It is important to establish cancer stem cell (CSC)-targeted therapies to eradicate cancer. As it is a CSC marker, we focused on Kruppel-like factor 5 (KLF5) in this study.
We searched for candidate ...microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines.
We identified one promising miRNA, miR-4711-5p, that downregulated KLF5 expression by direct binding. This miRNA suppressed cell proliferation, migration and invasion ability, as well as stemness, including decreased stem cell marker expression, reactive oxygen species activity and sphere formation ability. MiR-4711-5p inhibited the growth of DLD-1 xenografts in nude mice with no adverse effects. We found that miR-4711-5p provoked G1 arrest, which could be attributed to direct binding of miR-4711-5p to TFDP1 (a heterodimeric partner of the E2F family). Our findings also suggested that direct binding of miR-4711-5p to MDM2 could upregulate wild-type p53, leading to strong induction of apoptosis. Finally, we found that miR-4711-5p had a potent tumour-suppressive effect compared with a putative anti-oncomiR, miR-34a, in tumour cell cultures derived from five patients with colorectal cancer.
Our data suggest that miR-4711-5p could be a promising target for CSC therapy.
Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of ...CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E‐cadherin‐Fc chimera protein (E‐cad‐Fc) enhances cancer stem‐like properties because studies show that soluble E‐cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)‐degron–transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E‐cad‐Fc treatment, we found that E‐cad‐Fc treatment further suppressed proteasome activity and largely enhanced cancer stem‐like properties of ODC‐degron–transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi‐1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5‐fluorouracil (5‐FU) and oxaliplatin (L‐OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E‐cad‐Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E‐cad‐Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E‐cad‐Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation.
E‐cadherin matrix induces epithelial‐mesenchymal transition in colon cancer. It also facilitates cancer stem‐like properties in ODC‐degron–transduced cells.
Background and objective A cytokine storm is caused by inflammatory cells, including pro-inflammatory macrophage phenotype (M1), and play a critical role in the pathogenesis of COVID-19, in which ...diffuse alveolar damage occurs in the lungs due to oxidative stress exposure. Heme oxygenase (HO)-1 is a stress-induced protein produced by the anti-inflammatory / anti-oxidative macrophage phenotype (M2), which also produces soluble CD163 (sCD163). In our study, we investigated and determined that serum HO-1 can be a predictive biomarker for assessing both the severity and the outcome of COVID-19 patients. Method The serum concentrations of HO-1 and sCD163 of COVID-19 patients were measured on admission. The relationship between these biomarkers and other clinical parameters and outcomes were evaluated. Results Sixty-four COVID-19 patients (11 mild, 38 moderate, and 15 severe cases) were assessed. The serum HO-1 tended to increase (11.0 ng/mL vs. 24.3 ng/mL vs. 59.6 ng/mL with severity). Serum HO-1 correlated with serum lactate dehydrogenase (R = 0.422), C-reactive protein (R = 0.463), and the ground glass opacity (GGO) and consolidation score (R = 0.625) of chest computed tomography. The serum HO-1 showed a better area under the curve (AUC) for predicting ICU admission than the serum sCD163 (HO-1; 0.816 and sCD163; 0.743). In addition, composite parameters including serum HO-1 and the GGO and consolidation score showed a higher AUC for predicting ICU admission than the AUC of a single parameter. Conclusion Clinically, serum HO-1, reflecting the activation of M2, could be a very useful marker for evaluating disease severity and predicting prognoses for COVID-19 patients. In addition, controlling activated M2 might be a preventative COVID-19 therapeutic target.
Abstract
Glioblastoma is the most common brain tumor with dismal outcomes in adults. Metabolic remodeling is now widely acknowledged as a hallmark of cancer cells, but glioblastoma-specific metabolic ...pathways remain unclear. Here we show, using a large-scale targeted proteomics platform and integrated molecular pathway-level analysis tool, that the de novo pyrimidine synthesis pathway and serine synthesis pathway (SSP) are the major enriched pathways in vivo for patients with glioblastoma. Among the enzymes associated with nucleotide synthesis, RRM1 and NME1 are significantly upregulated in glioblastoma. In the SSP, SHMT2 and PSPH are upregulated but the upstream enzyme PSAT1 is downregulated in glioblastoma. Kaplan–Meier curves of overall survival for the GSE16011 and The Cancer Genome Atlas datasets revealed that high SSP activity correlated with poor outcome. Enzymes relating to the pyrimidine synthesis pathway and SSP might offer therapeutic targets for new glioblastoma treatments.
Theoretical methods, such as molecular mechanics and molecular dynamics, are very useful in understanding differences in interactions at the single molecule level. In the life sciences, small ...conformational changes, including substituent modifications, often have a significant impact on function in vivo. Changes in binding interactions between nucleic acid molecules and binding proteins are a prime example. In this study, we propose a strategy to predict the complex structure of DNA-binding proteins with arbitrary DNA and analyze the differences in their interactions. We tested the utility of our strategy using the anticancer drug trifluoro-thymidine (FTD), which exerts its pharmacological effect by incorporation into DNA, and confirmed that the binding affinity of the BCL-2-associated X sequence to the p53 tetramer is increased by FTD incorporation. On the contrary, in p53-binding sequences extracted from FTD-resistant cells, the binding affinity of DNA containing FTD was found to be greatly reduced compared to normal DNA. This suggests that thymidine randomly substituted for FTD in resistant cells may acquire resistance by entering a position that inhibits binding to DNA-binding proteins. We believe that this is a versatile procedure that can also take energetics into account and will increase the importance of computational science in the life sciences.
The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at ...the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.
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•Spatial and single-cell atlas of human normal and cancer colorectal tissues•Colorectal cancer cells at the invasive front co-localize with macrophages•Spatial intercellular communication occurs between tumor cells and stromal cells•HLA-G is essential for anti-tumor immunity in colorectal cancer
Ozato et al. utilize a spatial transcriptome analysis approach to identify malignant crosstalk among co-localized cells in the cancer microenvironment. CRC cells localized at the invasion front induce HLA-G to produce SPP1+ macrophages, simultaneously conferring anti-tumor immunity as well as proliferative and invasive properties to CRC cells.
The presence of some amino acid mutations in the amino acid sequence that determines a protein’s structure can significantly affect that 3D structure and its biological function. However, the effects ...upon structural and functional changes differ for each displaced amino acid, and it is very difficult to predict these changes in advance. Although computer simulations are very effective at predicting conformational changes, they struggle to determine whether the amino acid mutation of interest induces sufficient conformational changes, unless the researcher is a specialist in molecular structure calculations. Therefore, we created a framework that efficiently utilizes molecular dynamics and persistent homology methods to identify amino acid mutations that induce structural changes. We show that this framework can be used not only to predict conformational changes produced by amino acid mutations but also to extract groups of mutations that significantly alter similar molecular interactions, by capturing the resultant protein–protein interaction changes.
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We previously demonstrated that miR-29b-3p is a hopeful miRNA-based therapy against colorectal cancer. In this study, we aimed to clarify a value of miR-29b-1-5p as a next-generation treatment, ...especially for
-mutant colorectal cancer. RT-PCR assay showed that the expression of miR-29b-3p was high, and its partner strand, miR-29b-1-5p, level was only negligible in clinical colorectal cancer samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of
-mutant colorectal cancer cell lines DLD1 and SW480 and
wild-type HT29 cells. Proliferative activity was further examined by either miR-29b-1-5p strand or its opposite complementary sequence because miR-29b-1-5p is a passenger miRNA and may have no physiologic function. We found that completely opposite complementary strand to miR-29b-1-5p, but not miR-29b-1-5p, possessed a potent antitumor effect and named this byproduct miRNA sequence "MIRTX." MIRTX directly targeted the 3'-UTR of
and
mRNA and suppressed the NF-κB signaling pathway in
-mutated colorectal cancer cells. MIRTX induced apoptosis in DLD1 with downregulation of antiapoptotic BCL2, BCL-xL, and MCL1 and upregulation of cleaved caspase-3 and cleaved PARP. In mouse xenograft models, systemic administration of MIRTX using a super carbonate apatite as a delivery vehicle significantly inhibited tumor growth of DLD1 and HT29 cells without any particular toxicities. In conclusion, these findings indicate that inhibition of NF-κB signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory
-mutant colorectal cancer and
wild-type colorectal cancer.
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Objective Although malignant lymphoma (ML) can occur in every organ, diagnosing cardiac involvement without cardiac manifestations is difficult. We therefore investigated the incidence of cardiac ...involvement in ML in our hospital and clarified the transthoracic echocardiography (TTE) findings of cardiac involvement. Methods Patients with ML referred to our hospital between January 2013 and December 2019 were retrospectively reviewed. Patients During the study period, 453 patients were identified. The mean age was 64.9 years old, and 54% of the patients were men. Results Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma, followed by follicular lymphoma. Of the 453 patients, 394 (87.0%) underwent TTE at the initial diagnosis or during the clinical course. The performance rates of TTE in DLBCL, Hodgkin lymphoma, and mantle cell lymphoma were above 90%. Cardiac involvement was detected in 6 (five with DLBCL and one with B-cell lymphoma) (1.5%) of the 394 patients who underwent TTE. The involved lesions of the heart varied, and five patients had pericardial effusion. Five patients had a preserved left ventricular ejection fraction. All patients were treated with chemotherapy, and some were treated with radiation and surgery. Conclusion Cardiac involvement was observed in six (1.5%) of the patients with ML who underwent TTE. B-cell lymphoma, especially DLBCL, is a common ML with cardiac involvement. Although five patients had pericardial effusion, the involved lesions of the heart were not uniform. TTE is a useful imaging modality to noninvasively and repeatedly evaluate the tumor characteristics, response to ML treatment, and cardiac function.
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