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1.
Life (Basel) ; 13(7)2023 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-37511982

RESUMO

Although surgery followed by platinum-based therapy is effective as a standard treatment in the early stages of ovarian cancer, the majority of cases are diagnosed at advanced stages, leading to poor prognosis. Thus, the identification of novel therapeutic drugs is needed. In this study, we assessed the effectiveness of bepridil-a calcium channel blocker-in ovarian cancer cells using two cell lines: SKOV-3, and SKOV-3-13 (a highly metastatic clone of SKOV-3). Treatment of these cell lines with bepridil significantly reduced cell viability, migration, and invasion. Notably, SKOV-3-13 was more sensitive to bepridil than SKOV-3. The TGF-ß1-induced epithelial-mesenchymal transition (EMT)-like phenotype was reversed by treatment with bepridil in both cell lines. Consistently, expression levels of EMT-related markers, including vimentin, ß-catenin, and Snail, were also substantially decreased by the treatment with bepridil. An in vivo mouse xenograft model was used to confirm these findings. Tumor growth was significantly reduced by bepridil treatment in SKOV-3-13-inoculated mice, and immunohistochemistry showed consistently decreased expression of EMT-related markers. Our findings are the first to report anticancer effects of bepridil in ovarian cancer, and they suggest that bepridil holds significant promise as an effective therapeutic agent for targeting metastatic ovarian cancer.

2.
Biochem Biophys Res Commun ; 613: 120-126, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35550198

RESUMO

The mechanism of melanoma metastasis is poorly understood, especially at the single-cell level. To understand the evolution from primary melanoma to metastasis, we investigated single-cell transcriptome profiles of parental B16 melanoma cells (B16F0) and its highly metastatic subclone (B16F10). Genomic alterations between cells were also analyzed by whole-exome sequencing. We identified 274 differentially expressed genes (DEGs) in B16F10, including upregulated genes related to metastasis, Lgals3, Sparc, Met, and Tmsb4x, and downregulated Mitf pathway genes, Ptgds, Cyb5a, and Cd63. The proportion of cycling cells and cells highly expressing Kdm5b was significantly high in B16F10 cells. Among the five subclusters of B16 cells (C1-5), C3/C4 clusters comprised both B16F0 and B16F10 cells and exhibited intermediate DEG patterns, whereas the C5 cluster mostly comprised B16F10 and showed typical metastatic characteristics. In trajectory analysis, the C4 cluster in B16F0, which showed unique characteristics (mainly cycling cells and upregulation of Mitf pathway genes), have transition potential to the C5 cluster (B16F10). Regarding genomic alterations, stepwise evolution with shared mutations, including Braf, Pten, and Trp53, and further specific alterations led to metastatic development. Our results provide deeper understanding of melanoma metastasis at the single-cell level, thus aiding further studies in melanoma metastasis control.


Assuntos
Melanoma Experimental , Animais , Linhagem Celular , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Metástase Neoplásica , Análise de Sequência de RNA , Sequenciamento do Exoma
3.
Biochem Biophys Res Commun ; 547: 44-51, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33592378

RESUMO

Troponin C type 1 (TNNC1) is commonly overexpressed in ovarian cancer. However, the biological implications of TNNC1 overexpression on ovarian cancer malignization and its related mechanism remain unknown. To elucidate these implications, we knocked out the TNNC1 gene in TNNC1-overexpressing SKOV-3-13 ovarian cancer cells using CRISPR/Cas-9 technology and observed the changes in metastatic phenotypes and related molecular pathways. TNNC1-knockout (KO) cells showed significantly reduced proliferation and colony formation when compared with TNNC1 wild-type cells (P < 0.01). In TNNC1-KO cells, wound healing, migration, and invasive phenotypes decreased. Upon observation of upstream regulators of epithelial-mesenchymal transition (EMT), levels of phosphorylated AKT (Ser-473 and Thr-308) and GSK-3ß (inactive form) were found to be decreased in TNNC1-KO cells. Accordingly, SNAIL and SLUG expression decreased and were almost completely localized in the cytoplasm following TNNC1 silencing. Regarding downstream EMT markers, N-cadherin and vimentin expression decreased, but E-cadherin expression increased. Related matrix metalloproteinase and chemokine expression generally decreased. TNNC1 deficiency also suppressed F-actin polymerization. In conclusion, TNNC1 overexpression contributes to the metastatic behavior of ovarian cancer by perturbation of EMT and actin microfilaments. Our results provide a better understanding of the detailed molecular mechanism of ovarian cancer metastasis associated with TNNC1 overexpression.


Assuntos
Actinas/metabolismo , Neoplasias Ovarianas/prevenção & controle , Troponina I/metabolismo , Antígenos CD/metabolismo , Sistemas CRISPR-Cas , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Silenciamento de Genes/métodos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Metástase Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Troponina I/genética , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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