaker currents and suppressed the PGF2α-induced tonic inward currents.However,chelerythrine or calphostin C,protein kinase C inhibitors,did not block the PGF2α-induced effects on pacemaker currents.When recording intracellular Ca 2＋ （[Ca 2＋ ]i）concentration using fluo-3/AM,PGF2α broadly increased the spontaneous[Ca 2＋ ]i oscillations. CONCLUSION：These results suggest that PGF2αcan modulate pacemaker activity of ICC by acting non-selective action channels through phospholipase C-dependent pathway via[Ca2＋]i regulation
文摘Objective: To study the expression of activated epi-dermal growth factor receptor (EGFR) and transcrip-tion factor E2F (E2F) in Condyloma Accuminata(CA)patients. Methods: Immunofluorescent techniques were usedto investigate the expression of activated EGFR andE2F in CA patients. Results: The expression of activated EGFR on themembrane of epithelial cells in CA lesions was sig-nificantly greater compared to expression levers inthe control group (P<0.01). Moreover, the co-expres-sion of activated EGFR and E2F was significantly in-creased compared to the control group (P<0.01). Conclusion: Our observations suggest that the in-crease in activated EGFR expression may stimulatehyperplasia in CA patients through the activation oftranscription factor E2F.
文摘Estrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases.
