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1.
Mol Cancer ; 19(1): 85, 2020 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-32384893

RESUMEN

BACKGROUND: Long noncoding RNAs (lncRNAs) play crucial roles in tumor progression and are aberrantly expressed in various cancers. However, the functional roles of lncRNAs in breast cancer remain largely unknown. METHODS: Based on public databases and integrating bioinformatics analyses, the overexpression of lncRNA BCRT1 in breast cancer tissues was detected and further validated in a cohort of breast cancer tissues. The effects of lncRNA BCRT1 on proliferation, migration, invasion and macrophage polarization were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA BCRT1, miR-1303, and PTBP3. Chromatin immunoprecipitation (ChIP) and RT-PCR were used to evaluate the regulatory effect of hypoxia-inducible factor-1α (HIF-1α) on lncRNA BCRT1. RESULTS: LncRNA BCRT1 was significantly upregulated in breast cancer tissues, which was correlated with poor prognosis in breast cancer patients. LncRNA BCRT1 knockdown remarkably suppressed tumor growth and metastasis in vitro and in vivo. Mechanistically, lncRNA BCRT1 could competitively bind with miR-1303 to prevent the degradation of its target gene PTBP3, which acts as a tumor-promoter in breast cancer. LncRNA BCRT1 overexpression could promote M2 polarization of macrophages, mediated by exosomes, which further accelerated breast cancer progression. Furthermore, lncRNA BCRT1 was upregulated in response to hypoxia, which was attributed to the binding of HIF-1α to HREs in the lncRNA BCRT1 promoter. CONCLUSIONS: Collectively, these results reveal a novel HIF-1α/lncRNA BCRT1/miR-1303/PTBP3 pathway for breast cancer progression and suggest that lncRNA BCRT1 might be a potential biomarker and therapeutic target for breast cancer.

2.
Artículo en Inglés | MEDLINE | ID: mdl-32415984

RESUMEN

OBJECTIVE: To evaluate patterns of insulin secretion in pregnancy and analyze the association between insulin patterns and risks of gestational diabetes mellitus (GDM). METHODS: A prospective study was conducted to collect and analyze pregnant women's materials from January 2015 to December 2018. Pregnant women were grouped according to results of 75-g oral glucose tolerance test at 24-28 weeks of pregnancy: normal glucose tolerance (NGT) and GDM. Insulin secretion patterns were based on the time of peak(s) and shape of insulin secretion curve. The relationship between insulin secretion patterns and pregnant outcomes was analyzed. RESULTS: A total of 2432 pregnant women met the inclusion criteria during the study period. Among them, 737 (30.3%) women were grouped as GDM and 1695 (69.7%) as NGT. Type I insulin secretion represented the early phase of insulin secretion (peak time at 30 minutes or 60 minutes), while type II represented the delayed peak of insulin secretion (peak time at 120 minutes or 180 minutes). Logistic regression analysis showed that type II insulin secretion was a risk factor of pre-eclampsia, large-for-gestational-age, and neonatal hypoglycemia. CONCLUSION: The delayed insulin peak is a useful marker for risk of GDM and adverse pregnant outcomes in women with GDM.

3.
Am J Pathol ; 2020 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-32416098

RESUMEN

Interleukin 17A (IL-17A) plays critical role in the pathogenesis of autoimmune diseases through driving inflammatory cascades. However, the role of IL-17 in osteoarthritis (OA) is not well understood. TNF receptor associated factor 3 (TRAF3) is a receptor proximal negative regulator of IL-17 signaling. Whether TRAF3 exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of OA is not well understood. In this study, we found that TRAF3 notably suppressed IL-17-induced NF-κB and MAPK activation and subsequent the production of matrix-degrading enzymes. On the contrary, TRAF3 depletion enhanced IL-17 signaling, along with increased matrix-degrading enzymes production. In vivo, cartilage destruction caused by surgery-induced OA was markedly alleviated both in IL-17A deficient mice (IL17a-/-) and TRAF3 transgenic mice (T3TG). In contrast, silencing TRAF3 through adenoviruses worsened cartilage degradation in experimental OA. Moreover, the destructive effect of IL-17 on cartilage was abolished in T3TG mice in an IL-17 intra-articular (IA) injection animal model. Similarly, genetic deletion of IL-17 blocked TRAF3 knock down-mediated promotion of cartilage destruction, which suggests that the protective effect of TRAF3 on cartilage is mediated by its suppression of IL-17 signaling. Collectively, our results suggest that TRAF3 is critical in negative regulation of IL-17-mediated cartilage degradation and pathogenesis of OA, and may serve as a potential new therapy target for OA.

4.
ACS Chem Biol ; 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32364699

RESUMEN

Post-transcriptional modifications are intrinsic to RNA structure and function. However, methods to sequence RNA typically require a cDNA intermediate and are either not able to sequence these modifications or are tailored to sequence one specific nucleotide modification only. Interestingly, some of these modifications occur with <100% frequency at their particular sites, and site-specific quantification of their stoichiometries is another challenge. Here, we report a direct method for sequencing tRNAPhe without cDNA by integrating a two-dimensional hydrophobic RNA end-labeling strategy with an anchor-based algorithm in mass spectrometry-based sequencing (2D-HELS-AA MS Seq). The entire tRNAPhe was sequenced and the identity, location, and stoichiometry of all eleven different RNA modifications was determined, five of which were not 100% modified, including a 2'-O-methylated G (Gm) in the wobble anticodon position as well as an N2, N2-dimethylguanosine (m22G), a 7-methylguanosine (m7G), a 1-methyladenosine (m1A), and a wybutosine (Y), suggesting numerous post-transcriptional regulations in tRNA. Two truncated isoforms at the 3'-CCA tail of the tRNAPhe (75 nt with a 3'-CC tail (80% abundance) and 74 nt with a 3'-C tail (3% abundance)) were identified in addition to the full-length 3'-CCA-tailed tRNAPhe (76 nt, 17% abundance). We discovered a new isoform with A-G transitions/editing at the 44 and 45 positions in the tRNAPhe variable loop, and discuss possible mechanisms related to the emergence and functions of the isoforms with these base transitions or editing. Our method revealed new isoforms, base modifications, and RNA editing as well as their stoichiometries in the tRNA that cannot be determined by current cDNA-based methods, opening new opportunities in the field of epitranscriptomics.

5.
J Agric Food Chem ; 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32423215

RESUMEN

Fried pepper (Zanthoxylum bungeanum Maxim.) oil has been widely used in traditional Chinese cuisine and has recently become increasingly popular in food manufacturing. Thus, the aroma profiles of Hancheng pepper oil (HCPO) and Hanyuan pepper oil (HYPO) from two regions were investigated by aroma extract dilution analysis (AEDA) combined with gas chromatography-mass spectrometry-olfactometry (GC-MS-O). Results from AEDA showed that more aroma compounds with flavor dilution (FD) factors of ≥9 were detected in the HCPO than in the HYPO. The odor activity values (OAVs) revealed 28 odorants with OAVs of ≥1 in HCPO or HYPO. High OAVs were in particular obtained for 1,8-cineole, (E)-2-heptenal, ß-myrcene, ß-ocimene, limonene and linalool. Then, the aroma profiles of HCPO and HYPO were successfully simulated through aroma recombination models. Omission tests suggested that ß-phellandrene, p-cymene, acetic acid octyl ester, octanal, citronellol and sabinene played key roles in aroma differences between HCPO and HYPO. In addition, varying enantiomeric ratios of linalool (floral) and limonene (citrus-like and lemon-like) in HCPO and HYPO were observed by chiral GC-MS, and the odor impressions of limonene and linalool were in good agreement with the odor descriptions of S-(-)-limonene and S-(+)-linalool.

6.
Genome Biol ; 21(1): 120, 2020 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-32423473

RESUMEN

BACKGROUND: Vertebrate early embryogenesis is initially directed by a set of maternal RNAs and proteins, yet the mechanisms controlling this program remain largely unknown. Recent transcriptome-wide studies on RNA structure have revealed its pervasive and crucial roles in RNA processing and functions, but whether and how RNA structure regulates the fate of the maternal transcriptome have yet to be determined. RESULTS: Here we establish the global map of four nucleotide-based mRNA structures by icSHAPE during zebrafish early embryogenesis. Strikingly, we observe that RNA structurally variable regions are enriched in the 3' UTR and contain cis-regulatory elements important for maternal-to-zygotic transition (MZT). We find that the RNA-binding protein Elavl1a stabilizes maternal mRNAs by binding to the cis-elements. Conversely, RNA structure formation suppresses Elavl1a's binding leading to the decay of its maternal targets. CONCLUSIONS: Our study finds that RNA structurally variable regions are enriched in mRNA 3' UTRs and contain cis-regulatory elements during zebrafish early embryogenesis. We reveal that Elavl1a regulates maternal RNA stability in an RNA structure-dependent fashion. Overall, our findings reveal a broad and fundamental role of RNA structure-based regulation in vertebrate early embryogenesis.

7.
Medicine (Baltimore) ; 99(18): e19964, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32358368

RESUMEN

RATIONALE: Holocarboxylase synthetase (HCLS) deficiency, especially the late-onset type, is a rare disease. Affected patients can present with irreversible metabolic acidosis and may be misdiagnosed with a glucose metabolic disorder. Prompt and correct diagnosis and treatment can reduce mortality to a great extent. PATIENT CONCERNS: We report 2 Chinese patients who were diagnosed with late-onset HCLS deficiency. The age of onset of the 2 patients was approximately 8 months. The 2 patients had skin lesions, severe profound metabolic acidosis, dyspnea, and hyperglycemia. DIAGNOSES: The results of urinary and blood organic acid analysis with gas chromatography/mass spectrometry revealed multiple carboxylase deficiency. Maple syrup urine disease and diabetic ketoacidosis could not be excluded. This finding is different from those of hypoglycemic complications reported in previous reports. Human genetic analysis eventually provided a definite diagnosis. INTERVENTIONS: Prompt oral treatment with biotin dramatically corrected the metabolic imbalances of the 2 patients, and continued oral biotin therapy was essential to the improvement of their prognoses. OUTCOMES: Their metabolic disorders were corrected within 48 hours. During long-term follow-up, the patients achieved developmental milestones. LESSONS: Late-onset HCLS deficiency may present with obvious hyperglycemia. Human genetic analysis eventually provided a definite diagnosis. Prompt treatment with biotin is vital to correct metabolic imbalances, and continued therapy is essential to the improving long-term prognoses. Their mutations were p.R508W and c.1088T > A, and these mutations might represent hot-spot genes in Chinese populations with HCLS deficiency. The variants c.1484T > G(p.L495*) and c.835G > T(p.E279x) are likely pathogenic, and more studies are needed to confirm these results.

8.
Artículo en Inglés | MEDLINE | ID: mdl-32349478

RESUMEN

Graphene membranes with subnanopores are considered to be the next-generation materials for water desalination and ion separation, while their performance is mainly determined by the relative ion selectivity of the pores. However, the origin of this phenomenon has been controversial in the past few years, which strongly limits the development of related applications. Here, using direct Au ion bombardment, we fabricated the desired subnanopores with average diameters of 0.8 ± 0.16 nm in monolayer graphene. The pores showed the ability to sieve K+, Na+, Li+, Cs+, Mg2+, and Ca2+ cations, and the observed K+/Mg2+ selectivity ratio was over 4. With further molecular dynamics simulations, we demonstrated that the ion selectivity is primarily attributed to the dehydration process of ions that can be quantitatively described by the ion-dependent free-energy barriers. Hopefully, this work is helpful in further enhancing the ion selectivity of graphene nanopores and also presenting a new paradigm for improving the performance of other nanoporous atomically thin membranes, such as MXenes and MoS2.

9.
J Biomed Mater Res A ; 2020 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-32363683

RESUMEN

Mesenchymal stem cell (MSC)-based therapy is a promising strategy for bone repair. Furthermore, the innate immune system, and specifically macrophages, plays a crucial role in the differentiation and activation of MSCs. The anti-inflammatory cytokine Interleukin-4 (IL-4) converts pro-inflammatory M1 macrophages into a tissue regenerative M2 phenotype, which enhances MSC differentiation and function. We developed lentivirus-transduced IL-4 overexpressing MSCs (IL-4 MSCs) that continuously produce IL-4 and polarize macrophages toward an M2 phenotype. In the current study, we investigated the potential of IL-4 MSCs delivered using a macroporous gelatin-based microribbon (µRB) scaffold for healing of critical-size long bone defects in Mice. IL-4 MSCs within µRBs enhanced M2 marker expression without inhibiting M1 marker expression in the early phase, and increased macrophage migration into the scaffold. Six weeks after establishing the bone defect, IL-4 MSCs within µRBs enhanced bone formation and helped bridge the long bone defect. IL-4 MSCs delivered using macroporous µRB scaffold is potentially a valuable strategy for the treatment of critical-size long bone defects.

10.
J Int Med Res ; 48(5): 300060520914218, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32419546

RESUMEN

OBJECTIVES: Danshensu is a traditional Chinese medicine that is used for treatment of cardiovascular diseases. We previously demonstrated its preventive effect against early-stage hypoxic pulmonary hypertension (HPH) in a rat model. To determine whether danshensu treatment might be useful for patients with chronic HPH, we examined its therapeutic effect in rats with prolonged HPH. METHODS: Adult Sprague-Dawley rats received danshensu (80, 160, and 320 mg/kg) during or after hypoxia exposure to assess preventive and therapeutic effects, respectively. Right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI), and mean left carotid artery pressure (mCAP) were measured in each group. Western blotting was used to assess transforming growth factor (TGF)-ß expression levels in rats and cultured cells exposed to hypoxia. RESULTS: Preventive danshensu treatment significantly reduced the elevation of RVSP and RVHI in rats exposed to hypoxia, whereas therapeutic danshensu treatment did not; mCAP did not change in any treatment group. The increased expression levels of TGF-ß induced by hypoxia were inhibited by preventive danshensu treatment, but not by therapeutic danshensu treatment. CONCLUSIONS: Although danshensu treatment could prevent HPH, it had no obvious therapeutic effect after development of HPH. Therefore, danshensu might be suitable for clinical treatment of early-stage HPH.

11.
Clin Exp Med ; 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32350633

RESUMEN

This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated with the risk of lung cancer development. A case-control study was conducted among 510 patients with pathologically confirmed lung cancer as the case group and 504 healthy individuals as the control group. Four single-nucleotide polymorphisms of the CYP4F2 and CYP3A5 genes were genotyped, and their correlations with the risk of lung cancer were examined using Chi-square test and logistic regression analysis. Stratified analysis found that the rs3093105 and rs3093106 loci of CYP4F2 gene were significantly associated with lower risk of lung cancer (P = 0.012, OR 0.64, 95% CI 0.45-0.91). The correlation was related to patients' age and sex and pathological type of lung cancer. Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P = 0.018, OR 0.71, 95% CI 0.53-0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (dominant: OR 0.66, 95% CI 0.46-0.94, P = 0.021; additive: OR 0.71, 95% CI 0.53-0.95, P = 0.023). CYP4F2 and CYP3A5 gene polymorphisms are associated with the reduced risk of non-small cell lung cancer, and its correlation is related to patients' age and sex and pathological type of lung cancer.

12.
Plant Physiol ; 2020 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-32371523

RESUMEN

Wall-associated kinases (Waks) are important components of plant immunity against various pathogens, including the bacterium Pseudomonas syringae pv. tomato (Pst). However, the molecular mechanisms of their role(s) in plant immunity are largely unknown. In tomato (Solanum lycopersicum), wall-associated kinase 1, SlWak1, has been implicated in pattern recognition receptor (PRR)-triggered immunity (PTI) because its transcript abundance increases significantly after treatment with the flagellin-derived, microbe-associated molecular patterns (MAMPs) flg22 and flgII-28, which activate the PRRs Fls2 and Fls3, respectively. We generated two SlWak1 tomato mutants (Δwak1) using CRISPR/Cas9 gene editing technology and investigated the role of SlWak1 in tomato-Pst interactions. Late PTI responses activated in the apoplast by flg22 or flgII-28 were compromised in Δwak1 plants, but PTI at the leaf surface was unaffected. The Δwak1 plants developed fewer callose deposits than wild-type plants, but retained early PTI responses such as generation of reactive oxygen species and activation of mitogen-activated protein kinases (MAPKs) upon exposure to flg22 and flgII-28. Induction of Wak1 gene expression by flg22 and flgII-28 was greatly reduced in a tomato mutant lacking Fls2 and Fls3, but induction of Fls3 gene expression by flgII-28 was unaffected in Δwak1 plants. After Pst inoculation, Δwak1 plants developed disease symptoms more slowly than Δfls2.1/2.2/3 mutant plants, although ultimately, both plants were similarly susceptible. SlWak1 co-immunoprecipitated with both Fls2 and Fls3, independently of flg22/flgII-28 or of BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE 1 (BAK1). These observations suggest that SlWak1 acts in a complex with Fls2/Fls3 and is important at later stages of PTI in the apoplast.

14.
Food Chem ; 326: 126904, 2020 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-32413765

RESUMEN

In this paper, the interaction of silkworm pupae protein (SPP) with cyanidin-3-O-glucoside (C3G) was studied the protective anthocyanins stability. Characterization experiments suggested that C3G-SPP complexes mainly through hydrophobic interactions, with a decrease in the α-helix content and increases in the ß-sheet and ß-turn contents. Fluorescence results revealed that C3G quenched the intrinsic fluorescence of SPP by static quenching. The highest quenching constant, Kq, was recorded to be1.26 × 1012 M-1s-1 for the SPP preheated at 80 °C. Following the C3G-SPP complexes, the degradation rate constant decreased, and the half-life of C3G was prolonged from 64.81 ± 1.07 to 261.99 ± 13.32 min at 80 °C (p < 0.05). The SPP preheated at 80 °C exhibited the highest binding affinity towards C3G and also effectively increased the thermal and oxidative stability of the C3G. The obtained results suggest that the novel protein proposed in this study could expand the application of anthocyanins as stable, functional food ingredients.

15.
Biomed Res Int ; 2020: 2471915, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32420331

RESUMEN

Tobacco exposure is one of the major risks for the initiation and progress of lung cancer. The exact corresponding mechanisms, however, are mainly unknown. Recently, a growing body of evidence has been collected supporting the involvement of DNA methylation in the regulation of gene expression in cancer cells. The identification of tobacco-related signature methylation probes and the analysis of their regulatory networks at different molecular levels may be of a great help for understanding tobacco-related tumorigenesis. Three independent lung adenocarcinoma (LUAD) datasets were used to train and validate the tobacco exposure pattern classification model. A deep selecting method was proposed and used to identify methylation signature probes from hundreds of thousands of the whole epigenome probes. Then, BIMC (biweight midcorrelation coefficient) algorithm, SRC (Spearman's rank correlation) analysis, and shortest path tracing method were explored to identify associated genes at gene regulation level and protein-protein interaction level, respectively. Afterwards, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and GO (Gene Ontology) enrichment analysis were used to analyze their molecular functions and associated pathways. 105 probes were identified as tobacco-related DNA methylation signatures. They belong to 95 genes which are involved in hsa04512, hsa04151, and other important pathways. At gene regulation level, 33 genes are uncovered to be highly related to signature probes by both BIMC and SRC methods. Among them, FARSB and other eight genes were uncovered as Hub genes in the gene regulatory network. Meanwhile, the PPI network about these 33 genes showed that MAGOH, FYN, and other five genes were the most connected core genes among them. These analysis results may provide clues for a clear biological interpretation in the molecular mechanism of tumorigenesis. Moreover, the identified signature probes may serve as potential drug targets for the precision medicine of LUAD.

16.
Pharmacol Res ; : 104844, 2020 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-32438035

RESUMEN

Glutamine metabolism, described as major energy and building blocks supply to cell growth, has gained great attention. Alanine-Serine-Cysteine Transporter (ASCT2), which belongs to solute carried (SLC) family transporters and is encoded by the SLC1A5 gene serves as a significant role for glutamine transport. Indeed, ASCT2 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, ASCT2 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that ASCT2 inhibitors can provide a benefit strategy for cancer therapy. Herein, we describe the structure of ASCT2, and summarize its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for ASCT2 inhibitors. On the basis of case studies, our perspectives for targeting ASCT2 and development of ASCT2 antagonist are discussed in the final part.

17.
J Invest Surg ; : 1-9, 2020 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-32404009

RESUMEN

Objective: To compare the incidence of postmenstrual bleeding after hysteroscopic resection versus laparoscopic repair of previous cesarean scar defect (PCSD).Materials and methods: Retrospective analysis of computerized patient records. For the diagnosis of PCSD, patients underwent transvaginal ultrasound first without and then with saline-assisted sonohysterography. Hysteroscopic PCSD resection was performed under sonographic guidance, while laparoscopic repair was guided by hysteroscopy for the confirmation of scar margins.Results: Records of 62 patients presenting with PCSD-related postmenstrual bleeding were included in analysis. Hysteroscopic surgery had significantly shorter operative time compared to the laparoscopic approach (Mean =30.9 vs 71.0 minutes; p < 0.001). Blood loss and hospital stay were significantly less (p < 0.001) in hysteroscopic resection (10.4 ± 4.6 ml and 2.1 ± 0.4 days) than in laparoscopic repair (36.6 ± 4 ml, and 4.6 ± 1 days). After surgical interventions, the postmenstrual bleeding was resolved or improved. The effectiveness rates of hysteroscopic resection and laparoscopic repair were 91.4% and 96.3%, respectively. Incidence of post-treatment postmenstrual bleeding was not significantly different between hysteroscopy and laparoscopy (OR= 1.29 [95% confidence interval 0.367, 4.86]; p = 0.662). Pretreatment postmenstrual bleeding was associated with time since cesarean section (B= -0.091 [-0.158, -0.023]; p = 0.01) and PCSD length (B = 0.502 [0.085, 0.919]; p = 0.019).Conclusion: Both hysteroscopic resection and laparoscopic repair of PCSD yield comparable efficacy in reducing postmenstrual bleeding. However, hysteoroscopic resection of PCSD is associated with comparatively shorter operative time, less blood loss, and shorter hospital stay.

18.
FEBS Open Bio ; 2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32433824

RESUMEN

Post-transcriptional modification of mRNA sequences through RNA editing can increase transcriptome and proteome diversity in eukaryotes. Studies of fetal and adult tissues showed that A-to-I RNA editing plays a crucial role in early human development, but there is a lack of global understanding of dynamic RNA editing during mammalian early embryonic development. Therefore, here we used RNA sequence data from human, pig, and mouse during early embryonic development to detect edited genes that may regulate stem cell pluripotency. We observed that although most of the RNA editing sites are located in intergenic, intron and untranslated regions (UTR), a few editing sites are in coding regions (CDS), and may result in non-synonymous amino acid changes. Some editing sites are predicted to change the structure of a protein. We also report that HNF1A, TBX3, ACLY, ECI1 and ERDR1 are related to embryonic development and cell division.

19.
JCI Insight ; 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32427590

RESUMEN

Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by LGR5 expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human MUC1-transgenic mouse models of CACC that targeting the MUC1-C oncogenic protein, which is upregulated in inflammation, suppresses the (i) Lgr5+ ISC population, (ii) induction of Myc and core pluripotency stem cell factors, and (iii) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter and activates LGR5 expression. We also show in CRC cells that MUC1-C induces the cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2 and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a previously unrecognized target that is druggable for treating progression of colitis and CRC.

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