Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital proce...Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital process for large-scale cell movement during morphogenesis at the time of embryonic development.Tumor cells usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis.Several transcription factors and signals are involved in these events.In this review,we summarize recent advances in breast cancer researches that have provided new insights in the molecular mechanisms underlying EMT regulation during breast cancer progression and metastasis.We especially focus on the molecular pathways that control EMT.展开更多
AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with ris...AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.展开更多
Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that bind...Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.展开更多
Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a ...Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.展开更多
DNA mismatch repair （MMR） is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs...DNA mismatch repair （MMR） is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.展开更多
AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for p...AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.展开更多
7,8-dihydro-8-oxo-dGuanine （oxoG or GO, see Figure 1A） is one of the most abundant oxidative DNA lesions caused by exposure of DNA to reactive oxygen species. GO is highly mutagenic, frequently leading to G：C to T...7,8-dihydro-8-oxo-dGuanine （oxoG or GO, see Figure 1A） is one of the most abundant oxidative DNA lesions caused by exposure of DNA to reactive oxygen species. GO is highly mutagenic, frequently leading to G：C to T：A transversion, because it preferentially pairs with adenine （A） during DNA replication. To prevent genetic instability caused by GO and other mutagenic DNAbase lesions, all cells express a large number of DNA glycosylases,展开更多
Simvastatin （SIM） is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for t...Simvastatin （SIM） is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC-MS/MS method was developed to measure SIM and its acid form （SIMA） in plasma and peripheral blood mononuclear cells （PBMCs） obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75：25 （% v/v） acetonitrile：ammonium acetate （0.1 M, pH 5.0） mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5-500 ng/mL for SIM and 5-500 ng/mL for SIMA in plasma and 2.5-250 ng/mL for SIM and 5-250 ng/mL for SIMA in cell lysate. Recovery was 〉 58% for SIM and 〉 75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.展开更多
AIM:To evaluate the ability of anti-ricin A-chain antibodies,delivered intracellularly,to protect against ricininduced cytotoxicity in RAW264.7 cells. METHODS:Anti-deglycosylated ricin A-chain antibody and RAC18 anti-...AIM:To evaluate the ability of anti-ricin A-chain antibodies,delivered intracellularly,to protect against ricininduced cytotoxicity in RAW264.7 cells. METHODS:Anti-deglycosylated ricin A-chain antibody and RAC18 anti-ricin A-chain monoclonal antibody were delivered intracellularly by encapsulating in liposomes or via conjugation with the cell-penetrating MTS-transport peptide.RAW264.7 cells were incubatedwith these antibodies either before or after ricin exposure.The changes in cytotoxicity were estimated by MTT assay.Co-localization of internalized antibody and ricin was evaluated by fluorescence microscopy. RESULTS:Internalized antibodies significantly increased cell viability either before or after ricin exposure compared to the unconjugated antibodies.Fluorescence microscopy confirmed the co-localization of internalized antibodies and ricin inside the cells. CONCLUSION:Intracellular delivery of antibodies to neutralize the ricin toxin after cellular uptake supports the potential use of cell-permeable antibodies for postexposure treatment of ricin intoxication.展开更多
Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide i...Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase(PDI)family.As a critical member of the PDI family,thioredoxin domain containing protein 5(TXNDC5)assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions.Interestingly,TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer.In this review,we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development.Findings of TXNDC5 in the activation of intracellular signaling pathways,stimulation of cell growth&proliferation,facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed.These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.展开更多
Prostate cancer is(PCa)the second leading cause of cancer death in males in the United State,with 174,650 new cases and 31,620 deaths estimated in 2019.It has been documented that epigenetic deregulation such as histo...Prostate cancer is(PCa)the second leading cause of cancer death in males in the United State,with 174,650 new cases and 31,620 deaths estimated in 2019.It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression.EZH2(enhancer of zeste homolog 2),the catalytic subunit of the Polycomb Repressive Complex(PRC2)responsible for H3K27me3 and gene repression,has been identified as a promising target in PCa.In addition,overexpression of other epigenetic regulators such as DNA methyltransferases(DNMT)is also observed in PCa.These epigenetic regulators undergo extensive post-translational modifications,in particular,phosphorylation.AKT,CDKs,PLK1,PKA,ATR and DNA-PK are the established kinases responsible for phosphorylation of various epigenetic regulators.展开更多
Metabolic abnormalities are emerging as an active driver to the development,progression and metastasis of various tumors.In the recent issue of the EMBO Journal,Yang and colleagues identified that succinylacetone(SA)c...Metabolic abnormalities are emerging as an active driver to the development,progression and metastasis of various tumors.In the recent issue of the EMBO Journal,Yang and colleagues identified that succinylacetone(SA)could act as an oncometabolite and that accumulation of SA activates the NRF2/IGF1R axis in hepatocellular carcinoma(HCC)development.These discoveries not only yield great insights in the understanding of tumor biology,but also hold significant clinical ramifications,as these findings may pave a new way for the early diagnosis and treatment of HCC.展开更多
Extracellular matrix(ECM)is an essential component of the tumor microenvironment.Cancer development and progression are associated with increased ECM deposition and crosslink.The chemical and physical signals elicited...Extracellular matrix(ECM)is an essential component of the tumor microenvironment.Cancer development and progression are associated with increased ECM deposition and crosslink.The chemical and physical signals elicited from ECM are necessary for cancer cell proliferation and invasion.It is well recognized that stromal cells are a major source of ECM proteins.However,recent studies showed that cancer cells are also an active and important component in ECM remodeling.Cancer cells deposit a significant amount of collagen,fibronectin,and tenascin C(TNC).Recent studies demonstrate that these cancer cell-derived ECM proteins enhance cancer cell survival and promote cancer cell colonization at distant sites.ECM-related enzymes and chaperone proteins,such as prolyl-4-hydroxylase,lysyl-hydroxylase,lysyl oxidase,and heat shock protein 47,are also highly expressed in cancer cells.Inhibition of these enzymes significantly reduces cancer growth,invasion,and metastasis.These factors suggest that the cancer cell-derived ECM is crucial for cancer progression and metastasis.Therefore,targeting these ECM proteins and ECM-related enzymes is a potential strategy for cancer treatment.展开更多
Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the i...Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.展开更多
Rice blast is a devastating disease worldwide,threatening rice production and food security.The blast fun-gus Magnaporthe oryzae invades the host via the appressorium,a specialized pressure-generating struc-ture that ...Rice blast is a devastating disease worldwide,threatening rice production and food security.The blast fun-gus Magnaporthe oryzae invades the host via the appressorium,a specialized pressure-generating struc-ture that generates enormous turgor pressure to penetrate the host cuticle.However,owing to ongoing evolution of fungicide resistance,it is vitally important to identify new targets and fungicides.Here,we show that Trs85,a subunit of the transport protein particle III complex,is essential for appressorium-mediated infection in M.oryzae.We explain how Trs85 regulates autophagy through Ypt1(a small guano-sine triphosphatase protein)in M.oryzae.We then identify a key conserved amphipathic a helix within Trs85 that is associated with pathogenicity of M.oryzae.Through computer-aided screening,we identify a lead compound,SP-141,that affects autophagy and the Trs85–Ypt1 interaction.SP-141 demonstrates a substantial capacity to effectively inhibit infection caused by the rice blast fungus while also exhibiting wide-ranging potential as an antifungal agent with broad-spectrum activity.Taken together,our data show that Trs85 is a potential new target and that SP-141 has potential for the control of rice blast.Ourfindings thus provide a novel strategy that may help in thefight against rice blast.展开更多
Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate ...Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate by acetaldehyde dehydrogenase type 2(ALDH2).ALDH2 deficiency can lead to ACE accumulation and DNA damage.展开更多
Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing num...Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin I-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.展开更多
The Hedgehog （Hh） signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched （Ptc） inhibits the atypical G pro...The Hedgehog （Hh） signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched （Ptc） inhibits the atypical G protein- coupled receptor Smoothened （Smo） in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI（4）P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation.展开更多
基金supported by the grants from NIH (RO1CA125454)the Susan G. Komen Foundation (KG081310)the Mary Kay Ash Foundation (to B.P. Zhou)
文摘Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition(EMT) is a vital process for large-scale cell movement during morphogenesis at the time of embryonic development.Tumor cells usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis.Several transcription factors and signals are involved in these events.In this review,we summarize recent advances in breast cancer researches that have provided new insights in the molecular mechanisms underlying EMT regulation during breast cancer progression and metastasis.We especially focus on the molecular pathways that control EMT.
基金Supported by A Damon Runyon Cancer Research Foundation Clinical Investigator Award,CI-8An R25 training grant from the National Cancer Institute,R25T CA094186+1 种基金The Case Center for Transdisciplinary Research on Energetics and Cancer,1U54 CA-116867-01A National Cancer Institute K22 Award,1K22 CA120545-01
文摘AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.
文摘Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.
基金supported by the Henan Provincial Science and Technology Research Project(grant number 221100310100 to Z.L.and X.H.).
文摘Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.
文摘DNA mismatch repair （MMR） is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
基金Supported by Grants from Novartis Pharmaceuticals Corporation,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.
文摘7,8-dihydro-8-oxo-dGuanine （oxoG or GO, see Figure 1A） is one of the most abundant oxidative DNA lesions caused by exposure of DNA to reactive oxygen species. GO is highly mutagenic, frequently leading to G：C to T：A transversion, because it preferentially pairs with adenine （A） during DNA replication. To prevent genetic instability caused by GO and other mutagenic DNAbase lesions, all cells express a large number of DNA glycosylases,
文摘Simvastatin （SIM） is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC-MS/MS method was developed to measure SIM and its acid form （SIMA） in plasma and peripheral blood mononuclear cells （PBMCs） obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75：25 （% v/v） acetonitrile：ammonium acetate （0.1 M, pH 5.0） mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5-500 ng/mL for SIM and 5-500 ng/mL for SIMA in plasma and 2.5-250 ng/mL for SIM and 5-250 ng/mL for SIMA in cell lysate. Recovery was 〉 58% for SIM and 〉 75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.
基金Supported by NIEHS Center Grant ES00260(Tchou-Wong KM)NIAID R21 Grant AI059476(Tchou-Wong KM)from the National Institutes of Health
文摘AIM:To evaluate the ability of anti-ricin A-chain antibodies,delivered intracellularly,to protect against ricininduced cytotoxicity in RAW264.7 cells. METHODS:Anti-deglycosylated ricin A-chain antibody and RAC18 anti-ricin A-chain monoclonal antibody were delivered intracellularly by encapsulating in liposomes or via conjugation with the cell-penetrating MTS-transport peptide.RAW264.7 cells were incubatedwith these antibodies either before or after ricin exposure.The changes in cytotoxicity were estimated by MTT assay.Co-localization of internalized antibody and ricin was evaluated by fluorescence microscopy. RESULTS:Internalized antibodies significantly increased cell viability either before or after ricin exposure compared to the unconjugated antibodies.Fluorescence microscopy confirmed the co-localization of internalized antibodies and ricin inside the cells. CONCLUSION:Intracellular delivery of antibodies to neutralize the ricin toxin after cellular uptake supports the potential use of cell-permeable antibodies for postexposure treatment of ricin intoxication.
基金This work was partially supported by the National Institutes of Health(NCI grant number R01CA222596)Department of Defense(grant number W81XWH-16-1-0203)+1 种基金American Cancer Society(grant number RSG-16-213-01-TBE)Kentucky Lung Cancer Research Program(KLCRP2016).
文摘Correct folding of nascent peptides occurs in the endoplasmic reticulum(ER).It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase(PDI)family.As a critical member of the PDI family,thioredoxin domain containing protein 5(TXNDC5)assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions.Interestingly,TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer.In this review,we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development.Findings of TXNDC5 in the activation of intracellular signaling pathways,stimulation of cell growth&proliferation,facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed.These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.
基金NIH R01 CA157429(X.Liu)R01 CA192894(X.Liu)+2 种基金R01 CA196835(X.Liu)R01 CA196634(X.Liu)The work was also partially supported by University of Kentucky Cancer Center(P30 CA177558).
文摘Prostate cancer is(PCa)the second leading cause of cancer death in males in the United State,with 174,650 new cases and 31,620 deaths estimated in 2019.It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression.EZH2(enhancer of zeste homolog 2),the catalytic subunit of the Polycomb Repressive Complex(PRC2)responsible for H3K27me3 and gene repression,has been identified as a promising target in PCa.In addition,overexpression of other epigenetic regulators such as DNA methyltransferases(DNMT)is also observed in PCa.These epigenetic regulators undergo extensive post-translational modifications,in particular,phosphorylation.AKT,CDKs,PLK1,PKA,ATR and DNA-PK are the established kinases responsible for phosphorylation of various epigenetic regulators.
文摘Metabolic abnormalities are emerging as an active driver to the development,progression and metastasis of various tumors.In the recent issue of the EMBO Journal,Yang and colleagues identified that succinylacetone(SA)could act as an oncometabolite and that accumulation of SA activates the NRF2/IGF1R axis in hepatocellular carcinoma(HCC)development.These discoveries not only yield great insights in the understanding of tumor biology,but also hold significant clinical ramifications,as these findings may pave a new way for the early diagnosis and treatment of HCC.
基金supported by start-up funding from Markey Cancer Center and funding support from United States Department of Defense(W81XWH-15-1-0052 to R.X.).
文摘Extracellular matrix(ECM)is an essential component of the tumor microenvironment.Cancer development and progression are associated with increased ECM deposition and crosslink.The chemical and physical signals elicited from ECM are necessary for cancer cell proliferation and invasion.It is well recognized that stromal cells are a major source of ECM proteins.However,recent studies showed that cancer cells are also an active and important component in ECM remodeling.Cancer cells deposit a significant amount of collagen,fibronectin,and tenascin C(TNC).Recent studies demonstrate that these cancer cell-derived ECM proteins enhance cancer cell survival and promote cancer cell colonization at distant sites.ECM-related enzymes and chaperone proteins,such as prolyl-4-hydroxylase,lysyl-hydroxylase,lysyl oxidase,and heat shock protein 47,are also highly expressed in cancer cells.Inhibition of these enzymes significantly reduces cancer growth,invasion,and metastasis.These factors suggest that the cancer cell-derived ECM is crucial for cancer progression and metastasis.Therefore,targeting these ECM proteins and ECM-related enzymes is a potential strategy for cancer treatment.
基金supported by National Cancer Institute grants R00CA175189,R01AI155499(both to SHO),R01CA205246(to EAR),R01CA121044(to KPL),T32CA085183(to GAH and MML),and P30CA016056,involving the use of the Roswell Park Comprehensive Cancer Center Flow and Image Cytometry,Genomics,Laboratory Animal,and Immune Analysis Shared Resourcesby the Roswell Park Alliance Foundation.NMR experiments were carried out at the Center for Environmental and Systems Biochemistry Shared Resource Facility funded in part by the Markey Cancer Center(P30CA177558).
文摘Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.
基金supported by the Key Research and Development Project of Zhejiang Province,China (2021C02010)the National Natural Science Foundation of China (32270201,31972216,and 31970140)+1 种基金the Special Project for the Selection and Breeding of New Agricultural Varieties in Zhejiang Province,China (2021C02064)supported by a grant,Organism Interaction,from Zhejiang Xianghu Laboratory (to F.-C.L.).
文摘Rice blast is a devastating disease worldwide,threatening rice production and food security.The blast fun-gus Magnaporthe oryzae invades the host via the appressorium,a specialized pressure-generating struc-ture that generates enormous turgor pressure to penetrate the host cuticle.However,owing to ongoing evolution of fungicide resistance,it is vitally important to identify new targets and fungicides.Here,we show that Trs85,a subunit of the transport protein particle III complex,is essential for appressorium-mediated infection in M.oryzae.We explain how Trs85 regulates autophagy through Ypt1(a small guano-sine triphosphatase protein)in M.oryzae.We then identify a key conserved amphipathic a helix within Trs85 that is associated with pathogenicity of M.oryzae.Through computer-aided screening,we identify a lead compound,SP-141,that affects autophagy and the Trs85–Ypt1 interaction.SP-141 demonstrates a substantial capacity to effectively inhibit infection caused by the rice blast fungus while also exhibiting wide-ranging potential as an antifungal agent with broad-spectrum activity.Taken together,our data show that Trs85 is a potential new target and that SP-141 has potential for the control of rice blast.Ourfindings thus provide a novel strategy that may help in thefight against rice blast.
基金supported by grants from the National Nature Science Foundation of China(No.82172565,81620108022,81872245,91129303,991729302,81572759,,31900441,82003069,82103571,882002941,82072570,91129733,81502702).
文摘Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate by acetaldehyde dehydrogenase type 2(ALDH2).ALDH2 deficiency can lead to ACE accumulation and DNA damage.
文摘Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin I-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.
文摘The Hedgehog （Hh） signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched （Ptc） inhibits the atypical G protein- coupled receptor Smoothened （Smo） in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI（4）P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation.
