查看更多>>摘要：Leukemia is a malignancy in the blood that develops from the lymphatic system and bone marrow.Although various treatment options have been used for different types of leuke-mia,understanding the molecular pathways involved in the development and progression of leukemia is necessary.Recent studies showed that leukemia stem cells(LSCs)play essential roles in the pathogenesis of leukemia by targeting several signaling pathways,including Notch,Wnt,Hedgehog,and STAT3.LSCs are highly proliferative cells that stimulate tumor initiation,migration,EMT,and drug resistance.This review summarizes cellular pathways that stimulate and prevent LSCs'self-renewal,metastasis,and tumorigenesis.
查看更多>>摘要：Gastric cancer(GC)is one of the most common and deadly cancers worldwide.Early detection offers the best chance for curative treatment and reducing its mortality.How-ever,the optimal population-based early screening for GC remains unmet.Aberrant DNA methylation occurs in the early stage of GC,exhibiting cancer-specific genetic and epigenetic changes,and can be detected in the media such as blood,gastric juice,and feces,constituting a valuable biomarker for cancer early detection.Furthermore,DNA methylation is a stable epigenetic alteration,and many innovative methods have been developed to quantify it rapidly and accurately.Nonetheless,large-scale clinical validation of DNA methylation serving as tumor biomarkers is still lacking,precluding their implementation in clinical practice.In conclusion,after a critical analysis of the recent existing literature,we summarized the evolving roles of DNA methylation during GC occurrence,expounded the newly discovered noninvasive DNA methylation biomarkers for early detection of GC,and discussed its chal-lenges and prospects in clinical applications.
查看更多>>摘要：Microrchidia CW-type zinc finger 2(MORC2)is a member of the MORC superfamily of nuclear proteins.Growing evidence has shown that MORC2 not only participates in gene tran-scription and chromatin remodeling but also plays a key in human disease and tumor develop-ment by regulating the expression of downstream oncogenes or tumor suppressors.The present review provides an updated overview of MORC2 in the aspect of cancer hallmark and therapeutic resistance and summarizes its upstream regulators and downstream target genes.This systematic review may provide a favorable theoretical basis for emerging players of MORC2 in tumor development and new insight into the potential clinical application of basic science discoveries in the future.
查看更多>>摘要：Glioblastoma(GBM)is the most common intrinsic and aggressive primary brain tu-mor in adults,with a median survival of approximately 15 months.GBM heterogeneity is considered responsible for the treatment resistance and unfavorable prognosis.Proneural-mesenchymal transition(PMT)represents GBM malignant progression and recurrence,which might be a breakthrough to understand GBM heterogeneity and overcome treatment resis-tance.PMT is a complicated process influenced by crosstalk between GBM and tumor microen-vironment,depending on intricate ligand-receptor interactions.In this review,we summarize the autocrine and paracrine pathways in the GBM microenvironment and related ligand-recep-tor interactions inducing PMT.We also discuss the current therapies targeting the PMT-related autocrine and paracrine pathways.Together,this review offers a comprehensive understand-ing of the failure of GBM-targeted therapy and ideas for future tendencies of GBM treatment.
查看更多>>摘要：m6A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological functions.Insulin-like growth factor 2 mRNA-binding proteins(IGF2BP)are newly identified m6A'readers'.They belong to a family of RNA-binding proteins,which bind to the m6A sites on different RNA sequences and stabilize them to promote cancer progression.In this review,we summarize the mechanisms by which different upstream factors regulate IGF2BP in cancer.The current literature analyzed here re-veals that the IGF2BP family proteins promote cancer cell proliferation,survival,and chemore-sistance,inhibit apoptosis,and are also associated with cancer glycolysis,angiogenesis,and the immune response in the tumor microenvironment.Therefore,with the discovery of their role as'readers'of m6A and the characteristic re-expression of IGF2BPs in cancers,it is impor-tant to elucidate their mechanism of action in the immunosuppressive tumor microenviron-ment.We also describe in detail the regulatory and interaction network of the IGF2BP family in downstream target RNAs and discuss their potential clinical applications as diagnostic and prognostic markers,as well as recent advances in IGF2BP biology and associated therapeu-tic value.
查看更多>>摘要：Ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),also known as lysine(K)-specific demethylase 6A(KDM6A),functions as a tumor suppressor gene or oncogene depending on the tumor type and context.However,its tumor-suppressive mech-anisms remain largely unknown.Here,we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma(PDA)and determined the po-tential mechanisms of its dysregulation.UTX expression and its association with clinicopatho-logic characteristics of PDA patients were analyzed using immunohistochemistry.UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses.The biological functions of UTX in PDA cell growth,migration,and invasion were determined using gain-and loss-of-function assays with both in vitro and in vivo animal models.UTX expression was reduced in human PDA cell lines and specimens.Low UTX expression was associated with poor differentiation and prognosis in PDA.Forced UTX expression inhibited PDA proliferation,migration,and invasion in vitro and PDA growth and metastasis in vivo,whereas knockdown of UTX expression did the opposite.Mechanistically,UTX expression was trans-activated by GATA6 activation.GATA6-mediated PDA progression could be blocked,at least partially,by silencing UTX expression.In conclusion,loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis.Thus,UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.
查看更多>>摘要：As a widely used plasticizer,di-(2-ethylhexyl)phthalate(DEHP)is known to induce significant testicular injury.However,the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear.In vivo,postnatal day(PND)21 male rats were gavaged with 0,250,and 500 mg/kg DEHP for ten days.Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure.Meanwhile,oxidative stress-induced injury and pyroptosis were activated.Both endoplasmic reticulum(ER)stress and mitophagy were involved in this process.Monoethylhexyl phthalate(MEHP)was used as the biometabolite of DEHP in vitro.The GC-1 and GC-2 cell lines were exposed to 0,100 μM,200 μM,and 400 μM MEHP for 24 h.Reactive oxygen species(ROS)generation,oxidative stress damage,ER stress,mitophagy,and pyroptosis were significantly increased af-ter MEHP exposure.The ultrastructure of the ER and mitochondria was destroyed.X-box bind-ing protein 1(XBP1)was observed to be activated and translocated into the nucleus.ROS generation was inhibited by acetylcysteine.The levels of antioxidative stress,ER stress,mito-phagy,and pyroptosis were decreased as well.After the administration of the ER stress inhib-itor 4-phenyl-butyric acid,both mitophagy and pyroptosis were inhibited.Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis.The equilib-rium between pyroptosis and mitophagy was disturbed by XBP1 accumulation.In summary,our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1.Moreover,XBP1 might be the key target in DEHP-related testis dysfunction.
查看更多>>摘要：Osteosarcoma is the most common primary malignancy of bones and primarily oc-curs in adolescents and young adults.However,a second smaller peak of osteosarcoma inci-dence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tu-mor progression by metabolic reprogramming.Recent research has shown that methylmalo-nic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis acceler-ated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhib-itors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.
查看更多>>摘要：Mutation of the MAPK7 gene was related to human scoliosis.Mapk7 regulated the development of limb bones and skulls in mice.However,the role of MAPK7 in vertebral devel-opment is still unclear.In this study,we constructed Col2a1-cre;Mapk7f/f transgenic mouse model to delete Mapk7 in cartilage,which displayed kyphosis and osteopenia.Mechanistically,Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes,which impaired chondrocyte hypertrophy and attenu-ated vertebral ossification.In vivo,systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency.Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development,which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.
查看更多>>摘要：Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor progression.CD147 is a tumor biomarker with various PTMs,promoting tumor metastasis and metabolism reprogramming.Nevertheless,the relationship between the PTMs of CD147 and apoptosis has not been reported.In our study,we produced a specific anti-CD147-K71 di-methylation(CD147-K71me2)antibody by immu-nizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer(NSCLC)tissues were lower than that in NSCLC adjacent tissues.SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2.RNA-seq showed that FOSB was the most significant differentially expressed gene(DEG)between wild-type CD147(CD147-WT)and K71-mutant CD147(CD147-K71R)groups.Subsequently,we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38,leading to tumor cell apoptosis.In vivo experiments showed that CD147-K71me2 signif-icantly inhibited tumor progression by promoting cell apoptosis.Taken together,our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification,which is distinct from the pro-cancer function of CD147 itself,broadening our perspective on tumor-associated antigen CD147.
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