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 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
Maternal recognition of pregnancy refers to the requirement for the conceptus（embryo and its associated extraembryonic membranes） to produce a hormone that acts on the uterus and/or corpus luteum（CL） to ensure mai...Maternal recognition of pregnancy refers to the requirement for the conceptus（embryo and its associated extraembryonic membranes） to produce a hormone that acts on the uterus and/or corpus luteum（CL） to ensure maintenance of a functional CL for production of progesterone;the hormone required for pregnancy in most mammals.The pregnancy recognition signal in primates is chorionic gonadotrophin which acts directly on the CL via luteinizing hormone receptors to ensure maintenance of functional CL during pregnancy.In ruminants,interferon tau（IFNT） is the pregnancy recognition signal.IFNT is secreted during the peri-implantation period of pregnancy and acts on uterine epithelia to silence expression of estrogen receptor alpha and oxytocin receptor which abrogates the oxytocin-dependent release of luteolytic pulses of prostaglandin F2-alpha（PGF） by uterine epithelia;therefore,the CL continues to produce progesterone required for pregnancy.Pig conceptuses secrete interferon delta and interferon gamma during the peri-implantation period of pregnancy,but there is no evidence that they are involved in pregnancy recognition signaling.Rather,pig conceptuses secrete abundant amounts of estrogens between Days 11 to 15 of pregnancy required for maternal recognition of pregnancy.Estrogen,likely in concert with prolactin,prevents secretion of PGF into the uterine venous drainage（endocrine secretion）,but maintains secretion of PGF into the uterine lumen（exocrine secretion） where it is metabolized to a form that is not luteolytic.Since PGF is sequestered within the uterine lumen and unavailable to induce luteolysis,functional CL are maintained for production of progesterone.In addition to effects of chorionic gonadotrophin,IFNT and estrogens to signal pregnancy recognition,these hormones act on uterine epithelia to enhance expression of genes critical for growth and development of the conceptus.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 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
基金supported by the following grants:USA-Israel BARD Grant OEP 9604563NIH Grant HD32534 and NIH Grant HD38274
文摘Maternal recognition of pregnancy refers to the requirement for the conceptus（embryo and its associated extraembryonic membranes） to produce a hormone that acts on the uterus and/or corpus luteum（CL） to ensure maintenance of a functional CL for production of progesterone;the hormone required for pregnancy in most mammals.The pregnancy recognition signal in primates is chorionic gonadotrophin which acts directly on the CL via luteinizing hormone receptors to ensure maintenance of functional CL during pregnancy.In ruminants,interferon tau（IFNT） is the pregnancy recognition signal.IFNT is secreted during the peri-implantation period of pregnancy and acts on uterine epithelia to silence expression of estrogen receptor alpha and oxytocin receptor which abrogates the oxytocin-dependent release of luteolytic pulses of prostaglandin F2-alpha（PGF） by uterine epithelia;therefore,the CL continues to produce progesterone required for pregnancy.Pig conceptuses secrete interferon delta and interferon gamma during the peri-implantation period of pregnancy,but there is no evidence that they are involved in pregnancy recognition signaling.Rather,pig conceptuses secrete abundant amounts of estrogens between Days 11 to 15 of pregnancy required for maternal recognition of pregnancy.Estrogen,likely in concert with prolactin,prevents secretion of PGF into the uterine venous drainage（endocrine secretion）,but maintains secretion of PGF into the uterine lumen（exocrine secretion） where it is metabolized to a form that is not luteolytic.Since PGF is sequestered within the uterine lumen and unavailable to induce luteolysis,functional CL are maintained for production of progesterone.In addition to effects of chorionic gonadotrophin,IFNT and estrogens to signal pregnancy recognition,these hormones act on uterine epithelia to enhance expression of genes critical for growth and development of the conceptus.
