Mesenchymal-epithelial Transition Factor Regulates Monocyte Function during Mycobacterial Infection via Indoleamine 2,3-dioxygenase

Objective Mycobacterium tuberculosis(Mtb),the causative agent of tuberculosis(TB),causes an estimated 1.6 million human deaths annually,but the pathogenesis of TB remains unclear.Immunity plays a critical role in the onset and outcome of TB.This study aimed to uncover the roles of innate and adaptive immunity in TB.Methods The gene expression profiles generated by RNA sequencing from human peripheral blood mononuclear cells(PBMCs)stimulated with or without Mtb strain H37Rv antigens were analyzed.A total of 973 differentially expressed mRNAs were identified.Results The differentially expressed genes were enriched in innate immunity signaling functions.The mesenchymal-epithelial transition factor(MET)gene was significantly upregulated in CD14^(+)monocytes.A MET inhibitor improved the uptake of the BCG strain by monocytes and macrophages as well as inhibited the expression of indoleamine 2,3-dioxygenase(IDO).The expression of IDO was increased in PBMCs stimulated with Mtb antigens,and the IDO inhibitor promoted the expression of CD40,CD83,and CD86.Conclusion Our results might provide clues regarding the immunomodulatory mechanisms used by Mtb to evade the host defense system.

Variations in mesenchymal-epithelial transition-related transcription factors during reprogramming of somatic cells from different germ layers into iPSCs

Introducing a combination of transcription factors such as Oct4,Sox2,Klf4 and c-Myc（OSKM）enables reprogramming which converts somatic cells into induced pluripotent stem cells（i PSCs）（Takahashi and Yamanaka,2006）.i PSCs play an important role in clinical and regenerative medicine because they can be utilized to model a specific disease or differentiate into functional cells for transplantation.Enhancing the efficiency of induction and improving the qualities of iPSCs are constant themes in this field.

Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer:A focus on biological mechanisms and therapeutic opportunities

The liver is the most common site of metastases in patients with colorectal cancer.Colorectal liver metastases(CRLMs)are the result of molecular mechanisms that involve different cells of the liver microenvironment.The aberrant activation of Wingless/It(Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium,but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymalepithelial transition interactions.In liver microenvironment,metastatic cells can also survive and adapt through dormancy,which makes them less susceptible to pro-apoptotic signals and therapies.Treatment of CRLMs is challenging due to its variability and heterogeneity.Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been recognized in chemoresistance.At the state of art,there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie.In this review,current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered.In addition,an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.

Isolated lymphoid follicles in colon: Switch points between inflammation and colorectal cancer?

Gut-associated lymphoid tissue is supposed to play a central role in both the organization of colonic repair mechanisms and colorectal carcinogenesis. In inflammatory conditions, the number, diameter and density of isolated lymphoid follicles (ILFs) increases. They are not only involved in immune surveillance, but their presence is also indispensable in normal mucosal regeneration of the colon. In carcinogenesis, ILFs may play a dual role. On the one hand they may support tumor growth and the metastatic process by vascular endothelial growth factor receptor signaling and producing a specific cytokine and cellular milieu, but on the other hand their presence is sometimes associated with a better prognosis. The relation of ILFs to bone marrow derived stem cells, follicular dendritic cells, subepithelial myofibroblasts or crypt formation, which are all involved in mucosal repair and carcinogenesis, has not been directly studied. Data about the putative organizer role of ILFs is scattered in scientific literature.

Hepatocyte differentiation of human fibroblasts from cirrhotic liver in vitro and in vivo

BACKGROUND:Mesenchymal stem cells(MSCs)and fibro-blasts have intimate relationships,and the phenotypic homology between fibroblasts and MSCs has been recently described.The aim of this study was to investigate the hepatic differentiating potential of human fibroblasts in cirrhotic liver. METHODS:The phenotypes of fibroblasts in cirrhotic liver were labeled by biological methods.After that,the differentiation potential of these fibroblasts in vitro was characterized in terms of liver-specific gene and protein expression.Finally,an animal model of hepatocyte regeneration in severe combined immunodeficient(SCID)mice was created by retrorsine injection and partial hepatectomy,and the expression of human hepatocyte proteins in SCID mouse livers was checked by immunohistochemical analysis after fibroblast administration. RESULTS:Surface immunophenotyping revealed that a minority of fibroblasts expressed markers of MSCs and hepatic epithelial cytokeratins as well as alpha-smooth muscle actin, but homogeneously expressed vimentin,desmin,prolyl 4-hydroxylase and fibronectin.These fibroblasts presented the characteristics of hepatocytes in vitro and differentiated directly into functional hepatocytes in the liver of hepatecto-mized SCID mice.CONCLUSIONS:This study demonstrated that fibroblasts in cirrhotic liver have the potential to differentiate into hepatocyte-like cells in vitro and in vivo.Our findings infer that hepatic differentiation of fibroblasts may serve as a new target for reversion of liver fibrosis and a cell source for tissue engineering.

Re-evaluating the role of epithelial-mesenchymal-transition in cancer progression

Epithelial-mesenchymal transition（EMT） and mesenchymal-epithelial transition（MET） are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymallike cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal（E/M） tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.

Effective response to crizotinib of concurrent KIF5B-MET and MET-CDR2-rearranged non-small cell lung cancer:A case report

BACKGROUND Due to the rarity of mesenchymal-epithelial transition factor(MET)fusions,the clinical efficacy of crizotinib has only been described in a few patients with MET fusions involving various fusion partners.Herein,we report the clinical response to crizotinib of a patient with advanced poorly differentiated non-small cell carcinoma(NSCLC)having concurrent MET fusions.CASE SUMMARY A 46-year-old woman was diagnosed with poorly differentiated NSCLC(T4 N3 M1).With no classic driver mutations,she was treated with two cycles of gemcitabine and cisplatin without clinical benefit.Targeted sequencing revealed the detection of two concurrent MET fusions,KIF5 B-MET and novel MET-CDR2.Crizotinib was initiated at a dose of 250 mg twice daily.Within 4 wk of crizotinib therapy,repeat computed chromatography revealed a dramatic reduction in primary and metastatic lesions,assessed as partial response.She continued to benefit from crizotinib for 3 mo until disease progression and died within 1 mo despite receiving nivolumab therapy.CONCLUSION Crizotinib sensitivity was observed in an advanced poorly differentiated NSCLC patient with concurrent MET fusions KIF5 B-MET and MET-CDR2.Crizotinib can serve as a therapeutic option for patients with MET fusions.In addition,our case also highlights the importance of comprehensive genomic profiling particularly in patients with no classic driver mutation for guiding alternative therapeutic decisions.

The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response

Background:Desmoplastic small round cell tumor(DSRCT)is a rare,aggressive,and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1(EWSR1)-Wilm’s tumor suppressor(WT1)translocation.We used whole-exome sequencing to interrogate six consecutive pretreated DSRCTs whose gene expression was previously investigated.Methods:DNA libraries were prepared from formalin-fixed,paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500.Raw sequence data were aligned to the reference genome with Burrows-Wheeler Aligner algorithm.Somatic mutations and copy number alterations(CNAs)were identified using MuTect2 and EXCAVATOR2,respectively.Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis(IPA)software.Results:A total of 137 unique somatic mutations were identified:133 mutated genes were case-specific,and 2 were mutated in two cases but in different positions.Among the 135 mutated genes,27%were related to two biological categories:DNA damage-response(DDR)network that was also identified through IPA and mesenchymal-epithelial reverse transition(MErT)/epithelial-mesenchymal transition(EMT)already demonstrated to be relevant in DSRCT.The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA.Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins,which were recently rec-ognized as a new class of DDR players.CNAs in genes/gene families,involved in MErT/EMT and DDR,were recurrent across patients and mostly segregated in the MErT/EMT category.In addition,recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded.Conclusions:The emerging picture is an extreme inter-tumor heterogeneity,characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.

Positive feedback between retinoic acid and 2-phospho-L-ascorbic acid trisodium salt during somatic cell reprogramming

Retinoic acid(RA)and 2-phospho-L-ascorbic acid trisodium salt(AscPNa)promote the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells.In the current studies,the lower abilities of RA and AscPNa to promote reprogramming in the presence of each other suggested that they may share downstream pathways at least partially.The hypothesis was further supported by the RNA-seq analysis which demonstrated a high-level overlap between RA-activated and AscPNa activated genes during reprogramming.In addition,RA upregulated Glut1/3,facilitated the membrane transportation of dehydroascorbic acid,the oxidized form of L-ascorbic acid,and subsequently maintained intracellular L-ascorbic acid at higher level and for longer time.On the other hand,AscPNa facilitated the mesenchymal-epithelial transition during reprogramming,downregulated key mesenchymal transcriptional factors like Zeb1 and Twist1,subsequently suppressed the expression of Cyp26a1/b1 which mediates the metabolism of RA,and sustained the intracellular level of RA.Furthermore,the different abilities of RA and AscPNa to induce mesenchymal-epithelial transition,pluripotency,and neuronal differentiation explain their complex contribution to reprogramming when used individually or in combination.Therefore,the current studies identified a positive feedback between RA and AscPNa,or possibility between vitamin A and C,and further explored their contributions to reprogramming.