The global incidence of lung cancer is marked by a considerably elevated mortality rate.MicroRNAs(miRNAs)exert pivotal influence in the intricate orchestration of gene regulation,and their dysregulation can precipitate...The global incidence of lung cancer is marked by a considerably elevated mortality rate.MicroRNAs(miRNAs)exert pivotal influence in the intricate orchestration of gene regulation,and their dysregulation can precipitate dire consequences,notably cancer.Within this context,miRNAs encapsulated in exosomes manifest a diversified impact on the landscape of lung cancer,wherein their actions may either foster angiogenesis,cell proliferation,and metastasis,or counteract these processes.This comprehensive review article discerns potential targets for the prospective development of therapeutic agents tailored for lung cancer.Tumor-suppressive miRNAs,such as miR-204,miR-192,miR-30a,miR-34a,miR-34b,miR-203,and miR-212,exhibit heightened expression and demonstrate the capacity to inhibit cellular proliferation and invasiveness.Conversely,the deleterious effects of tumor-promoting miRNAs like miR-21,miR-106a,miR-155,miR-205,and miR-210 can be attenuated through the application of their respective inhibitors.Distinct miRNAs selectively target various oncogenes,including NUAK Family Kinase 1(NUAK1),Snail Family Transcriptional Repressor 1(Snai1),Astrocyte elevated gene-1(AEG-1),Vimentin,Proliferation and apoptosis adaptor protein 15(PEA-15/PED),Hypoxia-inducible factor 1-alpha(HIF1),as well as tumor suppressor genes such as phosphatase and tensin homolog(PTEN),Suppressor of cytokine signaling 1(SOCS1),Tumor protein P53 binding protein 1(TP53BP1),and PH Domain and Leucine Rich Repeat Protein Phosphatase 2(PHLP22).This investigative approach proves invaluable in elucidating the specific miRNAs implicated in the deregulation of crucial genes pivotal to the pathogenesis of cancer.展开更多
Natural exosomes can express specific proteins and carbohydratemolecules on the surface and hence have demonstrated the great potentials for gene therapy of cancer.However,the use of natural exosomes is restricted by ...Natural exosomes can express specific proteins and carbohydratemolecules on the surface and hence have demonstrated the great potentials for gene therapy of cancer.However,the use of natural exosomes is restricted by their low transfection efficiency.Here,we report a novel targeting tLyp-1 exosome by gene recombinant engineering for delivery of siRNA to cancer and cancer stem cells.To reach such a purpose,the engineered tLyp-1-lamp2b plasmids were constructed and amplified in Escherichia coli.The tLyp-1-lamp2b plasmids were further used to transfect HEK293T tool cells and the targeting tLyp-1 exosomes were isolated from secretion of the transfected HEK293T cells.Afterwards,the artificially synthesized siRNA was encapsulated into targeting tLyp-1 exosomes by electroporation technology.Finally,the targeting siRNA tLyp-1 exosomes were used to transfect cancer or cancer stem cells.Results showed that the engineered targeting tLyp-1 exosomes had a nanosized structure(approximately 100 nm)and high transfection efficiency into lung cancer and cancer stem cells.The function verifications demonstrated that the targeting siRNA tLyp-1 exosomes were able to knock-down the target gene of cancer cells and to reduce the stemness of cancer stem cells.In conclusion,the targeting tLyp-1 exosomes are successfully engineered,and can be used for gene therapy with a high transfection efficiency.Therefore,the engineered targeting tLyp-1 exosomes offer a promising gene delivery platform for future cancer therapy.展开更多
Objective: To develop a novel adenoviral vector system, which combines the advantages of the antiangiogenic gene therapy and virus therapy, and to investigate its antitumor activity on lung cancer. Methods: A new ki...Objective: To develop a novel adenoviral vector system, which combines the advantages of the antiangiogenic gene therapy and virus therapy, and to investigate its antitumor activity on lung cancer. Methods: A new kind of viral vector CNHK200, in which the Elb55kDa gene was deleted and the whole Ela gene was preserved, was constructed. Human angiostatin gene Kringle 1-5 (hA) was amplified and inserted into the genome of the replicative virus CNHK200, generating CNHK200-hA. The expression of hA and its effect on lung cancer cell growth in vitro and in vivo were studied. Results: The novel vector system CNHK200-hA, just like the replicative virus ONYX-015, replicated in p53-deficient tumor cells but not in normal cells, and thus specifically killed tumor cells. In in vitro experiment, both CNHK200-hA and the non-replicative virus Ad-hA could kill tumor cells but the latter needed 100 times more MOI to achieve the same level of cell killing. In in vivo experiment, the therapeutic effect of CNHK200-hA on human lung cancer A549 xenografts in nude mice was significantly better than that of Ad-hA or that of ONYX-015. Conclusion: CNHK200-hA, which carries the angiostatin gene, has the advantages of specific tumor targeting, high expression of transgene in tumor cells and potent antitumor activity.展开更多
Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion n...Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.展开更多
Peroxisome proliferator-activated receptors(PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily.Of the three PPARs identified to date(PPARγ,PPARβ/δ,and PPARα),...Peroxisome proliferator-activated receptors(PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily.Of the three PPARs identified to date(PPARγ,PPARβ/δ,and PPARα),PPARγ has been studied the most,in part because of the availability of PPARγagonists(also known as PPARγ ligands)and its significant effects on the management of several human diseases including type 2 diabetes,metabolic syndrome,cardiovascular disease and cancers.PPARγ is expressed in many tumors including lung cancer,and its function has been linked to the process of lung cancer development, progression and metastasis.Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARγ ligands.Furthermore,data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer.This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARγ ligands as a novel anti-lung cancer treatment strategy.展开更多
OBJECTIVE To explore the relationship between CAR and the development of human lung cancer, as well as to provide the basis for the clinical treatment of lung cancer using an adenovirus vector-based gene therapy. METH...OBJECTIVE To explore the relationship between CAR and the development of human lung cancer, as well as to provide the basis for the clinical treatment of lung cancer using an adenovirus vector-based gene therapy. METHODS CAR expression was assessed immunohisto- chemically in tumoral, paraneoplastic and normal samples from 112 lung cancer patients. At the same time, the mRNA and protein expression of CAR in 32 cases were determined by RT-PCR and Western blot. The relationship between CAR expression and clinicopathologic parameters was statistically analyzed. RESULTS There was no expression of CAR in normal lung tissue but a little in paraneoplastic tissue. The positive rate was 43% in squamous cell carcinoma, and 70% in adenocarcinoma. Both were much significantly higher than that in paraneoplastic tissue. The CAR expression level in adenocarcinoma was higher than that in squamous cell cancer, mRNA expression by RT-PCR and protein expression by Western blot were consistent with immunohistochemistry results. CONCLUSION CAR is overexpressed in human lung cancer, especially in adenocarcinoma. This data offer the reliable basis for adenovirus-mediated gene therapy of lung cancer; more important, CAR may take part in the formation or development of lung cancer; this may be exploitable for the development of antibody-directed therapy in human lung cancer.展开更多
Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL...Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter(AdTRAIL) was combined with drugs including gefitinib,elotinib,and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer(NSCLC) cell lines to investigate their antitumor activity.In vitro,compared to single reagent,AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460,A549,and SW1573 cell lines.Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT.In vivo,AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice.Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL.These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.展开更多
Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to...Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity.Here,we constructed an iRGD peptide(H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH_(2))modified nanoparticle(iDPP)to deliver plasmids encoding SEA for melanoma treatment.The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells(BMDCs)in vitro.In the subcutaneous B16-F10 melanoma model,the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration,thereby considerably decreased melanoma growth.Meanwhile,no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo.Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.展开更多
Objective: We explored the expression of coxsackie and adenovirus receptor (CAR) in small cell lung cancer (SCLC) tissue. Methods: CAR expression in 31 SCLC was assessed in formaldehyde-fixed, paraffin-embedded tissue...Objective: We explored the expression of coxsackie and adenovirus receptor (CAR) in small cell lung cancer (SCLC) tissue. Methods: CAR expression in 31 SCLC was assessed in formaldehyde-fixed, paraffin-embedded tissue according to the EnVision immunohistochemistry procedure, while 3 samples of surgical specimens of non-malignant lung disease were taken as the negative control. Results: We observed that the expression of CAR was detectable positive in all the 31 cases from the small cell lung cancer tissue, in contrasting that non-malignant lung tissue control. Conclusion: The high expression of CAR appeared in SCLC tissue indicates that it play an important role in of adenovirus vector-based gene therapy in SCLC.展开更多
OBJECTIVE To study the relationship between the coxsackie and adenovirus receptor (CAR) and the development of human lung cancer. To optimize adenovirus vector-based gene therapy.METHODS The expression of CAR in 112...OBJECTIVE To study the relationship between the coxsackie and adenovirus receptor (CAR) and the development of human lung cancer. To optimize adenovirus vector-based gene therapy.METHODS The expression of CAR in 112 cases of lung cancer was examined using immunohistochemistry. At the same time, the relationship between CAR expression and clinicopathologic characteristics was analyzed,RESULTS :lhere is a little expression of CAR in normal lung tissue. Compared with paraneoplastic epithelial tissue of the lung, the expression of CAR is generally up-regulated in tumor tissues showing a significant dif- ference (P〈0.01). The positive rate of CAR expression in squamous cell carcinoma was 43.1%, and in adenocarcinoma 70.2%, with the difference between the two rates being statistically significant (P〈0.01). Compared to the paraneoplastic tissues, the difference in CAR positive expression was 35.4% for squamous cell carcinoma and 38.3% for adenocarcinoma. But the difference in different stages of squamous cell carcinoma had no statistical significance (P〉0.05). However, the expression of CAR was at a high level in the bronchioalveolar carcinomas as 80.4% were CAR positive. This research showed that there was a specially high expression of CAR in adenocarcinomas.CONCLUSION CAR is expressed in human lungs at a low level and up-regulated in the tumor tissues, suggesting that there is a relationship between adenocarcinoma and CAR. This research provides a basis for planning a regimen of gene therapy using an adenovirus vector,展开更多
With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality fr...With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality from lungcancer has decreased significantly over the past 20 years, especially since theintroduction of targeted drugs in 2013. In 2022, targeted therapy for lungcancer has developed rapidly. The optimization of treatment modes and theexploration of new target drugs such as antibody‐drug conjugates will broadenthe selection range of nonsmall cell lung cancer patients with positive drivergenes. This article reviews the latest advances in targeted therapy for drivergene‐positive lung cancer in 2022.展开更多
Biodegradable polyamines have long been studied as potential recombinant viral gene vectors.Spermine(SPE) is an endogenous tetra-amine with excellent biocompatibility yet poor gene condensation capacity. We have previ...Biodegradable polyamines have long been studied as potential recombinant viral gene vectors.Spermine(SPE) is an endogenous tetra-amine with excellent biocompatibility yet poor gene condensation capacity. We have previously synthesized a polyspermine based on SPE and poly(ethylene glycol)(PEG)diacrylate(SPE-alt-PEG) for enhanced transfection performance, but the synthesized SPE-alt-PEG still lacked specificity towards cancer cells. In this study, folic acid(FA) was incorporated into SPE-alt-PEG to fabricate a targeted gene delivery vector(FA-SPE-PEG) via an acylation reaction. FA-SPE-PEG exhibited mild cytotoxicity in both cancer cells and normal cells. FA-SPE-PEG possessed higher transfection efficiency than PEI 25 K and Lipofectamines2000 in two tested cancer cell lines at functional weight ratios, and its superiority over untargeted SPE-alt-PEG was prominent in cells with overexpressed folate receptors(FRs). Moreover, in vivo delivery of green fluorescent protein(GFP) with FA-SPE-PEG resulted in highest fluorescent signal intensity of all investigated groups. FA-SPE-PEG showed remarkably enhanced specificity towards cancer cells both in vivo and in vitro due to the interaction between FA and FRs. Taken together, FA-SPE-PEG was demonstrated to be a prospective targeted gene delivery vector with high transfection capacity and excellent biocompatibility.展开更多
The combination of ionizing radiation and gene therapy has been investigated. However, there are very few reports about the combination of heavy-ion irradiation and gene therapy. To determine if the pre-exposure to lo...The combination of ionizing radiation and gene therapy has been investigated. However, there are very few reports about the combination of heavy-ion irradiation and gene therapy. To determine if the pre-exposure to low-dose heavy ion beam enhances the suppression of AdCMV-p53 on non-small lung cancer (NSLC), the cells pre-irradiated or non-irradiated were infected with 20, 40 MOI of AdCMV-p53. Survival fraction and the relative biology effect (RBE) were determined by clonogenic assay. The results showed that the proportions of p53 positive cells in 12C6+ beam induced AdCMV-p53 infected cells were more than 90%, which were signifi-cantly more than those in γ-ray induced AdCMV-p53 infected cells. The pre-exposure to low-dose 12C6+ beam significantly prevented the G0/G1 arrest and activated G2/M checkpoints. The pre-exposure to 12C6+ beam significantly improved cell to apoptosis. RBEs for the 12C6+ + AdCMV-p53 infection groups were 30%-60%, 20%-130% and 30%-70% more than those for the 12C6+-irradiated only, AdCMV-p53 infected only, and γ-irradiation induced AdCMVp53 infected groups, respectively. The data suggested that the pre-exposure to low-dose 12C6+ beam significantly promotes exogenous p53 expression in NSLC, and the suppression of AdCMV-p53 gene therapy on NSLC.展开更多
目的:探讨MACC1(metastasis-associated in colon cancer l)基因特异性siRNA(small interfering RNA)对肺癌细胞系SBC-5体外增殖和迁移的影响。方法:化学合成MACC1基因特异性siRNA,阳离子脂质体LipofectamineTM 2000转染肺癌细胞系SBC-...目的:探讨MACC1(metastasis-associated in colon cancer l)基因特异性siRNA(small interfering RNA)对肺癌细胞系SBC-5体外增殖和迁移的影响。方法:化学合成MACC1基因特异性siRNA,阳离子脂质体LipofectamineTM 2000转染肺癌细胞系SBC-5细胞,RT-PCR和Western blot方法检测转染后SBC-5细胞中MACC1基因和蛋白的表达情况;MTT法检测细胞的生长增殖状况;划痕试验观察细胞迁移能力的改变。结果:MACC1基因特异性siRNA转染细胞后,SBC-5细胞MACC1的mRNA和蛋白表达水平明显降低,MTT试验和划痕试验观察到转染MACC1-siRNA的SBC-5细胞增殖、迁移能力明显减弱。结论:MACC1基因特异性siRNA可以明显抑制肺癌SBC-5细胞增殖和迁移,MACC1可能成为肺癌治疗的新靶点。展开更多
文摘The global incidence of lung cancer is marked by a considerably elevated mortality rate.MicroRNAs(miRNAs)exert pivotal influence in the intricate orchestration of gene regulation,and their dysregulation can precipitate dire consequences,notably cancer.Within this context,miRNAs encapsulated in exosomes manifest a diversified impact on the landscape of lung cancer,wherein their actions may either foster angiogenesis,cell proliferation,and metastasis,or counteract these processes.This comprehensive review article discerns potential targets for the prospective development of therapeutic agents tailored for lung cancer.Tumor-suppressive miRNAs,such as miR-204,miR-192,miR-30a,miR-34a,miR-34b,miR-203,and miR-212,exhibit heightened expression and demonstrate the capacity to inhibit cellular proliferation and invasiveness.Conversely,the deleterious effects of tumor-promoting miRNAs like miR-21,miR-106a,miR-155,miR-205,and miR-210 can be attenuated through the application of their respective inhibitors.Distinct miRNAs selectively target various oncogenes,including NUAK Family Kinase 1(NUAK1),Snail Family Transcriptional Repressor 1(Snai1),Astrocyte elevated gene-1(AEG-1),Vimentin,Proliferation and apoptosis adaptor protein 15(PEA-15/PED),Hypoxia-inducible factor 1-alpha(HIF1),as well as tumor suppressor genes such as phosphatase and tensin homolog(PTEN),Suppressor of cytokine signaling 1(SOCS1),Tumor protein P53 binding protein 1(TP53BP1),and PH Domain and Leucine Rich Repeat Protein Phosphatase 2(PHLP22).This investigative approach proves invaluable in elucidating the specific miRNAs implicated in the deregulation of crucial genes pivotal to the pathogenesis of cancer.
基金Funding from National Natural Science Foundation of China(Grant nos.81673367 and 81874303)Beijing Natural Science Foundation(Key Grant no.7181004).
文摘Natural exosomes can express specific proteins and carbohydratemolecules on the surface and hence have demonstrated the great potentials for gene therapy of cancer.However,the use of natural exosomes is restricted by their low transfection efficiency.Here,we report a novel targeting tLyp-1 exosome by gene recombinant engineering for delivery of siRNA to cancer and cancer stem cells.To reach such a purpose,the engineered tLyp-1-lamp2b plasmids were constructed and amplified in Escherichia coli.The tLyp-1-lamp2b plasmids were further used to transfect HEK293T tool cells and the targeting tLyp-1 exosomes were isolated from secretion of the transfected HEK293T cells.Afterwards,the artificially synthesized siRNA was encapsulated into targeting tLyp-1 exosomes by electroporation technology.Finally,the targeting siRNA tLyp-1 exosomes were used to transfect cancer or cancer stem cells.Results showed that the engineered targeting tLyp-1 exosomes had a nanosized structure(approximately 100 nm)and high transfection efficiency into lung cancer and cancer stem cells.The function verifications demonstrated that the targeting siRNA tLyp-1 exosomes were able to knock-down the target gene of cancer cells and to reduce the stemness of cancer stem cells.In conclusion,the targeting tLyp-1 exosomes are successfully engineered,and can be used for gene therapy with a high transfection efficiency.Therefore,the engineered targeting tLyp-1 exosomes offer a promising gene delivery platform for future cancer therapy.
基金This work was supported by the NationalNatural Sciences Foundation of China (No.30572149) andthe National "863" High Technology R & D Project ofChina (No. 2003AA216030).
文摘Objective: To develop a novel adenoviral vector system, which combines the advantages of the antiangiogenic gene therapy and virus therapy, and to investigate its antitumor activity on lung cancer. Methods: A new kind of viral vector CNHK200, in which the Elb55kDa gene was deleted and the whole Ela gene was preserved, was constructed. Human angiostatin gene Kringle 1-5 (hA) was amplified and inserted into the genome of the replicative virus CNHK200, generating CNHK200-hA. The expression of hA and its effect on lung cancer cell growth in vitro and in vivo were studied. Results: The novel vector system CNHK200-hA, just like the replicative virus ONYX-015, replicated in p53-deficient tumor cells but not in normal cells, and thus specifically killed tumor cells. In in vitro experiment, both CNHK200-hA and the non-replicative virus Ad-hA could kill tumor cells but the latter needed 100 times more MOI to achieve the same level of cell killing. In in vivo experiment, the therapeutic effect of CNHK200-hA on human lung cancer A549 xenografts in nude mice was significantly better than that of Ad-hA or that of ONYX-015. Conclusion: CNHK200-hA, which carries the angiostatin gene, has the advantages of specific tumor targeting, high expression of transgene in tumor cells and potent antitumor activity.
基金supported by the National Key Basic Research Program(973 Project)(Grant Nos.2015CB931802 and 2017FYA0205301)the Special Fund for Science and Technology Innovation of Shanghai Jiao Tong University(Grant Nos.YG2017MS70,YG2015MS62,and AF0300179)+3 种基金the Shanghai Municipal Bureau of Economy and Information Technology(Grant No.XC-ZXSJ-02-2016-05)the National Natural Scientific Foundation of China(Grant Nos.8202010801,81921002,81225010,81028009,and 31170961)the 863 Project of China(Grant No.2014AA020700)and the Shanghai Science and Technology Fund(Grant No.13NM1401500)。
文摘Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.
基金Supported by The National Institutes of Health CA123104(HanSW) and CA116812(Roman J)
文摘Peroxisome proliferator-activated receptors(PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily.Of the three PPARs identified to date(PPARγ,PPARβ/δ,and PPARα),PPARγ has been studied the most,in part because of the availability of PPARγagonists(also known as PPARγ ligands)and its significant effects on the management of several human diseases including type 2 diabetes,metabolic syndrome,cardiovascular disease and cancers.PPARγ is expressed in many tumors including lung cancer,and its function has been linked to the process of lung cancer development, progression and metastasis.Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARγ ligands.Furthermore,data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer.This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARγ ligands as a novel anti-lung cancer treatment strategy.
文摘OBJECTIVE To explore the relationship between CAR and the development of human lung cancer, as well as to provide the basis for the clinical treatment of lung cancer using an adenovirus vector-based gene therapy. METHODS CAR expression was assessed immunohisto- chemically in tumoral, paraneoplastic and normal samples from 112 lung cancer patients. At the same time, the mRNA and protein expression of CAR in 32 cases were determined by RT-PCR and Western blot. The relationship between CAR expression and clinicopathologic parameters was statistically analyzed. RESULTS There was no expression of CAR in normal lung tissue but a little in paraneoplastic tissue. The positive rate was 43% in squamous cell carcinoma, and 70% in adenocarcinoma. Both were much significantly higher than that in paraneoplastic tissue. The CAR expression level in adenocarcinoma was higher than that in squamous cell cancer, mRNA expression by RT-PCR and protein expression by Western blot were consistent with immunohistochemistry results. CONCLUSION CAR is overexpressed in human lung cancer, especially in adenocarcinoma. This data offer the reliable basis for adenovirus-mediated gene therapy of lung cancer; more important, CAR may take part in the formation or development of lung cancer; this may be exploitable for the development of antibody-directed therapy in human lung cancer.
文摘Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can be regulated by the epidermal growth factor(EGF) signaling pathway.In this study,recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter(AdTRAIL) was combined with drugs including gefitinib,elotinib,and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer(NSCLC) cell lines to investigate their antitumor activity.In vitro,compared to single reagent,AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460,A549,and SW1573 cell lines.Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT.In vivo,AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice.Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL.These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.
基金supported by the National Natural Science Foundation(No.82073363)the Sichuan Science and Technology Program(Nos.2020YFQ0059,2022YFQ0004)the Natural Science Foundation of Sichuan Province(No.2022NSFSC1304).
文摘Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity.Here,we constructed an iRGD peptide(H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH_(2))modified nanoparticle(iDPP)to deliver plasmids encoding SEA for melanoma treatment.The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells(BMDCs)in vitro.In the subcutaneous B16-F10 melanoma model,the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration,thereby considerably decreased melanoma growth.Meanwhile,no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo.Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.
基金Supported by a grant from the Society Development Foundation of Jiangsu (No. BS2007025)
文摘Objective: We explored the expression of coxsackie and adenovirus receptor (CAR) in small cell lung cancer (SCLC) tissue. Methods: CAR expression in 31 SCLC was assessed in formaldehyde-fixed, paraffin-embedded tissue according to the EnVision immunohistochemistry procedure, while 3 samples of surgical specimens of non-malignant lung disease were taken as the negative control. Results: We observed that the expression of CAR was detectable positive in all the 31 cases from the small cell lung cancer tissue, in contrasting that non-malignant lung tissue control. Conclusion: The high expression of CAR appeared in SCLC tissue indicates that it play an important role in of adenovirus vector-based gene therapy in SCLC.
文摘OBJECTIVE To study the relationship between the coxsackie and adenovirus receptor (CAR) and the development of human lung cancer. To optimize adenovirus vector-based gene therapy.METHODS The expression of CAR in 112 cases of lung cancer was examined using immunohistochemistry. At the same time, the relationship between CAR expression and clinicopathologic characteristics was analyzed,RESULTS :lhere is a little expression of CAR in normal lung tissue. Compared with paraneoplastic epithelial tissue of the lung, the expression of CAR is generally up-regulated in tumor tissues showing a significant dif- ference (P〈0.01). The positive rate of CAR expression in squamous cell carcinoma was 43.1%, and in adenocarcinoma 70.2%, with the difference between the two rates being statistically significant (P〈0.01). Compared to the paraneoplastic tissues, the difference in CAR positive expression was 35.4% for squamous cell carcinoma and 38.3% for adenocarcinoma. But the difference in different stages of squamous cell carcinoma had no statistical significance (P〉0.05). However, the expression of CAR was at a high level in the bronchioalveolar carcinomas as 80.4% were CAR positive. This research showed that there was a specially high expression of CAR in adenocarcinomas.CONCLUSION CAR is expressed in human lungs at a low level and up-regulated in the tumor tissues, suggesting that there is a relationship between adenocarcinoma and CAR. This research provides a basis for planning a regimen of gene therapy using an adenovirus vector,
文摘With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality from lungcancer has decreased significantly over the past 20 years, especially since theintroduction of targeted drugs in 2013. In 2022, targeted therapy for lungcancer has developed rapidly. The optimization of treatment modes and theexploration of new target drugs such as antibody‐drug conjugates will broadenthe selection range of nonsmall cell lung cancer patients with positive drivergenes. This article reviews the latest advances in targeted therapy for drivergene‐positive lung cancer in 2022.
基金the National Natural Science Foundation of China(Grant Nos.81573369,21301191,81570696 and 31270985)the Natural Science Foundation of Jiangsu Province,China(Grant Nos.BK20130661 and BK20140659)the Research and Innovation Project of Jiangsu Province(Grant No.KYLX15_0640)
文摘Biodegradable polyamines have long been studied as potential recombinant viral gene vectors.Spermine(SPE) is an endogenous tetra-amine with excellent biocompatibility yet poor gene condensation capacity. We have previously synthesized a polyspermine based on SPE and poly(ethylene glycol)(PEG)diacrylate(SPE-alt-PEG) for enhanced transfection performance, but the synthesized SPE-alt-PEG still lacked specificity towards cancer cells. In this study, folic acid(FA) was incorporated into SPE-alt-PEG to fabricate a targeted gene delivery vector(FA-SPE-PEG) via an acylation reaction. FA-SPE-PEG exhibited mild cytotoxicity in both cancer cells and normal cells. FA-SPE-PEG possessed higher transfection efficiency than PEI 25 K and Lipofectamines2000 in two tested cancer cell lines at functional weight ratios, and its superiority over untargeted SPE-alt-PEG was prominent in cells with overexpressed folate receptors(FRs). Moreover, in vivo delivery of green fluorescent protein(GFP) with FA-SPE-PEG resulted in highest fluorescent signal intensity of all investigated groups. FA-SPE-PEG showed remarkably enhanced specificity towards cancer cells both in vivo and in vitro due to the interaction between FA and FRs. Taken together, FA-SPE-PEG was demonstrated to be a prospective targeted gene delivery vector with high transfection capacity and excellent biocompatibility.
文摘The combination of ionizing radiation and gene therapy has been investigated. However, there are very few reports about the combination of heavy-ion irradiation and gene therapy. To determine if the pre-exposure to low-dose heavy ion beam enhances the suppression of AdCMV-p53 on non-small lung cancer (NSLC), the cells pre-irradiated or non-irradiated were infected with 20, 40 MOI of AdCMV-p53. Survival fraction and the relative biology effect (RBE) were determined by clonogenic assay. The results showed that the proportions of p53 positive cells in 12C6+ beam induced AdCMV-p53 infected cells were more than 90%, which were signifi-cantly more than those in γ-ray induced AdCMV-p53 infected cells. The pre-exposure to low-dose 12C6+ beam significantly prevented the G0/G1 arrest and activated G2/M checkpoints. The pre-exposure to 12C6+ beam significantly improved cell to apoptosis. RBEs for the 12C6+ + AdCMV-p53 infection groups were 30%-60%, 20%-130% and 30%-70% more than those for the 12C6+-irradiated only, AdCMV-p53 infected only, and γ-irradiation induced AdCMVp53 infected groups, respectively. The data suggested that the pre-exposure to low-dose 12C6+ beam significantly promotes exogenous p53 expression in NSLC, and the suppression of AdCMV-p53 gene therapy on NSLC.
文摘目的:探讨MACC1(metastasis-associated in colon cancer l)基因特异性siRNA(small interfering RNA)对肺癌细胞系SBC-5体外增殖和迁移的影响。方法:化学合成MACC1基因特异性siRNA,阳离子脂质体LipofectamineTM 2000转染肺癌细胞系SBC-5细胞,RT-PCR和Western blot方法检测转染后SBC-5细胞中MACC1基因和蛋白的表达情况;MTT法检测细胞的生长增殖状况;划痕试验观察细胞迁移能力的改变。结果:MACC1基因特异性siRNA转染细胞后,SBC-5细胞MACC1的mRNA和蛋白表达水平明显降低,MTT试验和划痕试验观察到转染MACC1-siRNA的SBC-5细胞增殖、迁移能力明显减弱。结论:MACC1基因特异性siRNA可以明显抑制肺癌SBC-5细胞增殖和迁移,MACC1可能成为肺癌治疗的新靶点。