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1.
Sci Rep ; 14(1): 6053, 2024 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-38480774

RESUMEN

The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.


Asunto(s)
Neoplasias Colorrectales , Linfocitos T Citotóxicos , Humanos , Animales , Ratones , Interferón gamma/farmacología , Linfocitos T CD8-positivos , Microambiente Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología
2.
Steroids ; 178: 108967, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35085676

RESUMEN

Currently, the market demand of the non-animal-derived cholesterol is increasing. A novel synthetic route of producing cholesterol was developed through multiple reactions from plant-sourced and commercially available bisnoralcohol (BA). The key reaction conditions, including solvents, reaction temperatures, bases and reducing agents of the route were investigated and optimized. In this straightforward synthetic pathway of cholesterol, most of the reaction steps possess high conversions with average yields of 94%, and the overall yield is up to 74% (5 steps) from the BA. The epicholesterol and were also synthesized. This promising route offers economical and efficient strategies for potential large-scale production of plant-derived cholesterol.


Asunto(s)
Colesterol , Plantas , Solventes
3.
Cell Death Dis ; 11(3): 171, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32139668

RESUMEN

Microscopic indications of malignancy and hallmark molecules of cancer are pivotal to determining cancer patient prognosis and subsequent medical intervention. Here, we found that compared to apical expression of Cdc42, which indicated that basal expression of Cdc42 occurred at the migrating cell front, glandular basal expression of Cdc42 (cell division cycle 42) in tissues indicated poorer prognoses for colorectal cancer (CRC) patients. The current study shows that activated Cdc42 was rapidly recruited to the migrating CRC cell front after VEGF stimulation through engagement of membrane-anchored neuropilin-1 (NRP1). When VEGF signalling was blocked with NRP1 knockdown or ATWLPPR (A7R, antagonist of VEGF/NRP1 interaction), Cdc42 activation and relocation to the cell front was attenuated, and filopodia and invadopodia formation was inhibited. The VEGF/NRP1 axis regulates directional migration, invasion, and metastasis through Cdc42 activation and relocation resulting from actin filament polymerisation of the extensions of membrane protrusions. Collectively, the immuno-micromorphological pattern of subcellular Cdc42 at the cell front indicated aggressive behaviours and predicted poor prognosis in CRC patients. Disruption of the intra- and extracellular interactions of the VEGF/NRP1 axis or Cdc42 relocation could be performed in clinical practice because it might inhibit cancer cell motility and metastasis.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Neovascularización Patológica/metabolismo , Neuropilina-1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Movimiento Celular/fisiología , Neoplasias del Colon/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Células Endoteliales/metabolismo , Humanos , Seudópodos/metabolismo , Transducción de Señal/genética
4.
Pathol Res Pract ; 215(8): 152509, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31255330

RESUMEN

A hallmark of gastric cancer is the high rate of genomic instability associated with deregulation of DNA damage repair pathways. DNA-Dependent Protein Kinase Catalytic Subunit (PRKDC) is a key component of the non-homologous end-joining (NHEJ) pathway. By reanalyzing transcriptome data of 80 pairs of gastric cancer tumors and the adjacent normal tissues from non-treated patients, we identified PRKDC as the top upregulated DNA damage repair genes in gastric cancer. High expression of PRKDC is associated with poor survival of gastric cancer patients, and genomic amplification of the gene is frequently observed across most gastric cancer subtypes. Knockdown of PRKDC in gastric cell lines resulted in reduced proliferation and cell cycle arrest. Furthermore, we showed that loss of PRKDC induced DNA damage and enhanced gastric cancer cell chemosensitivity to DNA-damaging reagents. Together, our results suggest that PRKDC is a prognostic marker of poor survival and is a putative target to overcome chemoresistance in gastric cancer.


Asunto(s)
Proteína Quinasa Activada por ADN/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Apoptosis , Daño del ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Pronóstico , Neoplasias Gástricas/diagnóstico
5.
Mol Genet Genomic Med ; 7(11): e908, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31513357

RESUMEN

BACKGROUND: DNA-Dependent Protein Kinase Catalytic Subunit (PRKDC), a key component of the DNA damage repair pathway, is associated with chemotherapy resistance and tumor progression. METHODS: Here we analyzed transcriptome data of ~2,000 breast cancer patients and performed functional studies in vitro to investigate the function of PRKDC in breast cancer. RESULTS: Our results revealed overexpression of PRKDC in multiple breast cancer subtypes. Consistent with patients' data, overexpression of PRKDC was also observed in breast cancer cell lines compared to normal breast epithelial cells. Knockdown of PRKDC in MCF-7 and T47D breast cancer cell lines resulted in proliferation inhibition, reduced colony formation and G2/M cell cycle arrest. Furthermore, we showed that PRKDC knockdown induced proliferation inhibition through activation of p38 MAPK, but not ERK MAPK, signaling pathway in breast cancer cells. Blockage of p38 MAPK signaling could largely rescue proliferation inhibition and cell cycle arrest induced by PRKDC knockdown. Moreover, we analyzed gene expression and clinical data from six independent breast cancer cohorts containing ~1,000 patients. In all cohorts, our results consistently showed that high expression of PRKDC was significantly associated with poor survival in both treated and untreated breast cancer patients. CONCLUSION: Together, our results suggest that high expression of PRKDC facilitates breast cancer cell growth via regulation of p38 MAPK signaling, and is a prognostic marker for poor survival in breast cancer patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/mortalidad , Proteína Quinasa Activada por ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular , Proliferación Celular , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/genética , Femenino , Estudios de Seguimiento , Humanos , Pronóstico , ARN Interferente Pequeño/genética , Tasa de Supervivencia , Células Tumorales Cultivadas
6.
Chem Commun (Camb) ; 50(54): 7160-2, 2014 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-24853117

RESUMEN

We have developed a quantum dot-based microRNA nanosensor for point mutation assays using primer generation-mediated rolling circle amplification. The proposed method exhibits high sensitivity with a detection limit of as low as 50.9 aM and a large dynamic range of 7 orders of magnitude from 0.1 fM to 1 nM. Importantly, this method can be further applied to analyze the point mutation of mir-196a2 in the lung tissues of non small-cell lung cancer patients.


Asunto(s)
Técnicas Biosensibles , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Mutación Puntual , Puntos Cuánticos , Bioensayo , Humanos , Pulmón/metabolismo , Imagen Óptica
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