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
目的研究银杏叶提取物EGb(Extract of Ginkgo Biloba,EGb)对前列腺素F2α(PGF2α)所致心肌细胞肥大的作用及作用机制。方法实验选用正常培养的乳鼠心肌细胞作为对照组,PGF2α和PGF2α加不同浓度EGb作为实验组,在培养的新生乳鼠心肌细胞...目的研究银杏叶提取物EGb(Extract of Ginkgo Biloba,EGb)对前列腺素F2α(PGF2α)所致心肌细胞肥大的作用及作用机制。方法实验选用正常培养的乳鼠心肌细胞作为对照组,PGF2α和PGF2α加不同浓度EGb作为实验组,在培养的新生乳鼠心肌细胞上,采用Bradford蛋白浓度测定试剂盒检测心肌细胞总蛋白含量;相差显微镜检测细胞面积;荧光倒置显微镜测定心肌细胞内活性氧(reactive oxygen species.ROS)的活性。结果PGF2α10-7mol/L使心肌细胞面积明显增大和蛋白质含量明显增加(P<0.05),并使细胞内活性氧显著升高。与PGF2α组比较,银杏叶提取物EGb(40μg/ml,80μg/ml,100μg/ml)组可分别使心肌细胞面积缩小19%,27%,33%(P<0.05);蛋白质含量下降6%,19%,24%(P<0.05);心肌细胞内活性氧荧光密度的活性下降21%,39%,47%(P<0.01)。结论银杏叶提取物EGb可抑制PGF2α诱导的心肌细胞肥大,该作用可能与其抑制细胞内氧自由基活性有关。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.
