Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-...Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),and cytotoxic T-lymphocyte antigen-4(CTLA-4)show limited clinical efficacy in many breast cancers.B7H3 has been widely reported as an immunosuppressive molecule,but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program(TCGA)and the Gene Expression Omnibus(GEO)databases.MicroRNAs were selected using the TarBase,miRTarBase,and miRBase databases.The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays,which identified the specific action sites of interaction.The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR(qPCR).In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis.Additionally,the regulatory impact of hsa-miR-214-3p on B7H3 was examined.Enzyme-linked immunosorbent assays(ELISA)and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells(PBMCs)on immune cells and associated cytokines.Results:In breast cancer tissues,the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p,as well as with the regulatory effects on breast cancercell behavior.Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3.Importantly,our research identified,for the first time,two binding sites for hsa-miR-214-3p on the 3’UTR of B7H3,both of which exert similar effects independently.Co-culture experiments revealed that hsamiR-214-3p obstructs the suppressive function of B7H3 on CD8^(+)T cells and natural killer cells.Conclusions:This study confirms the existence of two hsa-miR-214-3p binding sites on the 3’UTR of B7H3,reinforcing the role of hsamiR-214-3p as a regulatory factor for B7H3.In breast cancer,hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3.These findings suggest new potential targets for the clinical treatment of breast cancer.展开更多
The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agent...The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.展开更多
It is now well known that non-coding RNAs(ncRNAs),rather than protein-coding transcripts,are the preponderant RNA transcripts.NcRNAs,particularly microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circR...It is now well known that non-coding RNAs(ncRNAs),rather than protein-coding transcripts,are the preponderant RNA transcripts.NcRNAs,particularly microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation,apoptosis,invasion,metastasis,and genomic instability.Despite recent discoveries in cancer therapy,resistance to chemotherapy,radiotherapy,targeted therapy.展开更多
One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor micro...One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions.To achieve this objective,cellular communication is a key factor.Classically,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and synapses.Nevertheless,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger RNA,DNA,microRNA or long non-coding RNA(lncRNAs).LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases.Exosomal lncRNAs are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid biopsy.Exosomal lncRNAs promote angiogenesis,cell proliferation and drug resistance.The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and immunotherapy.Overall,knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.展开更多
Development of drug resistance represents the major cause of cancer therapy failure,determines disease progression and results in poor prognosis for cancer patients.Different mechanisms are responsible for drug resist...Development of drug resistance represents the major cause of cancer therapy failure,determines disease progression and results in poor prognosis for cancer patients.Different mechanisms are responsible for drug resistance.Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance:drug transport and metabolism;alteration of drug targets;DNA damage repair;and deregulation of apoptosis,autophagy,and pro-survival signaling.On the other hand,a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance.Gut microbiota represents a new player in the regulation of a patient’s response to cancer therapies,including chemotherapy and immunotherapy.In particular,commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer.Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs,such as oxaliplatin,gemcitabine,and cyclophosphamide.Recently,it has been shown that such bacteria can produce extracellular vesicles(EVs)that can mediate intercellular communication with human host cells.Indeed,bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy.On the other hand,host cells can also deliver human EVs to commensal bacteria and similarly,regulate gene expression.EVmediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.展开更多
基金funded by the Natural Science Foundation of Guangdong Province(grant number 2022A1515012315)Guangdong Medical Science and Technology Research Fund Project(grant number A2023185)+2 种基金the Discipline Construction Project of Guangdong Medical University(grant number 4SG22005G)the 2023 Provincial Basic and Applied Basic Research Fund Enterprise Joint Fund Project(grant number 2023A1515220149)Southern Medical University Shunde Hospital 2023 Research Initiation Programme Project(SRSP2023016).
文摘Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),and cytotoxic T-lymphocyte antigen-4(CTLA-4)show limited clinical efficacy in many breast cancers.B7H3 has been widely reported as an immunosuppressive molecule,but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program(TCGA)and the Gene Expression Omnibus(GEO)databases.MicroRNAs were selected using the TarBase,miRTarBase,and miRBase databases.The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays,which identified the specific action sites of interaction.The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR(qPCR).In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis.Additionally,the regulatory impact of hsa-miR-214-3p on B7H3 was examined.Enzyme-linked immunosorbent assays(ELISA)and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells(PBMCs)on immune cells and associated cytokines.Results:In breast cancer tissues,the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p,as well as with the regulatory effects on breast cancercell behavior.Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3.Importantly,our research identified,for the first time,two binding sites for hsa-miR-214-3p on the 3’UTR of B7H3,both of which exert similar effects independently.Co-culture experiments revealed that hsamiR-214-3p obstructs the suppressive function of B7H3 on CD8^(+)T cells and natural killer cells.Conclusions:This study confirms the existence of two hsa-miR-214-3p binding sites on the 3’UTR of B7H3,reinforcing the role of hsamiR-214-3p as a regulatory factor for B7H3.In breast cancer,hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3.These findings suggest new potential targets for the clinical treatment of breast cancer.
基金supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination(OSC)the NIH/NCI grant 1 R01 CA182905-01+6 种基金a U54 grant-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Projecta Team DOD (Grant No.CA160445P1) granta Ladies Leukemia League granta CLL Moonshot Flagship projecta SINF 2017 grantthe Estate of C.G.Johnson,Jr.supported by a POC grant, entitled "Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance"-CANTEMIR, Competitively Operational Program, 2014-2020, Grant No.35/01.09.2016,My SMIS 103375
文摘The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.
基金We thank Bryan Tutt,Scientific Editor,Research Medical Library,MDACC for editorial support.The work of B.C.is supported by National Natural Science Foundation of China(No.81902462)M.P.D.is a participant in the BIH-CharitéJunior Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health.G.A.C.is the Felix L.Haas Endowed Professor in Basic Science.Work in G.A.C.’s laboratory is supported by NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1,NIGMS grant 1R01GM122775-01,DoD Idea Award W81XWH2110030,a Team DOD grant in Gastric Cancer,a Chronic Lymphocytic Leukemia Moonshot Flagship project,a CLL Global Research Foundation 2019 grant,a CLL Global Research Foundation 2020 grantThe G.Harold&Leila Y.Mathers Foundation,a grant from Torrey Coast Foundation,and an Institutional Research Grant and Development Grant associated with the Brain SPORE 2P50CA127001.
文摘It is now well known that non-coding RNAs(ncRNAs),rather than protein-coding transcripts,are the preponderant RNA transcripts.NcRNAs,particularly microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation,apoptosis,invasion,metastasis,and genomic instability.Despite recent discoveries in cancer therapy,resistance to chemotherapy,radiotherapy,targeted therapy.
基金Dr.Calin is the Felix L.Endowed Professor in Basic Science.Work in Dr.Calin’s laboratory is supported by National Institutes of Health(NIH/NCATS)grant UH3TR00943-01 through the NIH Common Fund,Office of Strategic Coordination(OSC)the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1,an NIGMS 1R01GM122775-01 grant,a U54 grant#CA096297/CA096300-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project,a Team DOD(CA160445P1)grant,a Ladies Leukemia League grant,a Chronic Lymphocytic Leukemia Moonshot Flagship project,a Sister Institution Network Fund(SINF)2017 grant,and the Estate of C.G.Johnson Jr.
文摘One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions.To achieve this objective,cellular communication is a key factor.Classically,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and synapses.Nevertheless,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger RNA,DNA,microRNA or long non-coding RNA(lncRNAs).LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases.Exosomal lncRNAs are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid biopsy.Exosomal lncRNAs promote angiogenesis,cell proliferation and drug resistance.The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and immunotherapy.Overall,knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.
文摘Development of drug resistance represents the major cause of cancer therapy failure,determines disease progression and results in poor prognosis for cancer patients.Different mechanisms are responsible for drug resistance.Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance:drug transport and metabolism;alteration of drug targets;DNA damage repair;and deregulation of apoptosis,autophagy,and pro-survival signaling.On the other hand,a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance.Gut microbiota represents a new player in the regulation of a patient’s response to cancer therapies,including chemotherapy and immunotherapy.In particular,commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer.Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs,such as oxaliplatin,gemcitabine,and cyclophosphamide.Recently,it has been shown that such bacteria can produce extracellular vesicles(EVs)that can mediate intercellular communication with human host cells.Indeed,bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy.On the other hand,host cells can also deliver human EVs to commensal bacteria and similarly,regulate gene expression.EVmediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.
