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1.
Mol Pharm ; 19(2): 558-567, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34958576

RESUMO

Stapled peptides are a promising class of conformationally restricted peptides for modulating protein-protein interactions (PPIs). However, the low membrane permeability of these peptides is an obstacle to their therapeutic applications. It is common that only a few hydrophobic amino acid residues are mandatory for stapled peptides to bind to their target proteins. Hoping to create a novel class of membrane-permeable PPI inhibitors, the phenylalanine, tryptophan, and leucine residues that play a critical role in inhibiting the p53-HDM2 interaction were grafted into the framework of CADY2─a cell-penetrating peptide (CPP) having a helical propensity. Two analogues (CADY-3FWL and CADY-10FWL) induced apoptotic cell death but lacked the intended HDM2 interaction. Pull-down experiments followed by proteomic analysis led to the elucidation of nesprin-2 as a candidate binding target. Nesprin-2 is considered to play a role in the nuclear translocation of ß-catenin upon activation of the Wnt signaling pathway, which leads to the expression of antiapoptosis proteins and cell survival. Cells treated with the two analogues showed decreased nuclear localization of ß-catenin and reduced mRNA expression of related antiapoptotic proteins. These data suggest inhibition of ß-catenin nuclear translocation as a possible mode of action of the described cell-penetrating stapled peptides.


Assuntos
Peptídeos Penetradores de Células , Aminoácidos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Proteômica , Via de Sinalização Wnt
2.
Dis Markers ; 2022: 1442441, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35531470

RESUMO

Endometrial cancer (EC) is the most common gynaecologic malignancy in the developed countries. Recent evidence suggests that histopathological subtyping together with molecular subgrouping can lead to more accurate assessment of the risk profile for the patient. Clinical studies suggest the currently used molecular classification improves the risk assessment of women with endometrial cancer but does not explain the differences in recurrence profiles clearly. This could be improved by novel markers. One of such are mutations in the ß-catenin (CTNNB1) gene, a frequently mutated gene in endometrial cancer. This shows mutations mostly at phosphorylation sites of the ß-catenin and almost exclusively in the endometrial subgroup of no specific molecular profile. CTNNB1 mutations lead to alterations in the Wnt/ß-catenin signalling pathway, involved in the carcinogenesis and progression of EC by inducing transcription of target genes, whose function is to regulate the cell cycle. Although tumours with mutations in CTNNB1 tend to have low-risk characteristics, they are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival.


Assuntos
Neoplasias do Endométrio , beta Catenina , Neoplasias do Endométrio/patologia , Feminino , Humanos , Mutação , Recidiva Local de Neoplasia/genética , Via de Sinalização Wnt , beta Catenina/genética
3.
Cell Mol Life Sci ; 79(5): 280, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35507080

RESUMO

Zinc-finger proteins (ZNFs) constitute the largest transcription factor family in the human genome. The family functions in many important biological processes involved in tumorigenesis. In our research, we identified ZNF334 as a novel tumor suppressor of triple-negative breast cancer (TNBC). ZNF334 expression was usually reduced in breast cancerv (BrCa) tissues and TNBC cell lines MDA-MB-231 (MB231) and YCCB1. We observed that promoter hypermethylation of ZNF334 was common in BrCa cell lines and tissues, which was likely responsible for its reduced expression. Ectopic expression of ZNF334 in TNBC cell lines MB231 and YCCB1 could suppress their growth and metastatic capacity both in vitro and in vivo, and as well induce cell cycle arrest at S phase and cell apoptosis. Moreover, re-expression of ZNF334 in TNBC cell lines could rescue Epithelial-Mesenchymal Transition (EMT) process and restrain stemness, due to up-regulation of SFRP1, which is an antagonist of Wnt/ß-catenin signaling. In conclusion, we verified that ZNF334 had a suppressive function of TNBC cell lines by targeting the SFRP1/Wnt/ß-catenin signaling axis, which might have the potentials to become a new biomarker for diagnosis and treatment of TNBC patients.


Assuntos
Neoplasias de Mama Triplo Negativas , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana , Neoplasias de Mama Triplo Negativas/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
4.
Sci Rep ; 12(1): 7217, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508623

RESUMO

Type 2 diabetes mellitus (T2DM) patients have compromised mandibular bone architecture/quality, which markedly increase the risks of tooth loosening, tooth loss, and failure of dental implantation. However, it remains lacks effective and safe countermeasures against T2DM-related mandibular bone deterioration. Herein, we studied the effects of pulsed electromagnetic fields (PEMF) on mandibular bone microstructure/quality and relevant regulatory mechanisms in T2DM db/db mice. PEMF exposure (20 Gs, 15 Hz) for 12 weeks preserved trabecular bone architecture, increased cortical bone thickness, improved material properties and stimulated bone anabolism in mandibles of db/db mice. PEMF also upregulated the expression of canonical Wnt3a ligand (but not Wnt1 or Wnt5a) and its downstream ß-catenin. PEMF improved the viability and differentiation of primary osteoblasts isolated from the db/db mouse mandible, and stimulated the specific activation of Wnt3a/ß-catenin signaling. These positive effects of PEMF on mandibular osteoblasts of db/db mice were almost totally abolished after Wnt3a silencing in vitro, which were equivalent to the effects following blockade of canonical Wnt signaling using the broad-spectrum antagonist DKK1. Injection with Wnt3a siRNA abrogated the therapeutic effects of PEMF on mandibular bone quantity/quality and bone anabolism in db/db mice. Our study indicates that PEMF might become a non-invasive and safe treatment alternative resisting mandibular bone deterioration in T2DM patients, which is helpful for protecting teeth from loosening/loss and securing the dental implant stability.


Assuntos
Diabetes Mellitus Tipo 2 , beta Catenina , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Campos Eletromagnéticos , Humanos , Mandíbula/metabolismo , Camundongos , Via de Sinalização Wnt/fisiologia , Proteína Wnt3A , beta Catenina/metabolismo
5.
J Transl Med ; 20(1): 194, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35509083

RESUMO

OBJECTIVE: Knowledge of the role of CYP2E1 in hepatocarcinogenesis is largely based on epidemiological and animal studies, with a primary focus on the role of CYP2E1 in metabolic activation of procarcinogens. Few studies have directly assessed the effects of CYP2E1 on HCC malignant phenotypes. METHODS: The expression of CYP2E1 in HCC tissues was determined by qRT-PCR, western blotting and immunohistochemistry. Overexpression of CYP2E1 in HCC cell was achieved by lentivirus transfection. The function of CYP2E1 were detected by CCK-8, wound healing, transwell assays, xenograft models and pulmonary metastasis model. TOP/FOPFlash reporter assay, western blotting, functional rescue experiments, Co-immunoprecipitation and reactive oxygen species detection were conducted to reveal the underlying mechanism of the tumor suppressive role of CYP2E1. RESULTS: CYP2E1 expression is down-regulated in HCC tissues, and this downregulation was associated with large tumor diameter, vascular invasion, poor differentiation, and shortened patient survival time. Ectopic expression of CYP2E1 inhibits the proliferation, invasion and migration and epithelial-to-mesenchymal transition of HCC cells in vitro, and inhibits tumor formation and lung metastasis in nude mice. Mechanistic investigations show that CYP2E1 overexpression significantly inhibited Wnt/ß-catenin signaling activity and decreased Dvl2 expression in HCC cells. An increase in Dvl2 expression restored the malignant phenotype of HCC cells. Notably, CYP2E1 promoted the ubiquitin-mediated degradation of Dvl2 by strengthening the interaction between Dvl2 and the E3 ubiquitin ligase KLHL12 in CYP2E1-stable HCC cells. CYP2E1-induced ROS accumulation was a critical upstream event in the Wnt/ß-Catenin pathway in CYP2E1-overexpressing HCC cells. CONCLUSIONS: These results provide novel insight into the role of CYP2E1 in HCC and the tumor suppressor role of CYP2E1 can be attributed to its ability to manipulate Wnt/Dvl2/ß-catenin pathway via inducing ROS accumulation, which provides a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Proteínas Desgrenhadas/genética , Proteínas Desgrenhadas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
6.
J Exp Clin Cancer Res ; 41(1): 168, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35524313

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. METHODS: Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. RESULTS: We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/ß-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/ß-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. CONCLUSIONS: Our findings elucidate WDR5/FOXM1/KIF23/Wnt/ß-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.


Assuntos
Proteína Forkhead Box M1 , Proteínas Associadas aos Microtúbulos , Neoplasias de Mama Triplo Negativas , Via de Sinalização Wnt , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , beta Catenina/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 47(9): 2400-2408, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35531687

RESUMO

Traditional Chinese medicine has unique advantages in the treatment of degenerative bone and joint diseases, and its widely used in clinical practice. In recent years, many scholars have conducted a large number of basic studies on the delay of intervertebral disc degeneration by herbal compound and monomeric components from different perspectives. In order to further elucidate its mechanism of action, this paper summarizes the in vivo and in vitro experimental studies conducted at the level of both herbal compound and single components, respectively, in order to provide references for the basic research on the treatment of lumbar intervertebral disc degeneration by Chinese medicine. A summary shows that commonly used herbal compound prescriptions include both classical prescriptions such as Duhuo Jisheng Decoction, as well as clinical experience prescriptions such as Yiqi Huoxue Recipe. Angelicae Sinensis Radix, Chuanxiong Rhizoma, Rehmanniae Radix Praeparata, Achyranthis Bidentatae Radix, and Eucommiae Cortex were used most frequently. Tonic for deficiency and blood stasis activators were used most frequently. The most utilized monomeric components include icariin, ginsenoside Re, salvianolic acid B and aucubin. The main molecular mechanisms by which herbal compound and monomeric components delay of lumbar intervertebral disc degeneration include improving the intervertebral disc microenvironment, promoting the synthesis of aggregated proteoglycans and type Ⅱ collagen in the intervertebral disc, reducing the degradation of the extracellular matrix, and inhibiting apoptosis in the nucleus pulposus cells, etc. The main signaling pathways involved include Wnt/ß-catenin signaling pathway, MAPK-related signaling pathway, mTOR signaling pathway, Fas/FasL signaling pathway, PI3 K/Akt signaling pathway, NF-κB signaling pathway, JAK/STAT signaling pathway, and hedgehog signaling pathway, etc.


Assuntos
Medicamentos de Ervas Chinesas , Degeneração do Disco Intervertebral , Núcleo Pulposo , China , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Hedgehog/metabolismo , Humanos , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Via de Sinalização Wnt
8.
Sci Rep ; 12(1): 7583, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534526

RESUMO

Osteoblast differentiation requires the interaction of various cell signaling pathways to modulate cell responses. Notch and Wnt signaling are among the crucial pathways that control numerous biological processes, including osteo/odontogenic differentiation. The aim of the present study was to examine the involvement of Wnt signaling in the Jagged1-induced osteo/odontogenic differentiation in human dental pulp stem cells (hDPSCs). The Wnt-related gene expression was analyzed from publicly available data of Jagged1-treated human dental pulp cells. The mRNA expression of Wnt ligands (WNT2B, WNT5A, WNT5B, and WNT16) and Wnt inhibitors (DKK1, DKK2, and SOST) were confirmed using real-time polymerase chain reaction. Among the Wnt ligands, WNT2B and WNT5A mRNA levels were upregulated after Jagged1 treatment. In contrast, the Wnt inhibitors DKK1, DKK2, and SOST mRNA levels were downregulated. Recombinant WNT5A, but not WNT2B, significantly promoted in vitro mineral deposition by hDPSCs. Wnt signaling inhibition using IWP-2, but not DKK1, inhibited Jagged1-induced alkaline phosphatase (ALP) activity, mineralization, and osteo/odontogenic marker gene expression in hDPSCs. In conclusion, Jagged1 promoted hDPSC osteo/odontogenic differentiation by modulating the non-canonical Wnt pathway.


Assuntos
Células-Tronco , Via de Sinalização Wnt , Diferenciação Celular , Células Cultivadas , Polpa Dentária , Humanos , Ligantes , Odontogênese , RNA Mensageiro/metabolismo
9.
Aquat Toxicol ; 247: 106180, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35490551

RESUMO

The posterior swim bladder is an important organ in teleost fishes, that primarily maintains buoyancy and motility for swimming and survival. In this study, we examined the molecular mechanisms of the toxicity of cadmium (Cd) on the early development of the swim bladder in zebrafish. Embryonic Cd exposure resulted in the non-inflation of the swim bladder when the ambient Cd concentration was greater than or equal to 0.25 mg/L. Cd disturbed surfactant lipid distribution and inhibited the formation of all three tissue layers in the swim bladder. Additionally, excessive Cd down-regulated Wnt (fzd3, nkd1, fzd7 and axin2) and Hedgehog (ihh, shh, ptc1 and ptc2) signaling pathways. Conversely, Wnt signaling activation partially neutralized Cd-induced swim bladder developmental defects. Moreover, ROS scavenger reduced Glutathione (GSH) effectively recovered Cd induced defects in swim bladder and Wnt/Hedgehog signaling. Taken together, our results first revealed that Cd caused swim bladder developmental defects via ROS-mediated inhibition of the Wnt and Hedgehog pathways. These results herein provide important data for future toxicological studies and risk assessments of Cd.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Cádmio/toxicidade , Embrião não Mamífero , Proteínas Hedgehog , Espécies Reativas de Oxigênio , Bexiga Urinária , Poluentes Químicos da Água/toxicidade , Via de Sinalização Wnt , Peixe-Zebra/fisiologia
10.
Elife ; 112022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35503096

RESUMO

Wnt/ß-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/ß-catenin signaling, as revealed by the Tcf/Lef-GFP reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that this ß-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.


Assuntos
Adipócitos , beta Catenina , Adipócitos/metabolismo , Adipogenia/fisiologia , Animais , Glucose/metabolismo , Mamíferos/metabolismo , Camundongos , Via de Sinalização Wnt/fisiologia , beta Catenina/genética , beta Catenina/metabolismo
11.
Commun Biol ; 5(1): 421, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513706

RESUMO

The Wnt signaling pathway plays a critical role in the developmental and physiological processes of metazoans. We previously reported that the Frizzled4 (FZD4) linker domain plays an important role in Norrin binding and signaling. However, the question remains whether the FZD linker contributes to Wnt signaling in general. Here, we show that the FZD linker is involved in Wnt binding and affects downstream Wnt signaling. A FZD4 chimera, in which the linker was swapped with that of the non-canonical receptor FZD6, impairs the binding with WNT3A and suppresses the recruitment of LRP6 and Disheveled, resulting in reduced canonical signaling. A similar effect was observed for non-canonical signaling. A FZD6 chimera containing the FZD1 linker showed reduced WNT5A binding and impaired signaling in ERK, JNK, and AKT mediated pathways. Altogether, our results suggest that the FZD linker plays an important role in specific Wnt binding and intracellular Wnt signaling.


Assuntos
Receptores Frizzled , Via de Sinalização Wnt , Proteínas de Transporte/metabolismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Domínios Proteicos , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
12.
Mol Cancer ; 21(1): 108, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513849

RESUMO

CircRNAs, covalently closed noncoding RNAs, are widely expressed in a wide range of species ranging from viruses to plants to mammals. CircRNAs were enriched in the Wnt pathway. Aberrant Wnt pathway activation is involved in the development of various types of cancers. Accumulating evidence indicates that the circRNA/Wnt axis modulates the expression of cancer-associated genes and then regulates cancer progression. Wnt pathway-related circRNA expression is obviously associated with many clinical characteristics. CircRNAs could regulate cell biological functions by interacting with the Wnt pathway. Moreover, Wnt pathway-related circRNAs are promising potential biomarkers for cancer diagnosis, prognosis evaluation, and treatment. In our review, we summarized the recent research progress on the role and clinical application of Wnt pathway-related circRNAs in tumorigenesis and progression.


Assuntos
Neoplasias , RNA Circular , Animais , Carcinogênese/genética , Humanos , Mamíferos/genética , Neoplasias/genética , RNA Circular/genética , RNA não Traduzido , Via de Sinalização Wnt
13.
Int J Biol Sci ; 18(7): 2807-2820, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541907

RESUMO

The self-renewal of spermatogonial stem cells (SSCs) requires a special microenvironment and is strictly controlled. Previously, we identified BMI1 as a key regulator of spermatogenesis in a knock-out mouse model. However, the mechanisms by which BMI1 regulates SSC maintenance remain largely unknown. Herein, we show that BMI1 is essential for SSC maintenance. BMI1 directs the transcriptional repression of target genes by increasing H2AK119ub and reducing H3K4me3 in SSCs. Furthermore, BMI1 inhibition resulted in the transcriptional activation of Wnt10b and thereby promoted the nuclear translocation of ß-catenin in SSCs. Importantly, the suppression of Wnt/ß-catenin signaling restored both the cytoplasmic expression of ß-catenin and SSC maintenance in BMI1-deficient SSCs. Finally, we demonstrated that Wnt/ß-catenin signaling was also involved in BMI1-mediated SSC maintenance in vivo. Altogether, our study not only reveals a novel mechanism for BMI1 in the process of SSC maintenance, but also provides a potential new strategy for treating male infertility.


Assuntos
Infertilidade Masculina , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas , Proteínas Wnt , beta Catenina , Animais , Proliferação de Células/genética , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espermatogênese/genética , Células-Tronco/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
14.
Clin Transl Med ; 12(5): e743, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35522902

RESUMO

BACKGROUND: To date, 5-fluorouracil-based chemotherapy is very important for locally advanced or metastatic colorectal cancer (CRC). However, chemotherapy resistance results in tumor recurrence and metastasis, which is a major obstacle for treatment of CRC. METHODS: In the current research, we establish 5-fluorouracil resistant cell lines and explore the potential targets associated with 5-fluorouracil resistance in CRC. Moreover, we perform clinical specimen research, in vitro and in vivo experiments and molecular mechanism research, to reveal the biological effects and the mechanism of DCLK1 promoting 5-fluorouracil resistance, and to clarify the potential clinical value of DCLK1 as a target of 5-fluorouracil resistance in CRC. RESULTS: We discover that doublecortin-like kinase 1 (DCLK1), a cancer stem cell maker, is correlated with 5-fluorouracil resistance, and functionally promotes cancer stemness and 5-fluorouracil resistance in CRC. Mechanistically, we elucidate that DCLK1 interacts with cell cycle and apoptosis regulator 1 (CCAR1) through the C-terminal domain, and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. Moreover, we find that DCLK1 positively regulates ß-catenin signalling via CCAR1, which is responsible for maintaining cancer stemness. Subsequently, we prove that blocking ß-catenin inhibits DCLK1-mediated 5-fluorouracil resistance in CRC cells. Importantly, we demonstrate that DCLK1 inhibitor could block CCAR1/ß-catenin pathway-mediated cancer stemness and consequently suppresses 5-fluorouracil resistant CRC cells in vitro and in vivo. CONCLUSIONS: Collectively, our findings reveal that DCLK1 promotes 5-fluorouracil resistance in CRC by CCAR1/ß-catenin pathway-mediated cancer stemness, and suggest that targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5-fluorouracil resistance in CRC.


Assuntos
Neoplasias Colorretais , Fluoruracila , beta Catenina , Proteínas Reguladoras de Apoptose/uso terapêutico , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Recidiva Local de Neoplasia , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
15.
J Exp Clin Cancer Res ; 41(1): 133, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35395804

RESUMO

BACKGROUND: Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown. METHODS: The role of Ninj1 in the survival of non-small cell lung cancer (NSCLC) CSCs within microenvironments exhibiting hazardous conditions was assessed by utilizing patient tissues and transgenic mouse models where Ninj1 repression and oncogenic KrasG12D/+ or carcinogen-induced genetic changes were induced in putative pulmonary stem cells (SCs). Additionally, NSCLC cell lines and primary cultures of patient-derived tumors, particularly Ninj1high and Ninj1low subpopulations and those with gain- or loss-of-Ninj1 expression, and also publicly available data were all used to assess the role of Ninj1 in lung tumorigenesis. RESULTS: Ninj1 expression is elevated in various human NSCLC cell lines and tumors, and elevated expression of this protein can serve as a biomarker for poor prognosis in patients with NSCLC. Elevated Ninj1 expression in pulmonary SCs with oncogenic changes promotes lung tumor growth in mice. Ninj1high subpopulations within NSCLC cell lines, patient-derived tumors, and NSCLC cells with gain-of-Ninj1 expression exhibited CSC-associated phenotypes and significantly enhanced survival capacities in vitro and in vivo in the presence of various cell death inducers. Mechanistically, Ninj1 forms an assembly with lipoprotein receptor-related protein 6 (LRP6) through its extracellular N-terminal domain and recruits Frizzled2 (FZD2) and various downstream signaling mediators, ultimately resulting in transcriptional upregulation of target genes of the LRP6/ß-catenin signaling pathway. CONCLUSIONS: Ninj1 may act as a driver of lung tumor formation and progression by protecting NSCLC CSCs from hostile microenvironments through ligand-independent activation of LRP6/ß-catenin signaling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Moléculas de Adesão Celular Neuronais , Neoplasias Pulmonares , Fatores de Crescimento Neural , Via de Sinalização Wnt , Animais , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular Neuronais/genética , Linhagem Celular Tumoral , Receptores Frizzled , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Neoplasias Pulmonares/patologia , Camundongos , Fatores de Crescimento Neural/genética , Microambiente Tumoral , beta Catenina/metabolismo
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(2): 418-424, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35395973

RESUMO

OBJECTIVE: To investigate the mechanism of miR-155 promoting drug resistance of children B-ALL to Ara-C by regulating Wnt/ß-Catenin signaling pathway. METHODS: The expression of miR-155 in bone marrow tissue and cell line of B-ALL was detected by PCR. The chemotherapy resistant strain REH/ Ara-C was constructed by using REH cells. REH/ Ara-C cells were transfected with miR-155 inhibitor. The proliferation of REH/Ara-C cells was detected by EdU. The apoptosis of REH/ Ara-C cells was detected by flow cytometry. The drug resistance of REH/Ara-C cells were analyzed by CCK-8 method and colony formation assay. The expression of Wnt/ß-Catenin signaling pathway related proteins were determined by Western blot. MiR-155 inhibitor and Wnt activator agonist were used to transfect REH/Ara-C cells, and their effects on cell proliferation, apoptosis and drug resistance were determined. RESULTS: Compared with normal tissues and cells, the expression level of miR-155 in B-ALL bone marrow tissue/cell line was increased (P<0.05); Compared with drug sensitive B-ALL tissues/cell lines, the expression level of miR-155 in drug resistant B-ALL tissues and cell lines was increased (P<0.05); Inhibition of miR-155 expression decreased the proliferation of REH/Ara-C cells (P<0.05), promoted apoptosis (P<0.05), enhanced the cytotoxicity of Ara-C (P<0.05), and inhibited Wnt/ß-Catenin signaling pathway related protein and MDR1 gene expression (P<0.05), which could be reversed by activating Wnt expression (P<0.05). CONCLUSION: The expression of miR-155 is up-regulated in bone marrow of children with B-ALL, which may be related to the activation of Wnt/ß-Catenin signaling pathway promotes the proliferation of B-ALL cells and inhibits apoptosis, which leads to chemotherapy resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs , Leucemia-Linfoma Linfoblástico de Células Precursoras , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Criança , Citarabina , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , beta Catenina/genética
17.
Bioengineered ; 13(4): 10313-10323, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35436412

RESUMO

The aim of this study was to investigate whether HUCMSCsWnt10b could promote long bone fracture healing. Commercially-available HUCMSCsEmp (human umbilical cord mesenchymal stem cells transfected with empty vector) in hydrogel, HUCMSCsWnt10b in hydrogel and HUCMSCsWnt10b with the Wnt signaling pathway inhibitor IWR-1 were transplanted into the fracture site in a rat model of femoral fracture. We found that transplantation of HUCMSCsWnt10b significantly accelerated bone healing in a rat model of femoral fracture. Meanwhile, three-point bending test proved that the mechanical properties of the bone at the fracture site in the HUCMSCWnt10b treatment group were significantly better than those of the other treatment groups. To understand the cellular mechanism, we explored the viability of periosteal stem cells (PSCs), as they contribute the greatest number of osteoblast lineage cells to the callus. In line with in vivo data, we found that conditioned medium from HUCMSCsWnt10b enhanced the migration and osteogenic differentiation of PSCs. Furthermore, conditioned medium from HUCMSCsWnt10b also induced endothelial cells to form capillary-like structures in a tube formation assay, which was blocked by SU5416, an angiogenesis inhibitor, suggesting that enhanced vessel formation and growth also contribute to accelerated hard callus formation. In summary, our study demonstrates that HUCMSCsWnt10b promote fracture healing via accelerated hard callus formation, possibly due to enhanced osteogenic differentiation of PSCs and vessel growth. Therefore, HUCMSCsWnt10b may be a promising treatment for long bone fractures.


Assuntos
Fraturas do Fêmur , Células-Tronco Mesenquimais , Animais , Remodelação Óssea , Cartilagem , Diferenciação Celular , Meios de Cultivo Condicionados/metabolismo , Células Endoteliais , Fraturas do Fêmur/metabolismo , Fraturas do Fêmur/terapia , Consolidação da Fratura , Hidrogéis , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Ratos , Cordão Umbilical , Via de Sinalização Wnt
18.
Bioengineered ; 13(4): 10026-10037, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35436415

RESUMO

Many dysregulated lncRNAs have been reported to perform an integral function in hepatocellular carcinoma (HCC). However, the role of long non-coding RNA (lncRNA) NRAV in HCC has not been elucidated. To address this issue, we investigated the function of NRAV in HCC in this research. Through bioinformatics prediction and real-time quantitative polymerase chain reaction validation, we found that NRAV plays an upmodulating role in HCC cells and tissues, and patients with high NRAV expression showed a poor prognosis. Cell viability was examined by conducting a Cell Counting Kit-8 analysis. Subsequently, the proliferation capacity of the cells was analyzed utilizing cell colony formation assay, and transwell invasion experiments were conducted to identify the cell invasion ability. To determine the association between NRAV and miR-199a-3p, and CDGSH iron-sulfur domain-containing protein 2 (CISD2), we conducted a dual luciferase assay. The protein and gene expressions were estimated utilizing Western blot. Findings illustrated that the overexpression of NRAV enhanced the HCC cell viability, proliferation and invasion, whereas they were inhibited significantly by down expression of NRAV. The dual-luciferase assay showed that miR-199a-3p is not only a target for NRAV but also interacts with the 3' UTR of CISD2 in HCC cells. MiR-199a-3p/CISD2 axis performs a function in NRAV-mediated cell behavior regulation. NRAV may trigger the Wnt/ß-catenin signaling via the modulation of the miR-199a-3p/CISD2 axis in HCC. The findings of this work can provide novel insights into clinical diagnosis and the treatment of HCC in the future.Abbreviations: HCC, hepatocellular carcinoma; LncRNA, long non-coding RNA; CISD2, CDGSH iron-sulfur domain-containing protein 2; CCK-8, Cell Counting Kit-8; cDNA, single-stranded complementary DNA; RT-qPCR, real-time quantitative polymerase chain reaction; BCA, bicinchoninic acid; ceRNA, competing endogenous RNAs.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Regiões 3' não Traduzidas , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ferro/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Enxofre , Via de Sinalização Wnt/genética
19.
BMC Musculoskelet Disord ; 23(1): 365, 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35436882

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway. METHODS: Bone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-ΔΔCt- Method. Statistical analysis comprised one-way analysis of variance (ANOVA). RESULTS: In T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p < 0.0001). TCF7L2 gene expression showed a significant reduction by 63% (p < 0.0001) and 18% (p = 0.0136) in diabetic Charcot arthropathy. In all diabetic patients BGLAP (Osteocalcin) was significantly decreased by at least 59% (p = 0.0019). CONCLUSIONS: For the first time with this study downregulation of members of the Wnt-signaling pathway has been shown in the bone of diabetic patients with and without Charcot arthropathy. This may serve as future therapeutic target for this severe disease.


Assuntos
Artropatia Neurogênica , Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Artropatia Neurogênica/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Neuropatias Diabéticas/complicações , Humanos , Osteocalcina/metabolismo , Via de Sinalização Wnt
20.
Molecules ; 27(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35408575

RESUMO

Various studies addressing the increasing problem of hair loss, using natural products with few side effects, have been conducted. 5-bromo-3,4-dihydroxybenzaldehyde (BDB) exhibited anti-inflammatory effects in mouse models of atopic dermatitis and inhibited UVB-induced oxidative stress in keratinocytes. Here, we investigated its stimulating effect and the underlying mechanism of action on hair growth using rat vibrissa follicles and dermal papilla cells (DPCs), required for the regulation of hair cycle and length. BDB increased the length of hair fibers in rat vibrissa follicles and the proliferation of DPCs, along with causing changes in the levels of cell cycle-related proteins. We investigated whether BDB could trigger anagen-activating signaling pathways, such as the Wnt/ß-catenin pathway and autophagy in DPCs. BDB induces activation of the Wnt/ß-catenin pathway through the phosphorylation of GSG3ß and ß-catenin. BDB increased the levels of autophagic vacuoles and autophagy regulatory proteins Atg7, Atg5, Atg16L, and LC3B. We also investigated whether BDB inhibits the TGF-ß pathway, which promotes transition to the catagen phase. BDB inhibited the phosphorylation of Smad2 induced by TGF-ß1. Thus, BDB can promote hair growth by modulating anagen signaling by activating Wnt/ß-catenin and autophagy pathways and inhibiting the TGF-ß pathway in DPCs.


Assuntos
Benzaldeídos , Cabelo , Fator de Crescimento Transformador beta , Via de Sinalização Wnt , Animais , Autofagia , Benzaldeídos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Células Cultivadas , Cabelo/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Ratos , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/metabolismo
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