Myofibrillogenesis regulator-1 (MR-1) is a gene overexpressed usually in many human cancers. However, the effects of MR-1 on cell proliferation, adhesion, migration and genome-wide gene regulation are still unclear. I...Myofibrillogenesis regulator-1 (MR-1) is a gene overexpressed usually in many human cancers. However, the effects of MR-1 on cell proliferation, adhesion, migration and genome-wide gene regulation are still unclear. In this study, a human hepatoma cell line that highly overexpresses MR-1, BEL-7402/MR-1 cells was established. While the high expression of MR-1 did not promote cell proliferation, it significantly increased cell spreading, adhesion and migration compared with control cells. A total of 147 genes were regulated by MR-1 expression, 46 genes were down-regulated and 101 genes were up-regulated by MR-1 overexpression. Many of these genes were related to cell adhesion, cytoskeletal regulation, MAPK signaling, and cell cycle related pathways. Western blot analysis further confirmed the regulation of pathways associated with migration by MR-1. These results suggest that MR-1 is involved in the regulation of cancer cell adhesion, migration and related gene expression.展开更多
Salmonella typhimurium is probably most extensively studied tumor-targeting bacteria and SL7207 is one of its attenuated strains.SL7207 was first made for bacterial vaccine development and its therapeutic efficacy and...Salmonella typhimurium is probably most extensively studied tumor-targeting bacteria and SL7207 is one of its attenuated strains.SL7207 was first made for bacterial vaccine development and its therapeutic efficacy and safety for hepatoellular carcinoma has not been characterized.In this study,the inhibitory ability of SL 7207-lux on human hepatoma HepG2 cells was tested in vitro and in vivo.A bacterial luminescent gene cluster(lux CDA BE)was transfected into SL7207 to better monitor the invasion of the bacteria.The results show that SL7207-lux can rapidly enter HepG2 cells and localize in the cytoplasm.This invasion represses ell proliferation and induces apoptosis.In vivo real-time invasion studies showed that the bacteria gradually accumulate in the tumor.This enrichment was confirmed by anatomic observation at 5 days after inoculation.About 40%of tumor growth was inhibited by SL7207-lxx at 34 days post-treatment without significant loss of body weight.The area of necrosis of tumor tissue was clearly increased in the treated group.Bacterial quantification showed that the number of colony-forming units per gram of bacteria within tumor tissue was approximately 1000-fold higher than that of liver and spleen.These data suggest that attenuated S.typhimurium strain SL7207 has potential for the treatment of cancers.展开更多
To the Editor:Hepatocellular carcinoma(HCC)is the sixth most common tumor and the third leading cause of cancer death globally in 2020.[1]The lack of early diagnosis and high intratumoral heterogeneity in HCC are impo...To the Editor:Hepatocellular carcinoma(HCC)is the sixth most common tumor and the third leading cause of cancer death globally in 2020.[1]The lack of early diagnosis and high intratumoral heterogeneity in HCC are important reasons for its high mortality.Genetic susceptibility and environmental stimuli lead to a tumor mass consisting of mixed tumor cells with different differentiation characteristics.Thus,intratumoral heterogeneity is the inevitable product of the differentiation of tumor stem cells.[2]展开更多
The authors regret that there was an error in the use of GAPDH image in PANC-1 cells of Fig.5B due to mistakenly pasting in the process of assembling figures.The wrong data are replaced by right ones of the same batch...The authors regret that there was an error in the use of GAPDH image in PANC-1 cells of Fig.5B due to mistakenly pasting in the process of assembling figures.The wrong data are replaced by right ones of the same batch as follows.The updated data does not impact the statistical results and the conclusion.展开更多
Pancreatic adenocarcinoma(PAAD) is one of the most lethal malignancies. Although gemcitabine(GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C(Sec C) is a natural com...Pancreatic adenocarcinoma(PAAD) is one of the most lethal malignancies. Although gemcitabine(GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C(Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect(80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-L-cysteine(NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum(ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation(ERAD) ubiquitinates anddownregulates YAP to enhance ER stress via destruction complex(YAP-Axin-GSK-βTr CP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.展开更多
Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally ...Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.展开更多
基金supported by the National Basic Research Program of China (2009CB521807)the National Natural Science Foundation of China (30772583, 30900237)National S&T Major Special Project on Major New Drug Innovation (2012ZX09301002-001)
文摘Myofibrillogenesis regulator-1 (MR-1) is a gene overexpressed usually in many human cancers. However, the effects of MR-1 on cell proliferation, adhesion, migration and genome-wide gene regulation are still unclear. In this study, a human hepatoma cell line that highly overexpresses MR-1, BEL-7402/MR-1 cells was established. While the high expression of MR-1 did not promote cell proliferation, it significantly increased cell spreading, adhesion and migration compared with control cells. A total of 147 genes were regulated by MR-1 expression, 46 genes were down-regulated and 101 genes were up-regulated by MR-1 overexpression. Many of these genes were related to cell adhesion, cytoskeletal regulation, MAPK signaling, and cell cycle related pathways. Western blot analysis further confirmed the regulation of pathways associated with migration by MR-1. These results suggest that MR-1 is involved in the regulation of cancer cell adhesion, migration and related gene expression.
基金This research was supported by grants from National Basic Research Program of China(No.2009CB521807)National Science Foundation of China(No.81101720)National S&T Major Special Project on Major New Drug Innovation(No.2010ZX09401-403).
文摘Salmonella typhimurium is probably most extensively studied tumor-targeting bacteria and SL7207 is one of its attenuated strains.SL7207 was first made for bacterial vaccine development and its therapeutic efficacy and safety for hepatoellular carcinoma has not been characterized.In this study,the inhibitory ability of SL 7207-lux on human hepatoma HepG2 cells was tested in vitro and in vivo.A bacterial luminescent gene cluster(lux CDA BE)was transfected into SL7207 to better monitor the invasion of the bacteria.The results show that SL7207-lux can rapidly enter HepG2 cells and localize in the cytoplasm.This invasion represses ell proliferation and induces apoptosis.In vivo real-time invasion studies showed that the bacteria gradually accumulate in the tumor.This enrichment was confirmed by anatomic observation at 5 days after inoculation.About 40%of tumor growth was inhibited by SL7207-lxx at 34 days post-treatment without significant loss of body weight.The area of necrosis of tumor tissue was clearly increased in the treated group.Bacterial quantification showed that the number of colony-forming units per gram of bacteria within tumor tissue was approximately 1000-fold higher than that of liver and spleen.These data suggest that attenuated S.typhimurium strain SL7207 has potential for the treatment of cancers.
基金supported by The Leading Talent of Hundred,Thousand and Ten Thousand Project of Xingliao Gifted Person Program of Liaoning Province(No.XLYC1905013)Type A Project of Leading Talent’s Innovative Research of Dalian,Capacity-Building Projects of Clinical Discipline of Traditional Chinese Medicine of Health,and Family Planning Commission of Liaoning Province in 2018(No.LNZYXZK201806).
文摘To the Editor:Hepatocellular carcinoma(HCC)is the sixth most common tumor and the third leading cause of cancer death globally in 2020.[1]The lack of early diagnosis and high intratumoral heterogeneity in HCC are important reasons for its high mortality.Genetic susceptibility and environmental stimuli lead to a tumor mass consisting of mixed tumor cells with different differentiation characteristics.Thus,intratumoral heterogeneity is the inevitable product of the differentiation of tumor stem cells.[2]
文摘The authors regret that there was an error in the use of GAPDH image in PANC-1 cells of Fig.5B due to mistakenly pasting in the process of assembling figures.The wrong data are replaced by right ones of the same batch as follows.The updated data does not impact the statistical results and the conclusion.
基金supported by the National Key Research and Development Program of China(2016YFA0201504)National Natural Science Foundation of China(No.81473249 and81102464)+2 种基金the National Mega-project for Innovative Drugs(2014ZX09201042,China)the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-2-002,China)Drug Innovation Major Project of China(2018ZX09711001-007-002)。
文摘Pancreatic adenocarcinoma(PAAD) is one of the most lethal malignancies. Although gemcitabine(GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C(Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect(80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-L-cysteine(NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum(ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation(ERAD) ubiquitinates anddownregulates YAP to enhance ER stress via destruction complex(YAP-Axin-GSK-βTr CP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.
基金supported by grants from CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-002,2021-I2M-1030,China)National Natural Science Foundation of China (No.81473249 and 81102464)+2 种基金Drug Innovation Major Project of China (2018ZX09711001-007-002)National Key Research and Development Program of China (2016YFA0201504)National Mega-project for Innovative Drugs (2014ZX09201042,China)。
文摘Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.
