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1.
FASEB J ; 38(4): e23476, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38334392

RESUMO

The prevalence of alopecia has increased recently. Hair loss is often accompanied by the resting phase of hair follicles (HFs). Dermal papilla (DP) plays a crucial role in HF development, growth, and regeneration. Activating DP can revive resting HFs. Augmenting WNT/ß-catenin signaling stimulates HF growth. However, the factors responsible for activating resting HFs effectively are unclear. In this study, we investigated epidermal cytokines that can activate resting HFs effectively. We overexpressed ß-catenin in both in vivo and in vitro models to observe its effects on resting HFs. Then, we screened potential epidermal cytokines from GEO DATASETs and assessed their functions using mice models and skin-derived precursors (SKPs). Finally, we explored the molecular mechanism underlying the action of the identified cytokine. The results showed that activation of WNT/ß-catenin in the epidermis prompted telogen-anagen transition. Keratinocytes infected with Ctnnb1-overexpressing lentivirus enhanced SKP expansion. Subsequently, we identified endothelin 1 (ET-1) expressed higher in hair-growing epidermis and induced the proliferation of DP cells and activates telogen-phase HFs in vivo. Moreover, ET-1 promotes the proliferation and stemness of SKPs. Western blot analysis and in vivo experiments revealed that ET-1 induces the transition from telogen-to-anagen phase by upregulating the PI3K/AKT pathway. These findings highlight the potential of ET-1 as a promising cytokine for HF activation and the treatment of hair loss.


Assuntos
Folículo Piloso , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Folículo Piloso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Endotelina-1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células Cultivadas , Proliferação de Células , Epiderme/metabolismo , Alopecia/metabolismo , Via de Sinalização Wnt , Derme/metabolismo , Citocinas/metabolismo
2.
Cell Mol Life Sci ; 81(1): 79, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334836

RESUMO

Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/ß-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3ß that destructs ß-catenin, while ligand-receptor interaction impairs GSK-3ß function to increase ß-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/ß-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance ß-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/ß-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/ß-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.


Assuntos
Neoplasias , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética
3.
Nat Commun ; 15(1): 1231, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336745

RESUMO

Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/ß-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/ß-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.


Assuntos
Androgênios , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Camundongos , Animais , Androgênios/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios/farmacologia , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Via de Sinalização Wnt , Proteínas Ribossômicas/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Linhagem Celular Tumoral , Fator de Crescimento de Hepatócito/metabolismo
4.
Cell Death Dis ; 15(2): 139, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355684

RESUMO

Radioresistance imposes a great challenge in reducing tumor recurrence and improving the clinical prognosis of individuals having oral squamous cell carcinoma (OSCC). OSCC harbors a subpopulation of CD44(+) cells that exhibit cancer stem-like cell (CSC) characteristics are involved in malignant tumor phenotype and radioresistance. Nevertheless, the underlying molecular mechanisms in CD44( + )-OSCC remain unclear. The current investigation demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in CD44(+) cells and promotes CSCs phenotype. Using RNA-sequencing analysis, we further showed that Spalt-like transcription factor 4 (SALL4) is involved in the maintenance of CSCs properties. Furthermore, the overexpression of SALL4 in CD44( + )-OSCC cells caused radioresistance in vitro and in vivo. In contrast, silencing SALL4 sensitized OSCC cells to radiation therapy (RT). Mechanistically, we illustrated that SALL4 is a direct downstream transcriptional regulation target of METTL3, the transcription activation of SALL4 promotes the nuclear transport of ß-catenin and the expression of downstream target genes after radiation therapy, there by activates the Wnt/ß-catenin pathway, effectively enhancing the CSCs phenotype and causing radioresistance. Herein, this study indicates that the METTL3/SALL4 axis promotes the CSCs phenotype and resistance to radiation in OSCC via the Wnt/ß-catenin signaling pathway, and provides a potential therapeutic target to eliminate radioresistant OSCC.


Assuntos
Adenina/análogos & derivados , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/radioterapia , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Recidiva Local de Neoplasia/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Proliferação de Células/genética , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Cell Mol Biol (Noisy-le-grand) ; 70(1): 194-199, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38372093

RESUMO

The goals of this study were to investigate whether Wnt/ß-catenin signaling plays a role in hypo-osmolality-related degeneration of nucleus pulposus (NP) cells, and if so, to define the mechanism underlying AQP1 in this effect. Human NP cells were cultured under hypo-osmotic (300/350/400 mOsm) and iso-osmotic (450 mOsm) conditions. The cell viability, AQP1, the expression of Wnt/ß-catenin signaling, collagen II/I, and MMP3/9 were evaluated. To determine the effects of the Wnt/ß-catenin signaling, we used the inhibitor and the activator of Wnt during the hypo-osmotic culture of NP cells. We also examined whether the silencing and overexpressing of the AQP1 gene would affect the Wnt/ß-catenin expression in NP cells. Hypo-osmolality caused NP cell degeneration and activated the Wnt/ß-catenin signaling but suppressed the AQP1 level. Inhibiting the Wnt/ß-catenin signaling alleviated the hypo-osmolality-induced NP cell degeneration. On the contrary, activating Wnt/ß-catenin aggravated the NP cell degeneration under hypo-osmotic conditions, which did not affect AQP1 expression. AQP1-overexpressed NP cells exhibited decreased Wnt/ß-catenin signaling and alleviated cell degeneration under the hypo-osmotic condition. Besides, AQP1 silencing accelerated NP cell degeneration and activated Wnt/ß-catenin expression compared with untreated control. Hypo-osmolality promotes NP cell degeneration via activating Wnt/ß-catenin signaling, which is suppressed by AQP1 expression. The upregulation of AQP1 suppressed the Wnt/ß-catenin signaling and alleviated the hypo-osmolality induced by the NP cell degeneration.


Assuntos
Degeneração do Disco Intervertebral , Núcleo Pulposo , Humanos , Núcleo Pulposo/metabolismo , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Células Cultivadas , Via de Sinalização Wnt/fisiologia , Aquaporina 1/genética , Aquaporina 1/metabolismo
6.
Cell Mol Biol (Noisy-le-grand) ; 70(1): 99-109, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38372107

RESUMO

This study aimed to explore the involvement of Transmembrane and coiled-coil domains 1 (TMCO1) in ovarian cancer progression and its regulatory mechanisms in cisplatin resistance. Using the GEPIA database, we analyzed TMCO1 expression in ovarian cancer and normal tissues. In a cohort of 99 ovarian cancer patients, immunohistochemistry and immunofluorescence were employed to assess TMCO1 expression in tumor and adjacent tissues, correlating findings with clinical and pathological characteristics. TMCO1 overexpression and knockout cell models were constructed, and their impact on non-cisplatin-resistant (SK-OV-3) and cisplatin-resistant (SK-OV-3-CDDP) ovarian cancer cells was investigated through cloning, wound healing, Fluo 4, and Transwell experiments. Knocking down CALR and VDAC1 was performed to examine their effects on TMCO1, cell proliferation, and malignant markers. Subcutaneous tumor models in nude mice elucidated the in vivo role of TMCO1 in tumor growth. Expression levels of CALR, VDAC1, angiogenesis indicators (CD34), and epithelial-mesenchymal transition (EMT) markers were evaluated. TMCO1 expression in ovarian cancer tissue significantly differed from normal tissue, correlating with survival rates. TMCO1 overexpression was associated with lymph node metastases, late FIGO stage, and larger tumors. TMCO1 promoted proliferation, calcium ion elevation, cytoskeletal remodeling, and metastasis in SK-OV-3 and SK-OV-3-CDDP cells, upregulating VDAC1, CALR, Vimentin, N-cadherin, ß-catenin, and downregulating E-cadherin. Silencing TMCO1 inhibited cell growth, proliferation, and angiogenesis in vivo, suppressing the expression of CALR, VDAC1, Vimentin, N-cadherin, and ß-catenin. Overall, this study highlighted TMCO1 as a crucial regulator in ovarian cancer progression, influencing VDAC1 through CALR and impacting diverse cellular processes, offering potential as a targeted therapeutic strategy for ovarian cancer.


Assuntos
Neoplasias Ovarianas , Animais , Camundongos , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , beta Catenina/metabolismo , Vimentina/metabolismo , Camundongos Nus , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Canais de Cálcio/farmacologia , Canais de Cálcio/uso terapêutico
7.
Diagn Pathol ; 19(1): 35, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365810

RESUMO

BACKGROUND: Breast cancer is one of the most common diseases worldwide that affects women of reproductive age. miR-221 and miR-222 are two highly homogeneous microRNAs that play pivotal roles in many cellular processes and regulate the Wnt/ß-catenin signaling pathway. Curcumin (CUR), a yellow polyphenolic compound, targets numerous signaling pathways relevant to cancer therapy. The main aim of this study was to compare the ability of chitosan curcumin nanoparticle (CC-CUR) formulation with the curcumin in modulating miR-221 and miR-222 expression through Wnt/ß-catenin signaling pathway in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines. METHOD: Chitosan-cyclodextrin-tripolyphosphate containing curcumin nanoparticles (CC-CUR) were prepared. Cytotoxicity of the CUR and CC-CUR was evaluated. Experimental groups including CC-CUR, CUR and negative control were designed. The expression of miR-221 and miR-222 and Wnt/ß-catenin pathway genes was measured. RESULTS: The level of miR-221 and miR-222 and ß-catenin genes decreased in MCF-7 and MDA-MB-231 cells and WIF1 gene increased in all cells in CC-CUR group. However, the results in SK-BR-3 cell line were unexpected; since miRs and WIF1 gene expressions were increased following CC-CUR administration and ß-catenin decreased by administration of CUR. CONCLUSION: Although the composite form of curcumin decreased the expression of miR-221 and miR-222 in MCF-7 and MDA cells, with significant decreasing of ß-catenin and increasing of WIF1 gene in almost all three cell lines, we can conclude than this formulation exerts its effect mainly through the Wnt/ß-catenin pathway. These preliminary findings may pave the way for the use of curcumin nanoparticles in the treatment of some known cancers.


Assuntos
Neoplasias da Mama , Quitosana , Curcumina , MicroRNAs , Humanos , Feminino , Curcumina/farmacologia , Via de Sinalização Wnt/genética , Células MCF-7 , beta Catenina/genética , beta Catenina/metabolismo , Quitosana/farmacologia , MicroRNAs/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células
8.
Cell Mol Life Sci ; 81(1): 93, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38367191

RESUMO

Stem Leydig cells (SLCs) are essential for maintaining normal spermatogenesis as the significant component of testis microenvironment and gonadal aging. Although progress has been achieved in the regulation of male germ cells in mammals and humans, it remains unknown about the genes and signaling pathways of human SLCs. Here we have demonstrated, for the first time, that WNT5A (Wnt family member 5a) mediates the proliferation, apoptosis, and stemness of human SLCs, namely NGFR+ Leydig cells. We revealed that NGFR+ Leydig cells expressed NGFR, PDGFRA, NES, NR2F2, and THY1, hallmarks for SLCs. RNA-sequencing showed that WNT5A was expressed at a higher level in human SLCs than non-SLCs, while immunohistochemistry and Western blots further illustrated that WNT5A was predominantly expressed in human SLCs. Notably, CCK-8, EdU and Western blots displayed that WNT5A enhanced the proliferation and DNA synthesis and retained stemness of human SLCs, whereas flow cytometry and TUNEL analyses demonstrated that WNT5A inhibited the apoptosis of these cells. WNT5A knockdown caused an increase in LC lineage differentiation of human SLCs and reversed the effect of WNT5A overexpression on fate decisions of human SLCs. In addition, WNT5A silencing  resulted in the decreases in nuclear translocation of ß-catenin and expression levels of c-Myc, CD44, and Cyclin D1. Collectively, these results implicate that WNT5A regulates the proliferation, apoptosis and stemness of human SLCs through the activation of the ß-catenin signaling pathway. This study thus provides a novel molecular mechanism underlying the fate determinations of human SLCs, and it offers a new insight into the niche regulation of human testis.


Assuntos
Células Intersticiais do Testículo , beta Catenina , Animais , Humanos , Masculino , Células Intersticiais do Testículo/metabolismo , beta Catenina/metabolismo , Testículo/metabolismo , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , Transdução de Sinais , Apoptose , Proliferação de Células , Via de Sinalização Wnt/genética , Mamíferos/metabolismo
9.
PLoS One ; 19(2): e0295030, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38324534

RESUMO

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths worldwide. The centrosome is the main microtubule-organizing center in animal cells and centrosome amplification is a hallmark of cancer cells. To investigate the importance of centrosomes in colorectal cancer, we induced centrosome loss in normal and cancer human-derived colorectal organoids using centrinone B, a Polo-like kinase 4 (Plk4) inhibitor. We show that centrosome loss represses human normal colorectal organoid growth in a p53-dependent manner in accordance with previous studies in cell models. However, cancer colorectal organoid lines exhibited different sensitivities to centrosome loss independently of p53. Centrinone-induced cancer organoid growth defect/death positively correlated with a loss of function mutation in the APC gene, suggesting a causal role of the hyperactive WNT pathway. Consistent with this notion, ß-catenin inhibition using XAV939 or ICG-001 partially prevented centrinone-induced death and rescued the growth two APC-mutant organoid lines tested. Our study reveals a novel role for canonical WNT signaling in regulating centrosome loss-induced growth defect/death in a subset of APC-mutant colorectal cancer independently of the classical p53 pathway.


Assuntos
Proteína da Polipose Adenomatosa do Colo , Neoplasias Colorretais , Proteína Supressora de Tumor p53 , beta Catenina , Animais , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Centrossomo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Pirimidinas , Sulfonas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo
10.
Cell Biochem Funct ; 42(2): e3945, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38362935

RESUMO

MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFß/SMAD, RAS/MAPK, Wnt/ß-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.


Assuntos
Carcinoma , MicroRNAs , Neoplasias Nasofaríngeas , Humanos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , beta Catenina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Transdução de Sinais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Movimento Celular/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo
11.
FASEB J ; 38(4): e23493, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38363575

RESUMO

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease that could cause blindness. It has been established that Norrin forms dimers to activate ß-catenin signaling, yet the core interface for Norrin dimerization and the precise mechanism by which Norrin dimerization contributes to the pathogenesis of FEVR remain elusive. Here, we report an NDP variant, c.265T>C (p.Phe89Leu), that interrupted ß-catenin signaling by disrupting Norrin dimerization. Structural and functional analysis revealed that the Phe-89 of one Norrin monomer interacts with Pro-98, Ser-101, Arg-121, and Ile-123 of another, forming two core symmetrical dimerization interfaces that are pivotal for the formation of a "hand-by-arm" dimer. Intriguingly, we proved that one of the two core symmetrical interfaces is sufficient for dimerization and activation of ß-catenin signaling, with a substantial contribution from the Phe-89/Pro-98 interaction. Further functional analysis revealed that the disruption of both dimeric interfaces eliminates potential binding sites for LRP5, which could be partially restored by over-expression of TSPAN12. In conclusion, our findings unveil a core dimerization interface that regulates Norrin/LRP5 interaction, highlighting the essential role of Norrin dimerization on ß-catenin signaling and providing potential therapeutic avenues for the treatment of FEVR.


Assuntos
Oftalmopatias Hereditárias , Doenças Retinianas , Humanos , Vitreorretinopatias Exsudativas Familiares/genética , beta Catenina/genética , beta Catenina/metabolismo , Dimerização , Oftalmopatias Hereditárias/genética , Transdução de Sinais , Doenças Retinianas/metabolismo , Mutação , Tetraspaninas/genética , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Receptores Frizzled/genética , Análise Mutacional de DNA
12.
Aging (Albany NY) ; 16(3): 2475-2493, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38305787

RESUMO

OBJECTIVE: The function of Kruppel-like factor 3 (KLF3) remains largely unexplored in colorectal cancer (CRC). METHODS: KLF3 expression in CRC was assessed through qPCR, western blotting, immunohistochemical assays, and The Cancer Genome Atlas (TCGA) database. The tumor-promoting capacity of KLF3 was explored by performing in vitro functional experiments using CRC cells. A subcutaneous nude mouse tumor assay was employed to evaluate tumor growth. To further elucidate the interaction between KLF3 and other factors, luciferase reporter assay, agarose gel electrophoresis, and ChIP analysis were performed. RESULTS: KLF3 was downregulated in CRC tissue and cells. Silencing of KLF3 increased the potential of CRC cells for proliferation, migration, and invasion, while its activation decreased these processes. Downregulated KLF3 was associated with accelerated tumor growth in vivo. Mechanistically, KLF3 was discovered to target the promoter sequence of WNT1. Consequently, the diminished expression of KLF3 led to the buildup of WNT1 and the WNT/ß-catenin pathway activation, consequently stimulating the progression of CRC. CONCLUSIONS: This investigation suggests that the involvement of KLF3/WNT1 regulatory pathway contributes to the progression of CRC, thereby emphasizing its promise as an important focus for future therapies aimed at treating CRC.


Assuntos
Neoplasias Colorretais , Fatores de Transcrição , Camundongos , Animais , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Proliferação de Células/genética , Regiões Promotoras Genéticas , Neoplasias Colorretais/patologia , Via de Sinalização Wnt/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética
13.
BMC Cancer ; 24(1): 175, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317072

RESUMO

BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Humanos , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo , Peixe-Zebra/metabolismo , Linhagem Celular Tumoral , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Transição Epitelial-Mesenquimal/genética , Movimento Celular , Proliferação de Células
15.
Vasc Med ; 29(1): 5-16, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38334094

RESUMO

INTRODUCTION: Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood. METHODS: Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules. RESULTS: PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of PDLIM1 inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of PDLIM1. Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of ß-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and ß-catenin downstream target genes was observed in human IA samples. CONCLUSION: Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/ß-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.


Assuntos
Aneurisma Intracraniano , Hemorragia Subaracnóidea , Animais , Humanos , Ratos , beta Catenina/genética , beta Catenina/metabolismo , Proliferação de Células , Células Endoteliais/metabolismo , Aneurisma Intracraniano/genética , Aneurisma Intracraniano/patologia , Transdução de Sinais , Via de Sinalização Wnt
16.
FASEB J ; 38(4): e23463, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38334393

RESUMO

With self-renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lineage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to various signaling pathways. SET domain-containing 3 (SETD3) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identified SETD3-dependent transcriptomic changes during endoderm differentiation of mESCs using time-course RNA-seq analysis. We found that SETD3 is involved in the timely activation of the endoderm-related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the absence of SETD3. The assessment of Wnt transcriptional activity revealed a significant reduction in Setd3-deleted (setd3∆) mESCs coincident with a decrease in the nuclear pool of the key TF ß-catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and ß-catenin. We were able to rescue the differentiation defect by stably re-expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of ß-catenin might contribute to the endoderm differentiation defect of setd3∆ mESCs.


Assuntos
Células-Tronco Embrionárias Murinas , beta Catenina , Animais , Camundongos , beta Catenina/metabolismo , Diferenciação Celular/genética , Endoderma , Via de Sinalização Wnt/fisiologia
17.
Radiol Oncol ; 58(1): 67-77, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38378037

RESUMO

BACKGROUND: Gastric cancer is an epidemic malignancy that is commonly diagnosed at the late stage. Evidence has elucidated that RAD54B exerts a crucial role in the progress of various tumors, but its specific role and mechanism in gastric cancer remain gloomy. MATERIALS AND METHODS: The level of RAD54B was detected by western blot. RAD54B expression was downregulated or upregulated in both MKN45 and AGS cells by the transfection of shRAD54B or overexpression plasmid, respectively. The role of RAD54B in the growth, migration, invasion and tube formation of gastric cancer was evaluated by Edu, colony formation, transwell and tube formation assays. In addition, the molecular mechanism of RAD54B in gastric cancer was also determined by western blot. Moreover, in vivo experiment was conducted in xenografted mice. RESULTS: The expression of RAD54B was discovered to be upregulated in gastric cancer based on the ATGC and GEPIA databases, which was also confirmed in gastric cancer cell lines. Moreover, overexpression of RAD54B enhanced the growth, migration, invasion, tube formation and Wnt/ß-catenin signaling axis in AGS and MKN45 cells. As expected, knockdown of RAD54B in AGS and MKN45 cells reversed these promotions. More importantly, in vivo assay also verified that RAD54B accelerated the growth of gastric cancer and Wnt/ß-catenin signaling pathway. CONCLUSIONS: Both loss-of-function and gain-of-function assays demonstrated that RAD54B facilitated gastric cancer cell progress and angiogenesis through the Wnt/ß-catenin axis.


Assuntos
Neoplasias Gástricas , Animais , Camundongos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Via de Sinalização Wnt , Humanos
18.
Nat Commun ; 15(1): 1611, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383543

RESUMO

We introduce a computational approach for the design of target-specific peptides. Our method integrates a Gated Recurrent Unit-based Variational Autoencoder with Rosetta FlexPepDock for peptide sequence generation and binding affinity assessment. Subsequently, molecular dynamics simulations are employed to narrow down the selection of peptides for experimental assays. We apply this computational strategy to design peptide inhibitors that specifically target ß-catenin and NF-κB essential modulator. Among the twelve ß-catenin inhibitors, six exhibit improved binding affinity compared to the parent peptide. Notably, the best C-terminal peptide binds ß-catenin with an IC50 of 0.010 ± 0.06 µM, which is 15-fold better than the parent peptide. For NF-κB essential modulator, two of the four tested peptides display substantially enhanced binding compared to the parent peptide. Collectively, this study underscores the successful integration of deep learning and structure-based modeling and simulation for target specific peptide design.


Assuntos
Aprendizado Profundo , Simulação de Dinâmica Molecular , beta Catenina/metabolismo , NF-kappa B/metabolismo , Ligação Proteica , Peptídeos/química
19.
J Transl Med ; 22(1): 133, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310229

RESUMO

BACKGROUND: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. METHODS: An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. RESULTS: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/ß-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/ß-catenin and IMPDH2. Blocking the Wnt/ß-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. CONCLUSIONS: IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.


Assuntos
Neoplasias Colorretais , beta Catenina , Humanos , Apoptose , beta Catenina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Oxirredutases/genética , Oxirredutases/metabolismo , Via de Sinalização Wnt
20.
Immun Inflamm Dis ; 12(2): e1172, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38358044

RESUMO

INTRODUCTION: Nuclear receptor subfamily five group A member two (NR5A2) plays a key role in the development of many tumor types, while it is uncertain in cutaneous squamous cell carcinoma (cSCC). The aim of this work was to determine the role of NR5A2 in cSCC proliferation, and to determine whether NR5A2 mediates the effect of cisplatin in cSCC. METHODS: We performed a systematic study of existing data and conducted a preliminary bioinformatics analysis of NR5A2 expression in cSCC using bioinformatics databases. Immunohistochemical staining was performed on cSCC tissues of seven patients to study NR5A2 expression. NR5A2 expression was examined in human keratin-forming cells (HaCaT) and human cSCC cells (A431, Colo-16, SCL-1, SCL-2, and HSC-5). Stable A431 and SCL-2 cell lines consisting of sh-RNA-NR5A2 were constructed to detect changes in cell proliferation, cell cycle, apoptosis, and to determine the key proteins in the Wnt/ß-catenin pathway. We also investigated changes in the effects of cisplatin on cSCC cells by CCK-8, clone formation assay, and Flow apoptosis assay after NR5A2 knockdown. RESULTS: NR5A2 showed enhanced expression in cSCC tissues than in healthy tissues. Downregulation of NR5A2 in cSCC cells led to the formation of a less malignant phenotype. In contrast, the proliferative capacity of the cSCC cells was enhanced posttreatment with RJW100, an NR5A2 agonist. Additionally, NR5A2 knockdown led to a decrease in the expression level of the proteins in the Wnt/ß-catenin pathway, and this inhibition was reversed by LiCl and recombinant antibody, Wnt3a. Moreover, NR5A2 knockdown resulted in diminished proliferative capacity and increased apoptotic cells after the addition of cisplatin. CONCLUSION: NR5A2 plays a crucial role in the progression of cSCC, and the Wnt/ß-catenin signaling pathway may be involved in the regulation of NR5A2-mediated cSCC. Knockdown of NR5A2 enhanced both the proliferation inhibiting and apoptosis promoting effects of cisplatin on cSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , beta Catenina/genética , beta Catenina/metabolismo , Cisplatino/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Receptores Citoplasmáticos e Nucleares
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