BackgroundCervical cancer is one of the most common causes of cancer‐associated mortality among affected women in the world. At present, treatment with weekly cisplatin plus ionizing radiation (IR) therapy is the standard regimen for cervical cancer, especially for locally advanced cervical cancer. The purpose of this study is to determine whether FEN1 inhibitors could enhance the therapeutic effect of IR therapy.MethodsWestern blot was applied to determine the expression of FEN1‐ and apoptosis‐related proteins. Cell growth inhibition assay and colony formation assay were used to determine the effects of FEN1 inhibitor and IR exposure for Hela cells in vitro. CRISPR technology was used to knockdown FEN1 expression level of 293T cells, and tumor xenograft in nude mice was employed to determine the effects of FEN1 inhibitor and IR exposure on tumor growth in vivo.ResultsOur data revealed that FEN1 is overexpressed in HeLa cell and can be upregulated further by IR. We also demonstrated that FEN1 inhibitor enhances IR sensitivity of cervical cancer in vitro and in vivo.ConclusionFEN1 inhibitor SC13 could sensitize radiotherapy of cervical cancer cell.
Amyloid β (Aβ)1–42 is strongly associated with Alzheimer's disease (AD). The effects of Aβ1–42 on astrocytes remain largely unknown. The present study focused on the effects of Aβ1–42 on U87 human glioblastoma cells as astrocytes for in vitro investigation and mouse brains for in vivo investigation. The mechanism and regulation of mitochondria and cytochrome P450 reductase (CPR) were also investigated. As determined by MTT assays, low doses of Aβ1–42 (<1 µM) marginally promoted astrocytosis compared with the 0 µM group within 24 h, however, after 48 h treatment these doses reduced cellular growth compared with the 0 µM group. Furthermore, Aβ1–42 doses >5 µM inhibited the growth of U87 cells compared with the 0 µM group after 24 and 48 h treatment. Immunofluorescence analysis demonstrated that astrocytosis was also observed in early stage AD mice compared with wild-type (WT) mice. In addition, concentrations of Aβ1–42 were also significantly higher in early stage AD mice compared with WT mice, however, the levels were markedly lower compared with later stage AD mice, as determined by ELISA. In addition to increased levels of Aβ1–42 in mice with later stage AD, reduced astrocyte staining was observed compared with WT mice. Western blotting indicated that the effect of Aβ1–42 on U87 cell apoptosis may be regulated via Bcl-2 and caspase-3 located in mitochondria, whose functions, including adenosine triphosphate generation, electron transport chain and mitochondrial membrane potential, were inhibited by Aβ1–42. During this process, the expression and activity of cytochrome P450 reductase was also downregulated. The current study provides novel insight into the effects of Aβ1–42 on astrocytes and highlights a potential role for astrocytes in the protection against AD.
ObjectiveTo evaluate plasma exosome-derived SUMO-specific protease (SENP)1 levels and assess their prognostic value in melanoma.Patients and MethodsWe extracted exosomes from the plasma of 126 melanoma patients, and identified them with transmission electron microscopy, nanoparticle tracking analysis and western blotting. The plasma exosome-derived SENP1 levels of melanoma patients and healthy controls were detected with ELISA.ResultsPlasma exosome-derived SENP1 levels in melanoma patients were significantly upregulated than in healthy controls (P < 0.001). Plasma exosome-derived SENP1 levels in melanoma patients with tumor size >10 cm, located in the mucosa or viscera, with Clark level IV/V, with lymph node metastasis, and TNM stages IIb–IV were significantly higher than in patients in with tumor size <10 cm, located in the skin, with Clark level I–III, without lymph node metastasis, and TNM stages IIb–IV (all P < 0.05). Disease-free survival (DFS) and overall survival (OS) were worse in melanoma patients who had higher plasma exosome-derived SENP1 levels than lower plasma exosome-derived SENP1 levels (both P < 0.001). Area under the receiver operating characteristic curve (AUROC) of plasma exosome-derived SENP1 for predicting 3-year DFS of melanoma patients was 0.82 [95% confidence interval (CI): 0.74–0.88], with a sensitivity of 81.2% (95% CI: 69.9–89.6%) and specificity of 75.4% (95% CI: 62.2–85.9%). The AUROC of plasma exosome-derived SENP1 for predicting 3-year OS of melanoma patients was 0.76 (95% CI: 0.67–0.83), with a sensitivity of 95.7% (95% CI: 85.5–99.5%) and specificity of 62.0% (95% CI: 50.4–72.7%).ConclusionsMelanoma patients with higher plasma exosome-derived SENP1 levels had worse DFS and OS. The plasma exosome-derived SENP1 levels may be a potential prognostic predictor for 3-year DFS and 3-year OS of melanoma.
Aim and Objective: Flap endonuclease-1 (FEN1) plays a central role in DNA replication and DNA damage repair process. In mammals, FEN1 functional sites variation is related to cancer and chronic inflammation, and supports the role of FEN1 as a tumor suppressor. However, FEN1 is overexpressed in multiple types of cancer cells and is associated with drug resistance, supporting its role as an oncogene. Hence, it is vital to explore the multi-functions of FEN1 in normal cell metabolic process. This study was undertaken to examine how the gene expression profile changes when FEN1 is downregulated in 293T cells. Materials and Methods: Using the RNA sequencing and real-time PCR approaches, the transcript expression profile of FEN1 knockdown HEK293T cells have been detected for the next step evaluation, analyzation, and validation. Results: Our results confirmed that FEN1 is important for cell viability. We showed that when FEN1 downregulation led to the interruption of nucleic acids related metabolisms, cell cycle related metabolisms are significantly interrupted. FEN1 may also participate in non-coding RNA processing, ribosome RNA processing, transfer RNA processing, ribosome biogenesis, virus infection and cell morphogenesis. Conclusion: These findings provide insight into how FEN1 nuclease might regulate a wide variety of biological processes, and laid the foundation for understanding the role of other RAD2 family nucleases in cell growth and metabolism.
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