查看更多>>摘要：Mitochondrial diseases are a heterogeneous group of inherited disorders character-ized by mitochondrial dysfunction,and these diseases are often severe or even fatal.Mito-chondrial diseases are often caused by mitochondrial DNA mutations.Currently,there is no curative treatment for patients with pathogenic mitochondrial DNA mutations.With the rapid development of traditional gene editing technologies,such as zinc finger nucleases and tran-scription activator-like effector nucleases methods,there has been a search for a mitochon-drial gene editing technology that can edit mutated mitochondrial DNA;however,there are still some problems hindering the application of these methods.The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing.In this paper,we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.
David Sánchez-MarínMacrina Beatriz Silva-CázaresFany Iris Porras-ReyesRebeca García-Román...
311-323页
查看更多>>摘要：Long non-coding RNAs(lncRNAs)are non-coding RNAs longer than 200 nucleotides with dynamic regulatory functions.They interact with a wide range of molecules such as DNA,RNA,and proteins to modulate diverse cellular functions through several mechanisms and,if deregulated,they can lead to cancer development and progression.Recently,it has been described that lncRNAs are susceptible to form gene fusions with mRNAs or other lncRNAs,breaking the paradigm of gene fusions consisting mainly of protein-coding genes.However,their biological significance in the tumor phenotype is still uncertain.Therefore,their recent identification opens a new line of research to study their biological role in tumor-igenesis,and their potential as biomarkers with clinical relevance or as therapeutic targets.The present study aimed to review the lncRNA fusions identified so far and to know which of them have been associated with a potential function.We address the current challenges to deepen their study as well as the reasons why they represent a future therapeutic window in cancer.
查看更多>>摘要：The liver is an important metabolic and detoxification organ and hence demands a large amount of energy,which is mainly produced by the mitochondria.Liver tissues of pa-tients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mito-chondrial lesions,mitochondrial DNA damage,disturbed mitochondrial dynamics,and compromised ATP production.Overproduction of mitochondrial reactive oxygen species in-duces oxidative damage to mitochondrial proteins and mitochondrial DNA,decreases mito-chondrial membrane potential,triggers hepatocyte inflammation,and promotes programmed cell death,all of which impair liver function.Mitochondrial DNA may be a poten-tial novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus.We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases,such as hepatocellular carcinoma,viral hepatitis,drug-induced liver injury,alcoholic liver disease,and non-alcoholic fatty liver disease.This review also discusses mito-chondrion-centric therapies for treating liver diseases.
查看更多>>摘要：The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor progression.AMPK is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy stores.Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer.In this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)stiffness.We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness.This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKβ.Hippo kinases directly phosphorylate AMPKα at Thr172 to activate AMPK at low ECM stiffness.Furthermore,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival outcome.The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth.Together,these findings establish a novel model for AMPK regulation by the me-chanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.
查看更多>>摘要：MYBL2(MYB proto-oncogene like 2)is an emerging prognostic marker for malignant tumors,and its potential role in osteosarcoma and its relationship with immune infiltration in pan-cancer is yet to be elucidated.We constructed a transcription factor activity profile of os-teosarcoma using the single-cell regulatory network inference algorithm based on single-cell RNA sequencing data obtained from the Gene Expression Omnibus.Subsequently,we calcu-lated the extent of MYBL2 activation in malignant proliferative osteoblasts.We also explored the association between MYBL2 and chemotherapy resistance in osteosarcoma.Furthermore,we systematically correlated MYBL2 with immunological signatures in the tumor microenviron-ment in pan-cancer,including immune cell infiltration,immune checkpoints,and tumor immu-notherapy prognosis.Finally,we developed and validated a risk score(MRGS),derived an osteosarcoma risk score nomogram based on MRGS,and tested its ability to predict prognosis.MYBL2 and gene enrichment analyses in osteosarcoma and pan-cancer revealed that MYBL2 was positively correlated with cell proliferation and tumor immune pathways.MYBL2 expres-sion positively correlated with SLC19A1 in pan-cancer and osteosarcoma cell lines.Pan-cancer immune infiltration analysis revealed that MYBL2 was correlated with myeloid-derived sup-pressor cells,Th2 cell infiltration,CD276,RELT gene expression,and tumor mutation burden.In summary,MYBL2 regulates proliferation,progression,and immune infiltration in osteosar-coma and pan-cancer.Therefore,we found that MYBL2 could be used as a potential marker for predicting the osteosarcoma prognosis.Patients with osteosarcoma and high MYBL2 expres-sion are theoretically more sensitive to methotrexate.An osteosarcoma prognostic nomogram can provide new ideas in the search for osteosarcoma prognostic markers.
查看更多>>摘要：Osteosarcoma is a differentiation-deficient disease,and despite the unique advan-tages and great potential of differentiation therapy,there are only a few known differentia-tion inducers,and little research has been done on their targets.Cell differentiation is associated with an increase in mitochondrial content and activity.The metabolism of some tu-mor cells is characterized by impaired oxidative phosphorylation,as well as up-regulation of aerobic glycolysis and pentose phosphate pathways.Leucine-containing zipper and EF-hand transmembrane protein 1(LETM1)is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression,as well as cancer cell stemness.We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function.Knockdown of LETM1 partially restored the mitochon-drial structure and function,inhibited the pentose phosphate pathway,promoted oxidative phosphorylation,and led to osteogenic differentiation.It also inhibited spheroid cell forma-tion,proliferation,migration,and invasion in an in vitro model.When LETM1 was knocked down in vivo,there was reduced tumor formation and lung metastasis.These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells,and knockdown of LETM1 partially restores the mitochondrial structure and function,inhibits the pentose phosphate pathway,promotes oxidative phosphorylation,and increases osteogenic differenti-ation,thereby reducing malignant biological behavior of the cells.
查看更多>>摘要：Glioma is a common tumor originating in the brain that has a high mortality rate.Temozolomide(TMZ)is the first-line treatment for high-grade gliomas.However,a large pro-portion of gliomas are resistant to TMZ,posing a great challenge to their treatment.In the study,the specific functions and mechanism(s)by which cortistatin(CORT)regulates TMZ resis-tance and glioma progression were evaluated.The decreased expression of CORT was detected in glioma tissues,and highly expressed CORT was associated with a better survival rate in pa-tients with glioma.CORT overexpression notably decreased the capacity of glioma cells to pro-liferate and migrate in vitro and to form tumors in vivo.CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT,p21,and Puma expression.Importantly,CORT overexpression reduced the resistance of gliomas to TMZ in vivo.CORT expression was negatively correlated with MGMT expression in both glioma tissues and cells,and it was found that CORT inhibited NF-KB pathway activation in glioma cells,thereby inhibiting MGMT expression.In conclusion,CORT regulates glioma cell growth,migration,apoptosis,and TMZ resistance by weakening the activity of NF-κB/p65 and thereby regulating MGMT expression.The CORT/NF-κB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ.Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells,independent of its effects on TMZ resistance,providing evidence of novel therapeutic targets for glioma that should be evaluated in further studies.
查看更多>>摘要：Ovarian cancer is the tumor with the highest mortality among gynecological malig-nancies.Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages(TAMs)in the microenvironment.Colony-stimu-lating factor 1(CSF-1)receptor(CSF-1R)plays a key role in regulating the number and differ-entiation of macrophages in certain solid tumors.There are few reports on the effects of targeted inhibition of CSF-1 R in combination with chemotherapy on ovarian cancer and the tu-mor microenvironment.Here,we explored the antitumor efficacy and possible mechanisms of the CSF-1R inhibitor pexidartinib(PLX3397)when combined with the first-line chemothera-peutic agent paclitaxel in the treatment of ovarian cancer.We found that CSF-1 R is highly ex-pressed in ovarian cancer cells and correlates with poor prognosis.Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo.Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.
查看更多>>摘要：The factors that determine fibrosis progression or normal tissue repair are largely unknown.We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Ⅱ(ATⅡ)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling.Here,we report that liver kinase B1(LKB1)inactivation in ATⅡ cells inhibits autophagy and induces EMT as a conse-quence.In IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATⅡ cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATⅡ cells and fibroblasts augmented myofibroblast differentiation.Together,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATⅡ cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.
查看更多>>摘要：Capsular contracture is a prevalent and severe complication that affects the post-operative outcomes of patients who receive silicone breast implants.At present,prosthesis replacement is the major treatment for capsular contracture after both breast augmentation procedures and breast reconstruction following breast cancer surgery.However,the mecha-nism(s)underlying breast capsular contracture remains unclear.This study aimed to identify the biological features of breast capsular contracture and reveal the potential underlying mechanism using RNA sequencing.Sample tissues from 12 female patients(15 breast capsules)were divided into low capsular contracture(LCC)and high capsular contracture(HCC)groups based on the Baker grades.Subsequently,41 lipid metabolism-related genes were identified through enrichment analysis,and three of these genes were identified as candidate genes by SVM-RFE and LASSO algorithms.We then compared the proportions of the 22 types of im-mune cells between the LCC and HCC groups using a CIBERSORT analysis and explored the cor-relation between the candidate hub features and immune cells.Notably,PRKAR2B was positively correlated with the differentially clustered immune cells,which were M1 macro-phages and follicular helper T cells(area under the ROC=0.786).In addition,the expression of PRKAR2B at the mRNA or protein level was lower in the HCC group than in the LCC group.Potential molecular mechanisms were identified based on the expression levels in the high and low PRKAR2B groups.Our findings indicate that PRKAR2B is a novel diagnostic biomarker for breast capsular contracture and might also influence the grade and progression of capsular contracture.
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