Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which acc...Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.展开更多
One of the major challenges that clinicians face is in the difficulties of accurately monitoring disease progression.Prostate cancer is among these diseases and greatly affects the health of men globally.Circulating t...One of the major challenges that clinicians face is in the difficulties of accurately monitoring disease progression.Prostate cancer is among these diseases and greatly affects the health of men globally.Circulating tumor cells(CTCs)are a rare population of cancer cells that have shed from the primary tumor and entered the peripheral circulation.Not until recently,clinical applications of CTCs have been limited to using enumeration as a prognostic tool in Oncology.However,advances in emerging CTC technologies point toward new applications that could revolutionize the field of prostate cancer.It is now possible to study CTCs as components of a liquid biopsy based on morphological phenotypes,biochemical analyses,and genomic profiling.These advances allow us to gain insight into the heterogeneity and dynamics of cancer biology and to further study the mechanisms behind the evolution of therapeutic resistance.These recent developments utilizing CTCs for clinical applications will greatly impact the future of prostate cancer research and pave the way towards personalized care for men.展开更多
German biochemist and cell physiologist,Otto H.Warburg(Figure 1),made a groundbreaking discovery in 1923.Specifically,tumors were shown to consume large amounts of glucose and ferment glucose into lactate,even in the ...German biochemist and cell physiologist,Otto H.Warburg(Figure 1),made a groundbreaking discovery in 1923.Specifically,tumors were shown to consume large amounts of glucose and ferment glucose into lactate,even in the presence of oxygen—a phenomenon termed"aerobic glycolysis"1,2.This phenomenon,later named the Warburg effect by Efraim Racker in the 1970s,remains pivotal in cancer research3.展开更多
The androgen receptor （AR） remains the primary molecular target forprostate cancer （PCa） treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown t...The androgen receptor （AR） remains the primary molecular target forprostate cancer （PCa） treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown that the AR is still functional during latestage disease in the absence of circulating hormone fol lowing castration therapy. The molecular mechanisms that operate during this ＇cas tration resistant＇ phase are still not well understood. Qi et al. have now implicated the ubiquitin ligase Siah2 as an important mediator of AR action in castration resis tant prostate cancer （CRPC）. Siah2 was found to target repressed AR chromatin complexes for degradation, resulting in activation of ARregulated genes involved in tumor cell proliferation, cell motility and lipid metabolism. The authors show a requirement for Siah2 activity for PCa cell growth under conditions of low androgen, and also that targeting Siah2 results in tumor growth suppression under castrate conditions. These findings identify a new mechanism of AR regulation in progressing disease as well as a novel enzymatic target for therapeutic intervention. The AR is a wellstudied hormone receptor that belongs to the large nuclear receptor gene superfamily. AR is activated by androgen binding （principally 5：~dihydrotestosterone, 5DHT）, which elicits changes in AR resident cytosolic complexes, translocation of the receptor to cell nuclei, formation of multiprotein transcriptional complexes onchromatin, and activation or repression of gene expression. Experiments with in vivo model systems have provided evidence that virtually all physiologic processes affected by androgens require the AR as a mediator of molecular effects at the gene level.1 AR is widely expressed beyond the reproductive systems and is believed to play important roles in several nonreproductive tissues, including muscle and brain. The fact that PCa growth is initially dependent on the pre sence of androgens in the circulation, and that prostate tumors will regress temporarily with castration, has been recognized for over half a century. Molecular cloning was initially felt to of the AR in the 1980s be a dispositive step toward pharmacological interventions that would greatly improve treatment outcomes for PCa. However, despite many advances since that time, there is currently no effec tive therapy for disease that has become unresponsive to treatment with hormone ablation. The ＇hormone refractory＇ phase of the disease is intriguing from a bioche mical perspective because the AR still appears to play a critical role under conditions where androgen concentrations in the blood are extremely low. RNA and gene profiling of many human PCa tumors has shown that hormone suppression provides a strong selec tion pressure that results in overexpression and/or amplification of the AR during meta static dissemination.2 Molecular and bio chemical studies of the AR have revealed a bewildering level of complexity involving over 150 protein partners. The AR is also posttranslationally modified by phosphory lation, sumoylation and acetylation, and AR expression can be controlled at transcrip tional and posttranscriptional levels, adding additional layers of regulatory complexity. One important locus of AR activity lies in the ubiquitin/proteasome pathway, which controls the specificity and rate of protein degradation. AR stability was shown pre viously to be regulated by ubiquitin ligases,3 proteins that form complexes with ubiquitin conjugating enzymes to catalyze attachment of the small protein ubiquitin to lysines on a protein target, thereby directing the modified protein to the proteasome for degradation. Siahl and Siah2 are RING finger E3 ubiquitin ligases that regulate ubiquitinationmediated degradation of a range of signaling proteins, resulting in diverse biological effects such as resistance to apoptosis and effects on mito chondrial function. Qi et al.4 previously showed that knockout of the Siah2 gene in the TRAMP transgenic mouse model of PCa, a system that rapidly produces aggres sive autochthonous prostate tumors that pro gress to metastasis, resulted in suppression of tumor formation. In a recent paper in Cancer Cell,5 the same group has now gone on to uncover the mechanism of this surprising effect. Further experiments in TRAMP mice indi cated that loss of Siah2 decreased prostate size, an indication of a loss of AR signaling, and also increased the sensitivity to castra tion, suggesting the possibility that Siah2 may operate under low androgen conditions. Knockdown of Siah2 in PCa cell lines indi cated that Siah2 controls a subset of AR regulated genes, including the gene encoding the important clinical biomarker, prostate specific antigen. Global transcriptional profi ling identified a Siah2regulated gene network consisting of almost 1000 genes, about 100 of which were found to be AR regulated. The AR and Siah2dependent genes were mostly associated with lipid, sterol and cholesterol metabolism. Analysis of human PCa profiling展开更多
DNA mismatch repair （MMR） processes the chemically induced mispairs following treatment with clinically important nucleoside analogs such as 6-thioguanine （6-TG） and 5-fluorouracil （5-FU）. MMR processing of thes...DNA mismatch repair （MMR） processes the chemically induced mispairs following treatment with clinically important nucleoside analogs such as 6-thioguanine （6-TG） and 5-fluorouracil （5-FU）. MMR processing of these drugs has been implicated in activation of a prolonged G2/M cell cycle arrest for repair and later induction of apoptosis and/or autophagy for irreparable DNA damage. In this study, we investigated the role of Bcl2 and adenovirus EIB Nineteen-kilodalton Interacting Protein （BNIP3） in the activation of autophagy, and the temporal relationship between a G2/M cell cycle arrest and the activation of BNIP3-mediated autophagy following MMR processing of 6-TG and 5-FU. We found that BNIP3 protein levels are upregulated in a MLHI （MMR＋）-dependent manner following 6-TG and 5-FU treatment. Subsequent small-interfering RNA （siRNA）-mediated BNIP3 knockdown abrogates 6-TG- induced autophagy. We also found that p53 knockdown or inhibition of mTOR activity by rapamycin cotreatment impairs 6-TG- and 5-FU-induced upregulation of BNIP3 protein levels and autophagy. Furthermore, suppression of Checkpoint kinase 1 （Chkl） expression with a subsequent reduction in 6-TG-induced G2/M cell cycle arrest by Chkl siRNA promotes the extent of 6-TG-induced autophagy. These findings suggest that BNIP3 mediates 6-TG- and 5-FU-induced autophagy in a p53- and mTOR-dependent manner. Additionally, the duration of Chkl-activated G2/ M cell cycle arrest determines the level of autophagy following MMR processing of these nucleoside analogs.展开更多
Chromosome segregation in mitosis is orchestrated by the interaction of the kinetochore with spindle microtubules. Our recent study shows that NEK2A interacts with MAD 1 at the kinetochore and possibly functions as a ...Chromosome segregation in mitosis is orchestrated by the interaction of the kinetochore with spindle microtubules. Our recent study shows that NEK2A interacts with MAD 1 at the kinetochore and possibly functions as a novel integrator of spindle checkpoint signaling. However, it is unclear how NEK2A regulates kinetochore-microtubule attachment in mitosis. Here we show that NEK2A phosphorylates human Sgo 1 and such phosphorylation is essential for faithful chromosome congression in mitosis. NEK2A binds directly to HsSgol in vitro and co-distributes with HsSgol to the kinetochore of mitotic cells. Our in vitro phosphorylation experiment demonstrated that HsSgo 1 is a substrate of NEK2A and the phosphorylation sites were mapped to Ser^14 and Ser^507 as judged by the incorporation of 32^P. Although such phosphorylation is not required for assembly of HsSgo 1 to the kinetochore, expression of non-phosphorylatable mutant HsSgo 1 perturbed chromosome congression and resulted in a dramatic increase in microtubule attachment errors, including syntelic and monotelic attachments. These findings reveal a key role for the NEK2A-mediated phosphorylation ofHsSgo 1 in orchestrating dynamic kinetochore-microtubule interaction. We propose that NEK2A-mediated phosphorylation of human Sgo 1 provides a link between centromeric cohesion and spindle microtubule attachment at the kinetochores.展开更多
AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were d...AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were designed （p27^Kip1, p53 and p27^Kip1＋p53） and tested in COS cells. A total of 20 adult CD-1 mice were used in the experiment. Mice were divided into fve different groups （four animals/group） depending on the AAV-shRNA construct they received and whether they received kanamycin or not. Saline and AAV-EGFP injected animals were used as controls. All constructs were injected through the round window membrane （RWM） into the cochlea. Cochleae were harvested after 1 mo. Apoptosis was detected with Tunel labeling from paraffin-embedded cochlear tissue sections.RESULTS： AAV2/2-p27^Kip1-shRNA and AAV2/2-p53-shRNA were tested in COS cells. Western blotting analysis confirmed that both constructs silenced their target genes effectively in the cell culture. AAV2/2-shRNA constructs were injected into the cochlea of CD-1 mice through the intact RWM. Cotransductionof Cotransduction of individual AAV2/2-shRNAs with AAV2/2-EGFP resulted in EGFP expression in the organ of Corti.Kanamycin Kanamycin treatment had no effect on the expression pattern of the EGFP. AAV2/2-shRNA treated mice （either with p53 or p27Kip1and p53 together） showed fewer apop-totic hair cells in the cochlea than the control group （P 〈 0.05; AAV2/2-p53-shRNA vs saline P = 0.00014; AAV2/2-p27＋p53-shRNA vs saline P = 0.0011）. AAV2/2-p27-shRNA injected cochleae showed no significant difference in the number of apoptotic cells when compared to the saline injected cochleae.CONCLUSION： Silencing of p53 protein in the kana-mycin treated ears may decrease cell death in the organ of Corti.展开更多
Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cell...Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.展开更多
The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody(Ab)secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protectio...The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody(Ab)secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection.With this backdrop,it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise,persist,and meet the challenge of secreting vast amounts of these glycoproteins.Whereas plasmablasts and plasma cells(PCs)are the primary sources of secreted Abs,the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates.At each step,cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients.Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription,translation,and metabolism.This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion.Salient findings of this group and others,sometimes exhibiting differences,will be summarized with regard to the journey to a distinctive metabolic program in PCs.展开更多
Esophageal adenocarcinoma is increasing in the US and Western countries and frequent gastresophageal reflux or gastresophageal reflux disease carrying gastric acid and bile acid could contribute to esophageal adenocar...Esophageal adenocarcinoma is increasing in the US and Western countries and frequent gastresophageal reflux or gastresophageal reflux disease carrying gastric acid and bile acid could contribute to esophageal adenocarcinogenesis. This study was designed to detect the expression of gastric acid-inducing gene Na＋/H＋ exchanger-1 （NHE-1） ex vivo and then to explore targeting of NHE-1 expression or activity to control esophageal cancer cell viability in vitro and in nude mouse xenografts. The data showed that NHE-1 was highly expressed in esophageal adenocarcinoma tissues （66 of 101 cases [65.3%｜, but not in normal esophageal squamous cell epithelium （1 of 26 cases [3.8~0]）. Knockdown of NHE-1 expression using NHE-1 shRNA or inhibition of NHE-1 activity using the NHE-1 inhibitor amiloride suppressed viability and induced apoptosis in esophageal cancer cells. Molecularly, amiloride inhibited expression of cyclooxygenase-2 and matrix metallopeptidase-9 but not NHE-1 mRNA in esophageal cancer cells. A combination of amiloride and guggulsterone （a natural bile acid receptor inhibitor） showed more than additive effects in suppressing esophageal cancer cell growth in vitro and in nude mouse xenografts. This study suggests that inhibition of NHE-1 expression or activity or combination of amiloride and guggulsterone could be useful in control of esophageal adenocarcinoma.展开更多
Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by t...Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by time-limited interventions such as traditional surgical resection,radiation therapy,and chemotherapy is short-lived.A new form of anti-cancer therapy called therapeutic alternating electric fields(AEFs)or tumor treating fields(TTFields)has been shown,either by itself or in combination with chemotherapy,to have anti-cancer effects that translate to improved survival outcomes in patients.Although the pre-clinical and clinical data are promising,the mechanisms of TTFields are not fully elucidated.Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation.The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies(both in vitro and in vivo).An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies,to further improve survival outcomes in patients with solid organ cancers.展开更多
Background:The past decade has witnessed a rapid progress in our understanding of the genetics of cancer and its progression.Probabilistic and statistical modeling played a pivotal role in the discovery of general pat...Background:The past decade has witnessed a rapid progress in our understanding of the genetics of cancer and its progression.Probabilistic and statistical modeling played a pivotal role in the discovery of general patterns from cancer genomics datasets and continue to be of central importance for personalized medicine.Results:In this review we introduce cancer genomics from a probabilistic and statistical perspective.We start from(1)functional classification of genes into oncogenes and tumor suppressor genes,then(2)demonstrate the importance of comprehensive analysis of different mutation types for individual cancer genomes,followed by(3)tumor purity analysis,which in turn leads to(4)the concept of ploidy and clonality,that is next connected to(5)tumor evolution under treatment pressure,which yields insights into cancer drug resistance.We also discuss future challenges including the non-coding genomic regions,integrative analysis of genomics and epigenomics,as well as early cancer detection.Conclusion:We believe probabilistic and statistical modeling will continue to play important roles for novel discoveries in the field o f cancer genomics and personalized medicine.展开更多
In a recent study published in Nature Cancer,Shi et al.reported the identification of the small molecule YC-1 as the selective drug against primary liver tumor cells due to the specific expression of sulfotransferase ...In a recent study published in Nature Cancer,Shi et al.reported the identification of the small molecule YC-1 as the selective drug against primary liver tumor cells due to the specific expression of sulfotransferase family 1A member 1(SULT1A1)in hepatocytelineage cells.1 This study offered new insights into repurposing an old anti-cancer drug via harnessing hepatocyte-specific metabolic enzymes to treat primary liver tumors.展开更多
Background:Triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Immune checkpoint inhibitors(ICIs)have been widely used to treat various tumors and have changed the landscape of tumor manage...Background:Triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Immune checkpoint inhibitors(ICIs)have been widely used to treat various tumors and have changed the landscape of tumor management,but the data from real-world studies of ICIs for TNBC treatment remain limited.The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates.Methods:The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army(PLA)General Hospital were collected.Treatment responses,outcomes and adverse events(AEs)were assessed.Results:Eighty-one patients were included in the study.The confirmed objective response rate(ORR)was 32.1%,and the disease control rate(DCR)was 64.2%.The median progression-free survival(PFS)was 4.2 months,and the median overall survival(OS)was 11.0 months.PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation;specifically,patients with higher TILs had longer PFS.Overall AEs were tolerable.Conclusions:ICIs are effective in the treatment of advanced TNBC,and the adverse reactions are tolerable.A panel of biomarkers including LDH,ALP,and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.展开更多
The C-type lectin receptors （CLRs） belong to a large family of proteins that contain a carbohydrate recognition domain （CRD） and calcium binding sites on their extracellular domains. Recent studies indicate that m...The C-type lectin receptors （CLRs） belong to a large family of proteins that contain a carbohydrate recognition domain （CRD） and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors （PRRs） recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs （ITAMs） or interacting with ITAM-containing adaptor proteins such as FcRy. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB （NF-KB） family of transcriptional factors through a Syk- and CARD9-dependent pathway（s）. The activation of NF-κB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs. and how these CLRs activate NF-κB and contribute to innate immune and inflammatory responses.展开更多
INTRODUCTION Granular cell tumor （GCT） of neurohypophysis was first reported by Boyce and Beadles in 1983.Iu In 2016 WHO classification of central nervous system （CNS） tumors, GCT of neurohypophysis was defined as...INTRODUCTION Granular cell tumor （GCT） of neurohypophysis was first reported by Boyce and Beadles in 1983.Iu In 2016 WHO classification of central nervous system （CNS） tumors, GCT of neurohypophysis was defined as a distinct diagnosis.121 Here, we reported two cases of GCT of neurohypophysis misdiagnosed as pituitary adenoma and craniopharyngioma. One of the cases was a very rare fully described neurohypophysial GCT which invaded into the right cavernous sinus [Figure 1a and 1b], indicating that the benign tumor might possess aggressive features.展开更多
Dear Editor,Chemotherapy is one of major means for cancer treatments, and many of chemotherapeutic drugs are DNA damaging agents that reduce tumor growth through triggering cancer cell apoptosis or necrosis. Following...Dear Editor,Chemotherapy is one of major means for cancer treatments, and many of chemotherapeutic drugs are DNA damaging agents that reduce tumor growth through triggering cancer cell apoptosis or necrosis. Following DNA damage, ataxia telangiectasia mutated （ATM）, a protein kinase, was acti- vated and a cytosolic complex containing ATM, NEMO, RIP1 were formed （Biton and Ashkenazi, 2011）.展开更多
This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting roles.Our data showed that Gal1 was highly expressed in human and ...This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting roles.Our data showed that Gal1 was highly expressed in human and mouse HCC.The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival.The roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by AAV9.Prior to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor load.The treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body weight.Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing.Within the tumors,silencing Gal1 inhibited translational initiation,elongation,and termination.Furthermore,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas CD8-dependent.Overall,Gal1 silencing has a promising potential for HCC treatment.展开更多
SKA2(spindle and KT associated 2),also referred to as FAM33A(family with sequence similarity 33,member A),is a recently identified gene involved in cell cycle regulation,and growing evidence is implicating its roles i...SKA2(spindle and KT associated 2),also referred to as FAM33A(family with sequence similarity 33,member A),is a recently identified gene involved in cell cycle regulation,and growing evidence is implicating its roles in tumorigenesis and psychiatric disorders.It has been demonstrated that SKA2,along with its coworkers SKA1 and SKA3,constitutes the SKA complex which plays a critical role in the maintenance of the metaphase plate and/or spindle checkpoint silencing during mitosis.SKA2 is over-expressed both in cancer cell lines and clinical samples including small cell lung cancer and breast cancer,whereas downregulation of SKA2 is associated with depression and suicidal ideation.The expression of SKA2 is regulated by transcription factors including NF-kB and CREB,miRNAs as well as DNA methylation.In this review,we provide an overview of studies that reveal SKA2 gene and protein characteristics as well as physiological function,with a special focus on its transcription regulatory mechanisms,and also provide a summary regarding the translational opportunity of the SKA2 gene as a clinical biomarker for cancers and psychiatric disorders.展开更多
Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein （ChREBP）. As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can ...Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein （ChREBP）. As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can also be regulated by the dietary polyphenoi curcumin. We also aimed to determine mechanisms underlying ChREBP stimulation by insulin and curcumin. The effect of insulin on ChREBP expression was assessed in mouse hepatocytes, while the effect of curcumin was assessed in mouse hepatocytes and with curcumin garage in mice. Chemical inhibitors for insulin signaling molecules were utilized to identify involved signaling molecules, and the involvement of p21-activated protein kinase 1 （Pakl） was determined with its chemical inhibitor and Pokl-/- hepatocytes. We found that both insulin and curcumin-stimulated ChREBP expression in Akt-independent but MEK/ERK-dependent manner, involving the inactivation of the transcriptional repressor Oct-1. Aged Pokl-/- mice showed reduced body fat volume. Pakl inhibition or its genetic deletion attenuated the stimulatory effect of insulin or curcumin on ChREBP expression. Our study hence suggests the existence of a novel signaling cascade Pakl/MEK/ERK/Oct-1 for both insulin and curcumin in exerting their glucose-lowering effect via promoting hepatic ChREBP production, supports the recognition of beneficial functions of ChREBP, and brings us a new overview on dietary polyphenols.展开更多
基金Supported by In part by Georgia Cancer Coalition Distinguished Cancer Scholar award,NIH-NCRR-RCMI,No.G-12-RR003034,No.U54 RR02613,and No.5P20RR11104NIHMD research endowment,No.2S21MD000101,and No.U54CA118638ING foundation grant to Rao VN
文摘Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.
基金The authors would like to extend thanks to the following organizations and groups for their continued support of CTC research efforts at the Samuel Oschin Comprehensive Cancer Institute:St.Anthony Fund for Prostate Cancer Discover,CD McKinnon Memorial Fund for Aggressive Variant Prostate Cancers,Michael&Trisha Berns Family Fund for Discovery,Steven Spielberg Family Prostate Cancer Discovery Fund,Prostate Cancer Research Program of the US Department of Defense(W81XWH-11-1-0422)Prostate Cancer Foundation,Alliance for Nanotechnology in Cancer(1U01CA198900-01)the National Cancer Institute.
文摘One of the major challenges that clinicians face is in the difficulties of accurately monitoring disease progression.Prostate cancer is among these diseases and greatly affects the health of men globally.Circulating tumor cells(CTCs)are a rare population of cancer cells that have shed from the primary tumor and entered the peripheral circulation.Not until recently,clinical applications of CTCs have been limited to using enumeration as a prognostic tool in Oncology.However,advances in emerging CTC technologies point toward new applications that could revolutionize the field of prostate cancer.It is now possible to study CTCs as components of a liquid biopsy based on morphological phenotypes,biochemical analyses,and genomic profiling.These advances allow us to gain insight into the heterogeneity and dynamics of cancer biology and to further study the mechanisms behind the evolution of therapeutic resistance.These recent developments utilizing CTCs for clinical applications will greatly impact the future of prostate cancer research and pave the way towards personalized care for men.
基金supported by a Stanford Maternal and Child Health Research Institute Research Scholar Award (2020)an American Cancer Society Research Scholar Grant (RSG-20-036-01)an Agilent Solutions Innovation Research Award (SIRA) to J.Y.
文摘German biochemist and cell physiologist,Otto H.Warburg(Figure 1),made a groundbreaking discovery in 1923.Specifically,tumors were shown to consume large amounts of glucose and ferment glucose into lactate,even in the presence of oxygen—a phenomenon termed"aerobic glycolysis"1,2.This phenomenon,later named the Warburg effect by Efraim Racker in the 1970s,remains pivotal in cancer research3.
文摘The androgen receptor （AR） remains the primary molecular target forprostate cancer （PCa） treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown that the AR is still functional during latestage disease in the absence of circulating hormone fol lowing castration therapy. The molecular mechanisms that operate during this ＇cas tration resistant＇ phase are still not well understood. Qi et al. have now implicated the ubiquitin ligase Siah2 as an important mediator of AR action in castration resis tant prostate cancer （CRPC）. Siah2 was found to target repressed AR chromatin complexes for degradation, resulting in activation of ARregulated genes involved in tumor cell proliferation, cell motility and lipid metabolism. The authors show a requirement for Siah2 activity for PCa cell growth under conditions of low androgen, and also that targeting Siah2 results in tumor growth suppression under castrate conditions. These findings identify a new mechanism of AR regulation in progressing disease as well as a novel enzymatic target for therapeutic intervention. The AR is a wellstudied hormone receptor that belongs to the large nuclear receptor gene superfamily. AR is activated by androgen binding （principally 5：~dihydrotestosterone, 5DHT）, which elicits changes in AR resident cytosolic complexes, translocation of the receptor to cell nuclei, formation of multiprotein transcriptional complexes onchromatin, and activation or repression of gene expression. Experiments with in vivo model systems have provided evidence that virtually all physiologic processes affected by androgens require the AR as a mediator of molecular effects at the gene level.1 AR is widely expressed beyond the reproductive systems and is believed to play important roles in several nonreproductive tissues, including muscle and brain. The fact that PCa growth is initially dependent on the pre sence of androgens in the circulation, and that prostate tumors will regress temporarily with castration, has been recognized for over half a century. Molecular cloning was initially felt to of the AR in the 1980s be a dispositive step toward pharmacological interventions that would greatly improve treatment outcomes for PCa. However, despite many advances since that time, there is currently no effec tive therapy for disease that has become unresponsive to treatment with hormone ablation. The ＇hormone refractory＇ phase of the disease is intriguing from a bioche mical perspective because the AR still appears to play a critical role under conditions where androgen concentrations in the blood are extremely low. RNA and gene profiling of many human PCa tumors has shown that hormone suppression provides a strong selec tion pressure that results in overexpression and/or amplification of the AR during meta static dissemination.2 Molecular and bio chemical studies of the AR have revealed a bewildering level of complexity involving over 150 protein partners. The AR is also posttranslationally modified by phosphory lation, sumoylation and acetylation, and AR expression can be controlled at transcrip tional and posttranscriptional levels, adding additional layers of regulatory complexity. One important locus of AR activity lies in the ubiquitin/proteasome pathway, which controls the specificity and rate of protein degradation. AR stability was shown pre viously to be regulated by ubiquitin ligases,3 proteins that form complexes with ubiquitin conjugating enzymes to catalyze attachment of the small protein ubiquitin to lysines on a protein target, thereby directing the modified protein to the proteasome for degradation. Siahl and Siah2 are RING finger E3 ubiquitin ligases that regulate ubiquitinationmediated degradation of a range of signaling proteins, resulting in diverse biological effects such as resistance to apoptosis and effects on mito chondrial function. Qi et al.4 previously showed that knockout of the Siah2 gene in the TRAMP transgenic mouse model of PCa, a system that rapidly produces aggres sive autochthonous prostate tumors that pro gress to metastasis, resulted in suppression of tumor formation. In a recent paper in Cancer Cell,5 the same group has now gone on to uncover the mechanism of this surprising effect. Further experiments in TRAMP mice indi cated that loss of Siah2 decreased prostate size, an indication of a loss of AR signaling, and also increased the sensitivity to castra tion, suggesting the possibility that Siah2 may operate under low androgen conditions. Knockdown of Siah2 in PCa cell lines indi cated that Siah2 controls a subset of AR regulated genes, including the gene encoding the important clinical biomarker, prostate specific antigen. Global transcriptional profi ling identified a Siah2regulated gene network consisting of almost 1000 genes, about 100 of which were found to be AR regulated. The AR and Siah2dependent genes were mostly associated with lipid, sterol and cholesterol metabolism. Analysis of human PCa profiling
文摘DNA mismatch repair （MMR） processes the chemically induced mispairs following treatment with clinically important nucleoside analogs such as 6-thioguanine （6-TG） and 5-fluorouracil （5-FU）. MMR processing of these drugs has been implicated in activation of a prolonged G2/M cell cycle arrest for repair and later induction of apoptosis and/or autophagy for irreparable DNA damage. In this study, we investigated the role of Bcl2 and adenovirus EIB Nineteen-kilodalton Interacting Protein （BNIP3） in the activation of autophagy, and the temporal relationship between a G2/M cell cycle arrest and the activation of BNIP3-mediated autophagy following MMR processing of 6-TG and 5-FU. We found that BNIP3 protein levels are upregulated in a MLHI （MMR＋）-dependent manner following 6-TG and 5-FU treatment. Subsequent small-interfering RNA （siRNA）-mediated BNIP3 knockdown abrogates 6-TG- induced autophagy. We also found that p53 knockdown or inhibition of mTOR activity by rapamycin cotreatment impairs 6-TG- and 5-FU-induced upregulation of BNIP3 protein levels and autophagy. Furthermore, suppression of Checkpoint kinase 1 （Chkl） expression with a subsequent reduction in 6-TG-induced G2/M cell cycle arrest by Chkl siRNA promotes the extent of 6-TG-induced autophagy. These findings suggest that BNIP3 mediates 6-TG- and 5-FU-induced autophagy in a p53- and mTOR-dependent manner. Additionally, the duration of Chkl-activated G2/ M cell cycle arrest determines the level of autophagy following MMR processing of these nucleoside analogs.
基金We thank members of our group for insightful discussion during the course of this study.This work was supported by grants from Chinese Academy of Science(KSCX1-YW-R65,KSCX2-YW-H10)National Basic Research Program of China(2002CB713700)+4 种基金Hi-Tech Research and Development Program of China(2001AA215331)Chinese Minister of Education(20020358051 to XY,PCSIRT0413 to XD)National Natural Science Foundation of China(39925018,30270293 to XY,30500183 to XD,30600222 to JY)National Institutes of Health(USA)(DK56292,CA92080)to XY(a Georgia Cancer Coalition Eminent Scholar)JY was supported by China Postdoctor(2005037560).
文摘Chromosome segregation in mitosis is orchestrated by the interaction of the kinetochore with spindle microtubules. Our recent study shows that NEK2A interacts with MAD 1 at the kinetochore and possibly functions as a novel integrator of spindle checkpoint signaling. However, it is unclear how NEK2A regulates kinetochore-microtubule attachment in mitosis. Here we show that NEK2A phosphorylates human Sgo 1 and such phosphorylation is essential for faithful chromosome congression in mitosis. NEK2A binds directly to HsSgol in vitro and co-distributes with HsSgol to the kinetochore of mitotic cells. Our in vitro phosphorylation experiment demonstrated that HsSgo 1 is a substrate of NEK2A and the phosphorylation sites were mapped to Ser^14 and Ser^507 as judged by the incorporation of 32^P. Although such phosphorylation is not required for assembly of HsSgo 1 to the kinetochore, expression of non-phosphorylatable mutant HsSgo 1 perturbed chromosome congression and resulted in a dramatic increase in microtubule attachment errors, including syntelic and monotelic attachments. These findings reveal a key role for the NEK2A-mediated phosphorylation ofHsSgo 1 in orchestrating dynamic kinetochore-microtubule interaction. We propose that NEK2A-mediated phosphorylation of human Sgo 1 provides a link between centromeric cohesion and spindle microtubule attachment at the kinetochores.
基金Supported by grants fromm a Helsinki University Central Hospital Research Fundsthe Sigrid Jusélius Foundation+1 种基金the Instrumentarium Research Foundationthe Finnish Medical Foundation
文摘AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were designed （p27^Kip1, p53 and p27^Kip1＋p53） and tested in COS cells. A total of 20 adult CD-1 mice were used in the experiment. Mice were divided into fve different groups （four animals/group） depending on the AAV-shRNA construct they received and whether they received kanamycin or not. Saline and AAV-EGFP injected animals were used as controls. All constructs were injected through the round window membrane （RWM） into the cochlea. Cochleae were harvested after 1 mo. Apoptosis was detected with Tunel labeling from paraffin-embedded cochlear tissue sections.RESULTS： AAV2/2-p27^Kip1-shRNA and AAV2/2-p53-shRNA were tested in COS cells. Western blotting analysis confirmed that both constructs silenced their target genes effectively in the cell culture. AAV2/2-shRNA constructs were injected into the cochlea of CD-1 mice through the intact RWM. Cotransductionof Cotransduction of individual AAV2/2-shRNAs with AAV2/2-EGFP resulted in EGFP expression in the organ of Corti.Kanamycin Kanamycin treatment had no effect on the expression pattern of the EGFP. AAV2/2-shRNA treated mice （either with p53 or p27Kip1and p53 together） showed fewer apop-totic hair cells in the cochlea than the control group （P 〈 0.05; AAV2/2-p53-shRNA vs saline P = 0.00014; AAV2/2-p27＋p53-shRNA vs saline P = 0.0011）. AAV2/2-p27-shRNA injected cochleae showed no significant difference in the number of apoptotic cells when compared to the saline injected cochleae.CONCLUSION： Silencing of p53 protein in the kana-mycin treated ears may decrease cell death in the organ of Corti.
基金supported by the National Institute of Neurological Disorders and Stroke grant R01 NS089754(to Z.L.)by the National Cancer Institute(NCI)grant 1R01 CA204996(to Z.L.)+1 种基金by the National Institutes of Health/NCI through MD Anderson’s Cancer Center Support grant P30CA016672Brain Cancer Specialized Program of Research Excellence grant 2P50 CA127001。
文摘Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.
基金The authors gratefully acknowledge the support from funds of the Department of Pathology,Microbiology&Immunology that made it possible to write this review and continue key lines of investigationprior support from expired NIH grants HL106812 and AI113292,including a supplement to support SKBand current NIH support(R01 AI149722).
文摘The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody(Ab)secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection.With this backdrop,it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise,persist,and meet the challenge of secreting vast amounts of these glycoproteins.Whereas plasmablasts and plasma cells(PCs)are the primary sources of secreted Abs,the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates.At each step,cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients.Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription,translation,and metabolism.This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion.Salient findings of this group and others,sometimes exhibiting differences,will be summarized with regard to the journey to a distinctive metabolic program in PCs.
文摘Esophageal adenocarcinoma is increasing in the US and Western countries and frequent gastresophageal reflux or gastresophageal reflux disease carrying gastric acid and bile acid could contribute to esophageal adenocarcinogenesis. This study was designed to detect the expression of gastric acid-inducing gene Na＋/H＋ exchanger-1 （NHE-1） ex vivo and then to explore targeting of NHE-1 expression or activity to control esophageal cancer cell viability in vitro and in nude mouse xenografts. The data showed that NHE-1 was highly expressed in esophageal adenocarcinoma tissues （66 of 101 cases [65.3%｜, but not in normal esophageal squamous cell epithelium （1 of 26 cases [3.8~0]）. Knockdown of NHE-1 expression using NHE-1 shRNA or inhibition of NHE-1 activity using the NHE-1 inhibitor amiloride suppressed viability and induced apoptosis in esophageal cancer cells. Molecularly, amiloride inhibited expression of cyclooxygenase-2 and matrix metallopeptidase-9 but not NHE-1 mRNA in esophageal cancer cells. A combination of amiloride and guggulsterone （a natural bile acid receptor inhibitor） showed more than additive effects in suppressing esophageal cancer cell growth in vitro and in nude mouse xenografts. This study suggests that inhibition of NHE-1 expression or activity or combination of amiloride and guggulsterone could be useful in control of esophageal adenocarcinoma.
基金supported by the McNair Medical Institute at The Robert and Janice McNair Foundation.
文摘Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by time-limited interventions such as traditional surgical resection,radiation therapy,and chemotherapy is short-lived.A new form of anti-cancer therapy called therapeutic alternating electric fields(AEFs)or tumor treating fields(TTFields)has been shown,either by itself or in combination with chemotherapy,to have anti-cancer effects that translate to improved survival outcomes in patients.Although the pre-clinical and clinical data are promising,the mechanisms of TTFields are not fully elucidated.Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation.The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies(both in vitro and in vivo).An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies,to further improve survival outcomes in patients with solid organ cancers.
文摘Background:The past decade has witnessed a rapid progress in our understanding of the genetics of cancer and its progression.Probabilistic and statistical modeling played a pivotal role in the discovery of general patterns from cancer genomics datasets and continue to be of central importance for personalized medicine.Results:In this review we introduce cancer genomics from a probabilistic and statistical perspective.We start from(1)functional classification of genes into oncogenes and tumor suppressor genes,then(2)demonstrate the importance of comprehensive analysis of different mutation types for individual cancer genomes,followed by(3)tumor purity analysis,which in turn leads to(4)the concept of ploidy and clonality,that is next connected to(5)tumor evolution under treatment pressure,which yields insights into cancer drug resistance.We also discuss future challenges including the non-coding genomic regions,integrative analysis of genomics and epigenomics,as well as early cancer detection.Conclusion:We believe probabilistic and statistical modeling will continue to play important roles for novel discoveries in the field o f cancer genomics and personalized medicine.
文摘In a recent study published in Nature Cancer,Shi et al.reported the identification of the small molecule YC-1 as the selective drug against primary liver tumor cells due to the specific expression of sulfotransferase family 1A member 1(SULT1A1)in hepatocytelineage cells.1 This study offered new insights into repurposing an old anti-cancer drug via harnessing hepatocyte-specific metabolic enzymes to treat primary liver tumors.
基金Health care special project,Grant/Award Number:17BJZ40。
文摘Background:Triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Immune checkpoint inhibitors(ICIs)have been widely used to treat various tumors and have changed the landscape of tumor management,but the data from real-world studies of ICIs for TNBC treatment remain limited.The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates.Methods:The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army(PLA)General Hospital were collected.Treatment responses,outcomes and adverse events(AEs)were assessed.Results:Eighty-one patients were included in the study.The confirmed objective response rate(ORR)was 32.1%,and the disease control rate(DCR)was 64.2%.The median progression-free survival(PFS)was 4.2 months,and the median overall survival(OS)was 11.0 months.PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation;specifically,patients with higher TILs had longer PFS.Overall AEs were tolerable.Conclusions:ICIs are effective in the treatment of advanced TNBC,and the adverse reactions are tolerable.A panel of biomarkers including LDH,ALP,and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.
文摘The C-type lectin receptors （CLRs） belong to a large family of proteins that contain a carbohydrate recognition domain （CRD） and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors （PRRs） recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs （ITAMs） or interacting with ITAM-containing adaptor proteins such as FcRy. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB （NF-KB） family of transcriptional factors through a Syk- and CARD9-dependent pathway（s）. The activation of NF-κB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs. and how these CLRs activate NF-κB and contribute to innate immune and inflammatory responses.
文摘INTRODUCTION Granular cell tumor （GCT） of neurohypophysis was first reported by Boyce and Beadles in 1983.Iu In 2016 WHO classification of central nervous system （CNS） tumors, GCT of neurohypophysis was defined as a distinct diagnosis.121 Here, we reported two cases of GCT of neurohypophysis misdiagnosed as pituitary adenoma and craniopharyngioma. One of the cases was a very rare fully described neurohypophysial GCT which invaded into the right cavernous sinus [Figure 1a and 1b], indicating that the benign tumor might possess aggressive features.
文摘Dear Editor,Chemotherapy is one of major means for cancer treatments, and many of chemotherapeutic drugs are DNA damaging agents that reduce tumor growth through triggering cancer cell apoptosis or necrosis. Following DNA damage, ataxia telangiectasia mutated （ATM）, a protein kinase, was acti- vated and a cytosolic complex containing ATM, NEMO, RIP1 were formed （Biton and Ashkenazi, 2011）.
基金The authors thank the Genomics Shared Resource(GSR)core facility at the University of California,Davis Health,Dr.Clifford G Tepper,Stephanie Liu,Ryan Davis,for helping in performing spatial RNA sequencing,and William Amato for his assistance in the quantification of immunohistochemistry slides.This manuscript is supported by grants funded by the USA National Institutes of Health(NIH)T32 CA108459e15,R01CA222490,R50CA243787.BioRender was used to draw mice figures in schematic experimental design.
文摘This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting roles.Our data showed that Gal1 was highly expressed in human and mouse HCC.The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival.The roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by AAV9.Prior to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor load.The treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body weight.Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing.Within the tumors,silencing Gal1 inhibited translational initiation,elongation,and termination.Furthermore,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas CD8-dependent.Overall,Gal1 silencing has a promising potential for HCC treatment.
基金This work was supported by the National Natural Science Foundation of China(No.81672301 to Youquan Bu)the Basic Sciences and Advanced Technology Key Project of CQ CSTC(No.cstc2017jcyjBX0069 to Youquan Bu).
文摘SKA2(spindle and KT associated 2),also referred to as FAM33A(family with sequence similarity 33,member A),is a recently identified gene involved in cell cycle regulation,and growing evidence is implicating its roles in tumorigenesis and psychiatric disorders.It has been demonstrated that SKA2,along with its coworkers SKA1 and SKA3,constitutes the SKA complex which plays a critical role in the maintenance of the metaphase plate and/or spindle checkpoint silencing during mitosis.SKA2 is over-expressed both in cancer cell lines and clinical samples including small cell lung cancer and breast cancer,whereas downregulation of SKA2 is associated with depression and suicidal ideation.The expression of SKA2 is regulated by transcription factors including NF-kB and CREB,miRNAs as well as DNA methylation.In this review,we provide an overview of studies that reveal SKA2 gene and protein characteristics as well as physiological function,with a special focus on its transcription regulatory mechanisms,and also provide a summary regarding the translational opportunity of the SKA2 gene as a clinical biomarker for cancers and psychiatric disorders.
文摘Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein （ChREBP）. As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can also be regulated by the dietary polyphenoi curcumin. We also aimed to determine mechanisms underlying ChREBP stimulation by insulin and curcumin. The effect of insulin on ChREBP expression was assessed in mouse hepatocytes, while the effect of curcumin was assessed in mouse hepatocytes and with curcumin garage in mice. Chemical inhibitors for insulin signaling molecules were utilized to identify involved signaling molecules, and the involvement of p21-activated protein kinase 1 （Pakl） was determined with its chemical inhibitor and Pokl-/- hepatocytes. We found that both insulin and curcumin-stimulated ChREBP expression in Akt-independent but MEK/ERK-dependent manner, involving the inactivation of the transcriptional repressor Oct-1. Aged Pokl-/- mice showed reduced body fat volume. Pakl inhibition or its genetic deletion attenuated the stimulatory effect of insulin or curcumin on ChREBP expression. Our study hence suggests the existence of a novel signaling cascade Pakl/MEK/ERK/Oct-1 for both insulin and curcumin in exerting their glucose-lowering effect via promoting hepatic ChREBP production, supports the recognition of beneficial functions of ChREBP, and brings us a new overview on dietary polyphenols.
