scholarly journals Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours

2018 ◽  
Vol 19 (7) ◽  
pp. 2045 ◽  
Author(s):  
Ricardo Coelho ◽  
Lara Marcos-Silva ◽  
Nuno Mendes ◽  
Daniela Pereira ◽  
Catarina Brito ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Ovarian Carcinomas ◽  
Cellular Models ◽  
Ovarian Cancer Cell Lines ◽  
Ovca Cell

Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer.

scholarly journals Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4

2019 ◽  
Vol 317 (5) ◽  
pp. G670-G681 ◽  
Author(s):  
Jixiang Niu ◽  
Zhen Li ◽  
Fuzhou Li
Keyword(s):  
Gallbladder Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Nude Mice ◽  
Expression Profiles ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

In recent studies, microRNAs (miRs) have been widely explored as important regulators in tumor suppression. miR-136 has been suggested to participate in tumor inhibition through control of vital cellular processes, such as angiogenesis, proliferation, and apoptosis. This study aimed to evaluate the effects of overexpressed miR-136 by transferring mimics in gallbladder cancer (GBC) and to assess the functional role of miR-136 in GBC cell behaviors with the involvement of the mitogen-activated protein kinase kinase 4 ( MAP2K4)-dependent JNK signaling pathway. Differentially expressed miRs associated with GBC were screened using microarray expression profiles, which identified that miR-136 expression was decreased in GBC. Furthermore, MAP2K4 was validated as a target gene of miR-136. To uncover functional relevance regarding miR-136 and MAP2K4 in GBC, cultured GBC cell lines were prepared to transfect with mimic, inhibitor, siRNA, or vectors. At the same time, the transfected GBC cells were inoculated into nude mice to validate findings in vivo. The obtained results demonstrated that overexpressed miR-136 inhibited angiogenesis and cell proliferation and promoted apoptosis in GBC cell lines in vitro, accompanied by impeded cellular tumorigenicity in nude mice via the suppression of MAP2K4. Moreover, the overexpression of MAP2K4 and the activation of the JNK signaling pathway reversed the inhibitory effects of miR-136 on the angiogenesis and tumorigenicity of GBC cells. Together, our results indicated that overexpressed miR-136 attenuates angiogenesis and enhances cell apoptosis in GBC via the JNK signaling pathway by downregulating the expression of MAP2K4. NEW & NOTEWORTHY This study is based on previous studies suggesting the tumor-suppressive role of microRNA (miR)-136 in various cancers. We aim to clarify whether miR-136 could function as a tumor suppressor in gallbladder cancer (GBC) and an underlying mechanism. In vitro and in vivo assays delineated that the tumor-suppressive role of miR-136 in GBC is achieved through inactivation of the JNK signaling pathway by downregulation of MAP2K4.

scholarly journals Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5908
Author(s):  
Adam Neal ◽  
Tiffany Lai ◽  
Tanya Singh ◽  
Neela Rahseparian ◽  
Tristan Grogan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancer Cell Lines ◽  
Poor Outcomes

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.

scholarly journals Knockdown of TRIM44 inhibits the progression of human epithelial ovarian cancer via the FOXM1-EZH2 signaling pathway

2021 ◽  
Author(s):  
Fanling Meng ◽  
Jing Ding ◽  
Xihai Chen ◽  
Lin Sui ◽  
Yuanlong Hu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Tumor Model ◽  
Ovarian Cancer Cells ◽  
In Vitro Proliferation

Abstract Background. Tripartite motif‑containing protein 44 (TRIM44) was recently identified as a novel oncogene that is overexpressed in several types of human cancers. However, the biological functions of TRIM44 in epithelial ovarian cancer (EOC) remain unclear. Here, we aimed to investigate the role of TRIM44 in EOC and its clinical implications.Methods. The expression of TRIM44 in different ovarian cancer cell lines were detected by western blot. TRIM44 was knocked down by shRNA transfection. The in vitro proliferation, invasion, migration and apoptosis of ovarian cancer cells were detected by CCK8, colony formation assay, transwell filters, tube formation assay and flow cytometry analysis, respectively. The growth ability of xenograft tumors in vivo was examined by a nude mouse metastatic tumor model. Finally, we carried out gene chip analysis and IPA to analyze the potential gene network.Results. High expression of TRIM44 was observed in EOC tissues and cell lines. Knockdown of TRIM44 expression substantially suppressed the proliferation, migration, invasion and colony-forming ability of EOC cells in vitro and attenuated tumor growth in vivo. Mechanistic studies showed that silencing TRIM44 dramatically down regulated the expression of FOXM1, EZH2, CCNE2, CCND3 and BIRC5 in EOC cells, at least in part through inactivation of the FOXM1-EZH2 signaling pathway.Conclusion. Collectively, these data suggest that TRIM44 downregulation inhibits the progression of EOC cells through the suppression of the FOXM1-EZH2 signaling pathway. These results provide novel insight into the role of TRIM44 in tumorigenesis and suggest it could be a potential therapeutic target of ovarian carcinoma.

scholarly journals PAX8 orchestrates an angiogenic program through interaction with SOX17

2020 ◽  
Author(s):  
Daniele Chaves-Moreira ◽  
Marilyn A. Mitchell ◽  
Cristina Arruza ◽  
Priyanka Rawat ◽  
Simone Sidoli ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Therapeutic Target ◽  
Ovarian Carcinomas ◽  
Molecular Feature ◽  
Current Therapies ◽  
Bona Fide ◽  
The Impact

ABSTRACTWorldwide, the number of new ovarian cancer cases approaches 300,000 with more than 180,000 deaths every year. The low survival-rate reflects the limitations of current therapies and highlights the importance of identifying new therapeutic targets. Despite significant recent efforts to identify novel vulnerabilities in ovarian cancer, none have led to effective durable therapies with improvement in overall survival. PAX8, a lineage-transcription factor, whose expression is a major molecular feature of ovarian carcinomas, represents a novel therapeutic target. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated the impact of this interaction on the development of ovarian cancer. Importantly, we found that PAX8 and SOX17 regulate tumor angiogenesis in vitro and in vivo. The role of PAX8 and SOX17 in the regulation of angiogenesis reveals a novel function for these factors in regulating the tumor microenvironment and highlight this pathway as a viable therapeutic target.

scholarly journals LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity

2020 ◽  
Vol 27 (2) ◽  
pp. 81-95 ◽  
Author(s):  
Wei-Chun Chang ◽  
Hsiao-Ching Wang ◽  
Wei-Chung Cheng ◽  
Juan-Cheng Yang ◽  
Wei-Min Chung ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Density Lipoprotein ◽  
Lipoprotein Receptor ◽  
Ovarian Carcinomas ◽  
Platinum Based Chemotherapy ◽  
Cisplatin Sensitivity

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients’ disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

scholarly journals MicroRNA-320a Promotes Epithelial Ovarian Cancer Cell Proliferation and Invasion by Targeting RASSF8

2021 ◽  
Vol 11 ◽  
Author(s):  
Lili Zhang ◽  
Huixiao Chen ◽  
Fengxi He ◽  
Shiqian Zhang ◽  
Aihua Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Target Gene ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation

MicroRNAs (miRNAs) play important roles in tumorigenesis by controlling target gene expression. With opposing roles as a tumor suppressor or oncogene, microRNA-320a (miR-320a) was found to participate in tumor genesis and progression and also identified as a potentially useful marker in cancer diagnosis, treatment, and prognosis. To better understand the role of miR-320a in ovarian cancer, we investigated miR-320a expression in epithelial ovarian cancer (EOC) specimens as well as EOC cell lines and analyzed correlations between miR-320a expression and processes associated with EOC progression. The miR-320a level in EOC specimens was found to be associated with ovarian cancer progression and infiltration. Through in vitro and in vivo studies, we found that miR-320a significantly promoted the proliferation, migration, and invasion of EOC cells, and we identified RASSF8 as a target gene of miR-320a that was downregulated in EOC tissues and cell lines. In vitro downregulation of RASSF8 promoted the growth, migration, and invasion of EOC cells. Together these findings indicate that RASSF8 is a direct target of miR-320a, through which miR-320a promotes the progression of EOC.

scholarly journals Progression and Differentiation of Alveolar Rhabdomyosarcoma Is Regulated by PAX7 Transcription Factor—Significance of Tumor Subclones

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1870
Author(s):  
Klaudia Skrzypek ◽  
Grażyna Adamek ◽  
Marta Kot ◽  
Bogna Badyra ◽  
Marcin Majka
Keyword(s):  
Transcription Factor ◽  
Cell Lines ◽  
Migration Activity ◽  
Id Proteins ◽  
Rh30 Cell ◽  
Str Profile ◽  
And Migration

Rhabdomyosarcoma (RMS), is the most frequent soft tissue tumor in children that originates from disturbances in differentiation process. Mechanisms leading to the development of RMS are still poorly understood. Therefore, by analysis of two RMS RH30 cell line subclones, one subclone PAX7 negative, while the second one PAX7 positive, and comparison with other RMS cell lines we aimed at identifying new mechanisms crucial for RMS progression. RH30 subclones were characterized by the same STR profile, but different morphology, rate of proliferation, migration activity and chemotactic abilities in vitro, as well as differences in tumor morphology and growth in vivo. Our analysis indicated a different level of expression of adhesion molecules (e.g., from VLA and ICAM families), myogenic microRNAs, such as miR-206 and transcription factors, such as MYOD, MYOG, SIX1, and ID. Silencing of PAX7 transcription factor with siRNA confirmed the crucial role of PAX7 transcription factor in proliferation, differentiation and migration of RMS cells. To conclude, our results suggest that tumor cell lines with the same STR profile can produce subclones that differ in many features and indicate crucial roles of PAX7 and ID proteins in the development of RMS.

scholarly journals Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 969
Author(s):  
John S. Lazo ◽  
Elizabeth R. Sharlow ◽  
Robert Cornelison ◽  
Duncan J. Hart ◽  
Danielle C. Llaneza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Tyrosine Phosphatase ◽  
In Vitro Cytotoxicity ◽  
Mrna Levels ◽  
High Grade ◽  
Drug Resistant ◽  
Ovca Cell

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.

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