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Journal of Bioenergetics and... Aug 2022Circular RNAs (circRNAs) play vital roles in human diseases, including acute kidney injury (AKI). In this paper, we focused on the effect of circRNA zinc finger protein...
Circular RNAs (circRNAs) play vital roles in human diseases, including acute kidney injury (AKI). In this paper, we focused on the effect of circRNA zinc finger protein 644 (circZNF644) on AKI cell model progression. qRT-PCR was conducted for the levels of circZNF644, ZNF644, miR-140-5p and mixed lineage kinase domain like pseudokinase (MLKL). RNase R assay, actinomycin D assay and subcellular fraction analysis were conducted to analyze the features of circZNF644. CCK-8 assay and EdU assay were used to explore cell proliferation. Flow cytometry analysis was conducted to analyze cell cycle and cell apoptosis. Western blot assay was executed for protein levels. ELISA was performed for the levels of inflammatory cytokines. The relationships among circZNF644, miR-140-5p and MLKL were analyzed by dual-luciferase reporter assay and RIP assay. CircZNF644 was upregulated in LPS-stimulated HK-2 cells. LPS-mediated inhibitory effects on cell proliferation and cell cycle and promotional effects on apoptosis and inflammation were reversed by circZNF644 knockdown. CircZNF644 directly interacted with miR-140-5p and MLKL was the target gene of miR-140-5p. The impact of circZNF644 knockdown on HK-2 cell injury was relieved by miR-140-5p inhibition. Moreover, miR-140-5p enhancement alleviated LPS-triggered HK-2 cell damage, while MLKL elevation reversed the effect. CircZNF644 knockdown protected HK-2 cells from LPS-induced injury by altering miR-140-5p/MLKL pathway, suggesting that circZNF644 may be a hopeful therapeutic target for AKI.
Topics: Acute Kidney Injury; Apoptosis; Cell Proliferation; Cytokines; Dactinomycin; Humans; Lipopolysaccharides; MicroRNAs; Protein Kinases; RNA, Circular
PubMed: 35976517
DOI: 10.1007/s10863-022-09946-3 -
Biochemical and Biophysical Research... Dec 2022Actinomycin D (ActD) is an antineoplastic antibiotic that has been commonly used for the treatment of various tumors, including Wilms' tumor, rhabdomyosarcoma, and...
Actinomycin D (ActD) is an antineoplastic antibiotic that has been commonly used for the treatment of various tumors, including Wilms' tumor, rhabdomyosarcoma, and gestational trophoblastic neoplasia. Recent studies have proposed actinomycin D (ActD) as a novel therapeutic candidate for glioblastoma. ActD significantly reduces tumor growth in recurrent glioblastoma patient-derived mouse models and increases survival by downregulating SOX2 expression. However, ActD treatment of brain tumors can lead to unnecessary exposure of surrounding neurons and normal glial cells to ActD. Cellular and molecular studies are required to estimate and minimize the neurological side effects of ActD. This study investigated the short- and long-term toxicological responses of the primary cortical neurons to ActD. We examined concentration-dependent survival of primary cortical neurons and differential susceptibilities of excitatory, inhibitory neurons, and glial cells to ActD. Distinct alterations in intracellular signaling pathways in cortical neurons were also studied when exposed to ActD. Importantly, we found that primary cortical neurons after ActD discontinuation showed active intracellular signaling pathways responding to extracellular neurotropic factors, but they had extremely poor transcription activity reversibility that was inhibited even by 30-min low-dose ActD exposure. These findings indicate the direct toxicity and extremely poor reversibility of ActD in neurons during chemotherapy for brain tumors.
Topics: Mice; Animals; Dactinomycin; Glioblastoma; Neoplasm Recurrence, Local; Neurons; Brain Neoplasms
PubMed: 36332475
DOI: 10.1016/j.bbrc.2022.10.083 -
Life (Basel, Switzerland) May 2023(1) Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the first two decades of life. One third of cases appear in the head and neck, with 60%...
(1) Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the first two decades of life. One third of cases appear in the head and neck, with 60% of these being embryonal type. RMS is extremely rare in adults, comprising only 1% of adult malignancies, and of those, only 3.3% are rhabdomyosarcomas. (2) Case report: A 46 y.o. male presented with a 1 cm exophytic pediculated painless lesion on the dorsum of his tongue, with progressive growth for 3 months. An excisional biopsy revealed an "embryonal rhabdomyosarcoma with fusocellular areas, with negative rearrangement for gen FOXO1A, negative MDM2 (only focal positivity), and positive INI-1". Subsequent contrast-enhanced MRI concluded the presence of a lesion with imprecise margins in the right half-tongue, 15 × 8 × 7 mm (longitudinal × transverse × craniocaudal), compatible with a sarcoma. The patient underwent a partial centrolingual glossectomy followed by reconstruction with a buccinator muscle local flap. After surgery, he received chemotherapy with eight cycles of VAC (vincristine, actinomycin, and cyclophosphamide) protocol. The patient is now disease free after 42 months, with good tongue function. (3) Discussion and conclusions: Embryonal RMS is an extremely rare sarcoma in adults, and the location in the tongue is even more exceptional (only two more similar cases are reported in the literature). The prognosis in adults is significantly poorer than in children. A complete margin-free resection with an adequate chemotherapy protocol is the treatment of choice in cases such as these.
PubMed: 37374040
DOI: 10.3390/life13061255 -
International Journal of Gynaecology... Aug 2023To provide clinical guidance for early diagnosis and effective management of primary cesarean scar choriocarcinoma, which is an extremely rare but highly malignant... (Review)
Review
OBJECTIVES
To provide clinical guidance for early diagnosis and effective management of primary cesarean scar choriocarcinoma, which is an extremely rare but highly malignant trophoblastic tumor.
METHODS
This retrospective case series summarized the clinical courses of seven patients diagnosed with cesarean scar choriocarcinoma.
RESULTS
We identified two patients in our institution with cesarean scar choriocarcinoma. In addition, details of the previous five patients were extracted from databases and analyzed to provide more clinical information. The seven patients had an average age of 31.14 years, their tumor sizes ranged from 2.0 to 6.5 cm, and their pretreatment serum β-human chorionic gonadotropin (β-hCG) levels ranged from 3664 to 312 468 mIU/mL. All the patients were categorized as having FIGO Stage I disease, with four patients at low risk and three at high risk. Six of the seven were misdiagnosed with ectopic pregnancy before pathologic examination.
CONCLUSIONS
Clinicians should pay attention to masses in cesarean scar and to continuous elevation of serum β-hCG levels after treatment. When cesarean scar choriocarcinoma is suspected, diagnostic surgery can be chosen for tentative treatment and pathologic sampling. Salvage EMA-CO chemotherapy (etoposide, actinomycin D, methotrexate, cyclophosphamide and vincristine) should be performed as early as possible to prevent metastasis and recurrence after pathologic diagnosis.
Topics: Pregnancy; Female; Humans; Adult; Cicatrix; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Methotrexate; Etoposide
PubMed: 36710632
DOI: 10.1002/ijgo.14702 -
Cell Cycle (Georgetown, Tex.) Oct 2021CircRNA LNPEP has been shown to promote the development of hepatocellular carcinoma, but its function in ovarian cancer (OC) remains unclear. The Kaplan-Meier method was...
CircRNA LNPEP has been shown to promote the development of hepatocellular carcinoma, but its function in ovarian cancer (OC) remains unclear. The Kaplan-Meier method was used to analyze the clinical significance of circLNPEP expression in OC patients. The stability of circLNPEP was detected by actinomycin D and RNase R treatment. The correlations between miR-876-3p and two genes (circLNPEP and WNT5A) were predicted by bioinformatics analysis and confirmed by dual-luciferase reporter assay. Expressions of circLNPEP, miR-876-3p, and WNT5A were determined by qRT-PCR and western blot. The effect of circLNPEP/miR-876-3p/WNT5A axis on viability, proliferation, migration, and invasion, and angiogenesis of cells was determined by cell function experiment and rescue experiment. Xenograft tumor mice were constructed for verification. Expressions of apoptosis, epithelial mesenchymal transition (EMT)-related genes, and CD34 were determined by qRT-PCR, western blot and immunohistochemistry. High level of circLNPEP was related to poor prognosis in OC. CircLNPEP was highly expressed in OC tissues and cell lines, mainly distributed in the cytoplasm, while miR-876-3p was the opposite. MiR-876-3p targeted and negatively correlated with circLNPEP and WNT5A. Sh-circLNPEP repressed cell viability, proliferation, migration, invasion, angiogenesis, and EMT but promoted apoptosis, which were related to its regulation of expression of EMT- and apoptosis-related genes, WNT5A, and CD34. The regulatory effect of sh-circLNPEP can be reversed by miR-876-3p inhibitor, and that of miR-876-3p inhibitor can be reversed by sh-WNT5A. CircLNPEP promoted cancer cell proliferation, EMT and angiogenesis, and inhibited apoptosis by regulating miR-876-3p/WNT5A axis.
Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Liver Neoplasms; Mice; MicroRNAs; Ovarian Neoplasms; Wnt-5a Protein
PubMed: 34465271
DOI: 10.1080/15384101.2021.1965723 -
Nucleic Acids Research May 2023Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here,...
Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.
Topics: Humans; Animals; Mice; Dactinomycin; Echinomycin; Thymine; Base Sequence; Binding Sites; Nucleic Acid Conformation; DNA; Colorectal Neoplasms
PubMed: 36919604
DOI: 10.1093/nar/gkad156 -
Journal of Clinical Oncology : Official... Nov 2022Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
PATIENTS AND METHODS
In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
RESULTS
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% ( < .0001) and 3-year OS 60.0% versus 26.0% ( < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
CONCLUSION
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.
Topics: Child; Humans; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Rhabdomyosarcoma; Sarcoma; Ifosfamide; Vincristine; Cyclophosphamide; Dactinomycin; Doxorubicin; Neoplasms, Second Primary
PubMed: 35709412
DOI: 10.1200/JCO.21.02981 -
Journal of Integrative Bioinformatics Sep 2022Breast cancer metastases are most commonly found in bone, an indication of poor prognosis. Pathway-based biomarkers identification may help elucidate the cellular...
Breast cancer metastases are most commonly found in bone, an indication of poor prognosis. Pathway-based biomarkers identification may help elucidate the cellular signature of breast cancer metastasis in bone, further characterizing the etiology and promoting new therapeutic approaches. We extracted gene expression profiles from mouse macrophages from the GEO dataset, GSE152795 using the GEO2R webtool. The differentially expressed genes (DEGs) were filtered by log2 fold-change with threshold 1.5 (FDR < 0.05). STRING database and Enrichr were used for GO-term analysis, miRNA and TF analysis associated with DEGs. Autodock Vienna was exploited to investigate interaction of anti-cancer drugs, Actinomycin-D and Adriamycin. Sensitivity and specificity of DEGs was assessed using receiver operating characteristic (ROC) analyses. A total of 61 DEGs, included 27 down-regulated and 34 up-regulated, were found to be significant in breast cancer bone metastasis. Major DEGs were associated with lipid metabolism and immunological response of tumor tissue. Crucial DEGs, Bcl3, ADGRG7, FABP4, VCAN, and IRF4 were regulated by miRNAs, miR-497, miR-574, miR-138 and TFs, CCDN1, STAT6, IRF8. Docking analysis showed that these genes possessed strong binding with the drugs. ROC analysis demonstrated Bcl3 is specific to metastasis. DEGs Bcl3, ADGRG7, FABP4, IRF4, their regulating miRNAs and TFs have strong impact on proliferation and metastasis of breast cancer in bone tissues. In conclusion, present study revealed that DEGs are directly involved in of breast tumor metastasis in bone tissues. Identified genes, miRNAs, and TFs can be possible drug targets that may be used for the therapeutics. However, further experimental validation is necessary.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Computational Biology; Dactinomycin; Doxorubicin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Interferon Regulatory Factors; Mice; MicroRNAs; Neoplasms
PubMed: 35388653
DOI: 10.1515/jib-2021-0041 -
Proceedings of the National Academy of... Aug 2021Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only...
Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.
Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Cell Line; Cyclosporine; Dactinomycin; Doxorubicin; Enzyme Inhibitors; Fas Ligand Protein; Gene Deletion; Gene Expression Regulation, Enzymologic; Hexokinase; Humans; Mitochondria; TNF-Related Apoptosis-Inducing Ligand; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 34385311
DOI: 10.1073/pnas.2021175118 -
BMC Gastroenterology Dec 2022Colorectal cancer (CRC) is a prevalent malignancy of the gastrointestinal. Circular RNAs (circRNAs) act as important roles in CRC malignant progression. However, the...
BACKGROUND
Colorectal cancer (CRC) is a prevalent malignancy of the gastrointestinal. Circular RNAs (circRNAs) act as important roles in CRC malignant progression. However, the role of circ_0039857 in CRC is still unclear. Therefore, this study aimed to explore the function and mechanism of hsa_circ_0039857 in the CRC.
METHODS
The mRNA and protein expression were measured via RT-qPCR. RNase R assay and Actinomycin D were employed to evaluate the stability of circ_0039857. Functional experiments, such as proliferation and apoptosis, were applied to study the function of circ_0039857 in CRC cells. The underlying mechanisms of circ_0039857 were then analyzed by bioinformatics, dual-luciferase reporter gene assay, RNA pull-down and rescue experiments.
RESULTS
We revealed that circ_0039857 was significantly enhanced in CRC. Circ_0039857 was stabler than linear RNA in cells and valuable for the disease diagnosis. In addition, circ_0039857 knockdown inhibited proliferation and promoted apoptosis. Mechanistically, circ_0039857 positively regulated the expression of RAB32 via sponging miR-338-3p.
CONCLUSION
This study demonstrated that circ_0039857 knockdown suppressed CRC malignant progression through miR-338-3p/RAB32 axis. Most importantly, this will help us to better understand the circRNA network in CRC, and may find potential biomarkers and targets for CRC clinical treatment.
Topics: Humans; Colorectal Neoplasms; Cell Proliferation; MicroRNAs; RNA, Circular; Biomarkers; rab GTP-Binding Proteins
PubMed: 36539702
DOI: 10.1186/s12876-022-02622-1