scholarly journals PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance

2022 ◽  
Author(s):  
Kevin Tabury ◽  
Mehri Monavarian ◽  
Eduardo Listik ◽  
Abigail K Shelton ◽  
Alex Seok Choi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Cell Survival ◽  
Cancer Metastasis ◽  
Cellular Stress ◽  
Stress Factors ◽  
Cellular Stress Response ◽  
Ovarian Cancer Cells ◽  
Dependent Manner

Metastatic growth of ovarian cancer cells into the peritoneal cavity requires adaptation to various cellular stress factors to facilitate cell survival and growth. Here we demonstrate the role of PVT1, one such stress induced long non-coding RNA, in ovarian cancer growth and metastasis. PVT1 is an amplified and overexpressed lncRNA in ovarian cancer with strong predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by ovarian tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1 dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation models in vivo. We find that reducing PVT1 causes widespread transcriptome changes leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which directly impacts chemosensitivity. Together, these findings implicate PVT1 as a promising therapeutic target to suppress metastasis and avoid chemoresistance in ovarian cancer.

scholarly journals LncRNA SPOCD1-AS from ovarian cancer extracellular vesicles remodels mesothelial cells to promote peritoneal metastasis via interacting with G3BP1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Conghui Wang ◽  
Jiaying Wang ◽  
Xiameng Shen ◽  
Mingyue Li ◽  
Yongfang Yue ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Vesicles ◽  
Peritoneal Metastasis ◽  
Cancer Metastasis ◽  
Cancer Therapeutics ◽  
Mesothelial Cells ◽  
Ovarian Cancer Cells ◽  
Adhesion Assay ◽  
Mesenchymal Transition

Abstract Background Metastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis. Methods EVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo. Results We found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo. Conclusions Our findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

scholarly journals Cordyceps militaris Exerts Antitumor Effect on Carboplatin-Resistant Ovarian Cancer via Activation of ATF3/TP53 Signaling In Vitro and In Vivo

2020 ◽  
Vol 15 (1) ◽  
pp. 1934578X2090255
Author(s):  
Eunbi Jo ◽  
Hyun-Jin Jang ◽  
Kyeong E. Yang ◽  
Min S. Jang ◽  
Yang H. Huh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
B Cell Lymphoma ◽  
Cordyceps Militaris ◽  
Exponential Growth Phase ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Parp 1

This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of carboplatin- resistant SKOV-3 and determine the underlying mechanisms for overcoming carboplatin resistance in human ovarian cancer. We cultured the carboplatin-resistant SKOV-3 cells in vitro until the exponential growth phase and then treated with different concentrations of C. militaris for 24, 48, and 72 hours. We performed cell proliferation assay, cell morphological change assessment using transmission electron microscopy, apoptosis assay, and immunoblotting to measure the protein expression of caspase-3 and -8, poly (ADP-ribose) polymerase (PARP)-1, B-cell lymphoma (Bcl)-2, and activating transcription factor 3 (ATF3)/TP53 signaling-related proteins. As a result, C. militaris reduced the viability of carboplatin-resistant SKOV-3 and induced morphological disruptions in a dose- and time-dependent manner. The gene expression profiles indicated a reprogramming pattern of the previously known and unknown genes and transcription factors associated with the action of TCTN3 on carboplatin-resistant SKOV-3 cells. We also confirmed the C. militaris-induced activation of the ATF3/TP53 pathway. Immunoblotting indicated that cotreatment of C. militaris and carboplatin-mediated ATF3/TP53 upregulation induced apoptosis in the carboplatin-resistant SKOV-3 cells, which are involved in the serial activation of pro-apoptotic proteins, including Bcl-2, Bax, caspases, and PARP-1. Further, when the ATF3 and TP53 expression increased, the CHOP and PUMA expressions were upregulated. Consequently, the upregulated CHOP/PUMA expression activated the positive regulation of the apoptotic signaling pathway. In addition, it decreased the Bcl-2 expression, leading to marked ovarian cancer cells sensitive to carboplatin by enhancing apoptosis. We then corroborated these results using in vivo experiments. Taken together, C. militaris inhibits carboplatin-resistant SKOV-3 cell proliferation and induces apoptosis possibly through ATF3/TP53 signaling upregulation and CHOP/PUMA activation. Therefore, our findings provide new insights into the treatment of carboplatin-resistant ovarian cancer using C. militaris.

scholarly journals Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells

2006 ◽  
Vol 119 (10) ◽  
pp. 2304-2312 ◽  
Author(s):  
Hua Yang ◽  
Lili He ◽  
Patricia Kruk ◽  
Santo V. Nicosia ◽  
Jin Q. Cheng
Keyword(s):  
Ovarian Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Aurora A

scholarly journals Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Yun Li ◽  
Hua Liu ◽  
Jiahui Zhang ◽  
Jie Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Ovarian Cancer Cells ◽  
Skov3 Cell ◽  
Anoikis Resistance ◽  
Primary Tumors ◽  
Genome Wide

Abstract Background The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance. Methods Genome-wide CRISPR/Cas9 knockout screen was used to identify critical drivers of anoikis resistance using SKOV3 cell line and found protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) as a candidate. Quantitative real-time PCR (qRT-PCR) and immune-histochemistry (IHC) were used to measure differentially expressed PCMT1 in primary tissues and metastatic cancer tissues. PCMT1 knockdown/knockout and overexpression were performed to investigate the functional role of PCMT1 in vitro and in vivo. The expression and regulation of PCMT1 and integrin-FAK-Src pathway were evaluated using immunoprecipitation followed by mass spectrometry (IP-MS), western blot analysis and live cell imaging. Results We found that PCMT1 enhanced cell migration, adhesion, and spheroid formation in vitro. Interestingly, PCMT1 was released from ovarian cancer cells, and interacted with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer progression. Strikingly, treatment with an antibody against extracellular PCMT1 effectively reduced ovarian cancer cell invasion and adhesion. Our in vivo results indicated that overexpression of PCMT1 led to increased ascites formation and distant metastasis, whereas knockout of PCMT1 had the opposite effect. Importantly, PCMT1 was highly expressed in late-stage metastatic tumors compared to early-stage primary tumors. Conclusions Through systematically identifying the drivers of anoikis resistance, we uncovered the contribution of PCMT1 to focal adhesion (FA) dynamics as well as cancer metastasis. Our study suggested that PCMT1 has the potential to be a therapeutic target in metastatic ovarian cancer.

scholarly journals The lnc-CTSLP8 upregulates CTSL1 as a competitive endogenous RNA and promotes ovarian cancer metastasis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xinjing Wang ◽  
Xiaoduan Li ◽  
Feikai Lin ◽  
Huizhen Sun ◽  
Yingying Lin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Lentiviral Vector ◽  
Metastatic Tumor ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Competitive Endogenous Rna

Abstract Background Ovarian cancer is highly lethal and has a poor prognosis due to metastasis. Long non-coding RNAs (lncRNAs) are key regulators of tumor development, but their role in ovarian cancer metastasis remains unclear. Methods The expression of lnc-CTSLP8 in ovarian cancer was analyzed in public databases (TCGA and GEO) and validated via qRT-PCR. Lnc-CTSLP8 overexpression and knockout cell lines were constructed using a lentiviral vector and the CRISP/Cas9 system. Cell proliferation, colony formation, migration, and invasion were analyzed. An ovarian orthotopic tumor mouse model was used for the in vivo study. Changes in autophagosomes, autolysosomes, and mitochondria in ovarian cancer cells were observed via transmission electron microscopy. EMT markers were detected by immunoblotting and immunofluorescence assays. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assays were performed to confirm the interaction between lnc-CTSLP8 and miR-199a-5p. Results A novel pseudogene, lnc-CTSLP8, was identified in ovarian cancer, with significantly elevated expression in metastatic tumor tissues compared to primary ovarian tumors. When overexpressed, lnc-CTSLP8 promoted ovarian cancer in vitro and in vivo by acting as a sponge for miR-199a-5p. Autophagy and EMT in ovarian cancer were also enhanced by lnc-CTSLP8. Mechanistically, lnc-CTSLP8 upregulated CTSL1 as a competitive endogenous RNA and exhibited oncogenic effects. Moreover, CTSL1 inhibitor treatment and miR-199a-5p overexpression abrogated the effects of lnc-CTSLP8 overexpression. Conclusions lnc-CTSLP8 acts as a ceRNA in ovarian cancer and represents a potential therapeutic target for metastatic ovarian cancer.

The metastatic phenotype shift toward myofibroblast of adipose-derived mesenchymal stem cells promotes ovarian cancer progression

2019 ◽  
Vol 41 (2) ◽  
pp. 182-193 ◽  
Author(s):  
Huijuan Tang ◽  
Yijing Chu ◽  
Zaiju Huang ◽  
Jing Cai ◽  
Zehua Wang
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cancer Metastasis ◽  
Abdominal Cavity ◽  
Ovarian Cancer Cells ◽  
Proliferation And Invasion ◽  
Tgf Β1

Abstract Ovarian cancer metastasizes to organs in the abdominal cavity, such as the omentum that is a rich source of adipose-derived mesenchymal stem cells (ADSCs). In present, ADSCs have received more and more attention for their roles in the development of cancer. In this study, we examined α-smooth muscle actin (α-SMA) expression and carcinoma-associated fibroblast (CAF)-like differentiation capabilities in ADSCs from omentum of different patients. The effects of ADSCs on the proliferation and invasion of epithelial ovarian cancer cells (EOCCs) were also assessed in vitro and in vivo. Our results showed that ADSCs from omentum of ovarian cancer patients, no matter whether metastasis or not, expressed higher levels of α-SMA than ADSCs from patients with benign gynecologic disease. Using direct and indirect co-culture system, we found that EOCCs induced ADSCs to express CAF markers, including α-SMA and fibroblast activation protein, via the transforming growth factor beta 1 (TGF-β1) signaling pathway. Moreover, co-cultured ADSCs exhibited functional properties similar to those of CAFs, including the ability to promote EOCCs proliferation, progression and metastasis both in vitro and in vivo. Furthermore, blocking the TGF-β1 pathway can counteract the CAF-like differentiation and tumor promotion effect of ADSCs. Our results suggest that ADSCs are a source of CAFs and that they participate in the interaction between EOCCs and the omental microenvironment. EOCCs could induce ADSCs in the omentum to differentiate before ovarian cancer metastasis, which participate in the formation of omental metastatic niches and promote the proliferation and invasion of ovarian cancer.

scholarly journals Exosomes in ovarian cancer ascites promote epithelial–mesenchymal transition of ovarian cancer cells by delivery of miR-6780b-5p

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Jing Cai ◽  
Lanqing Gong ◽  
Guodong Li ◽  
Jing Guo ◽  
Xiaoqing Yi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Metastasis ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ovarian Cancer Cells ◽  
Specific Mechanism ◽  
Mesenchymal Transition

AbstractThe poor prognosis of ovarian cancer is mainly due to metastasis, and the specific mechanism underlying ovarian cancer metastasis is not clear. Ascites-derived exosomes (ADEs) play an important role in the progression of ovarian cancer, but the mechanism is unknown. Here, we found that ADEs promoted ovarian cancer metastasis not only in vitro but also in vivo. This promotive function was based on epithelial–mesenchymal transition (EMT) of ovarian cancer cells. Bioinformatics analysis of RNA sequencing microarray data indicated that miR-6780b-5p may be the key microRNA (miRNA) in ADEs that facilitates cancer metastasis. Moreover, the expression of exosomal miR-6780b-5p correlated with tumor metastasis in ovarian cancer patients. miR-6780b-5p overexpression promoted and miR-6780b-5p downregulation suppressed EMT of ovarian cancer cells. These results suggest that ADEs transfer miR-6780b-5p to ovarian cancer cells, promoting EMT and finally facilitating ovarian cancer metastasis.

scholarly journals Plasma Treatment of Ovarian Cancer Cells Mitigates Their Immuno-Modulatory Products Active on THP-1 Monocytes

Plasma ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 201-217 ◽  
Author(s):  
Sander Bekeschus ◽  
Can Wulf ◽  
Eric Freund ◽  
Dominique Koensgen ◽  
Alexander Mustea ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Plasma Treatment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Expression Patterns ◽  
Cell Phenotype ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Ovarian Carcinomas

Cancers modulate their microenvironment to favor their growth. In particular, monocytes and macrophages are targeted by immuno-modulatory molecules installed by adjacent tumor cells such as ovarian carcinomas. Cold physical plasma has recently gained attention as innovative tumor therapy. We confirmed this for the OVCAR-3 and SKOV-3 ovarian cancer cell lines in a caspase 3/7 independent and dependent manner, respectively. To elaborate whether plasma exposure interferes with their immunomodulatory properties, supernatants of control and plasma-treated tumor cells were added to human THP-1 monocyte cultures. In the latter, modest effects on intracellular oxidation or short-term metabolic activity were observed. By contrast, supernatants of plasma-treated cancer cells abrogated significant changes in morphological and phenotypic features of THP-1 cells compared to those cultured with supernatants of non-treated tumor cell counterparts. This included cell motility and morphology, and modulated expression patterns of nine cell surface markers known to be involved in monocyte activation. This was particularly pronounced in SKOV-3 cells. Further analysis of tumor cell supernatants indicated roles of small particles and interleukin 8 and 18, with MCP1 presumably driving activation in monocytes. Altogether, our results suggest plasma treatment to alleviate immunomodulatory secretory products of ovarian cancer cells is important for driving a distinct myeloid cell phenotype.

scholarly journals 4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1187 ◽  
Author(s):  
Noor A. Lokman ◽  
Zoe K. Price ◽  
Emily K. Hawkins ◽  
Anne M. Macpherson ◽  
Martin K. Oehler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Survival ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Primary Cells ◽  
Spheroid Formation ◽  
Primary Ovarian Cancer

We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.

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