scholarly journals TAGLN mediated stiffness-regulated ovarian cancer progression via RhoA/ROCK pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiao Wei ◽  
Hua Lou ◽  
Dongchen Zhou ◽  
Yijuan Jia ◽  
Huayi Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Cross Linking ◽  
Matrix Stiffness ◽  
Transwell Assay ◽  
Primary Tumors ◽  
Atomic Force ◽  
Therapeutic Value

Abstract Background Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer (EOC), we were inspired to investigate OC progression from the perspective of biomechanics. Methods Atomic Force Microscope (AFM) was used to measure the Young’s modulus of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN was evaluated both in vitro and in vivo using transwell assay, immunofluorescence, western blot analysis and immunohistochemistry. Results We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. Conclusions These data demonstrate that targeting extra-cellular matrix (ECM) stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy.

scholarly journals HNRNPH1-stabilized LINC00662 promotes ovarian cancer progression by activating the GRP78/p38 pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Yong Wu ◽  
Qinhao Guo ◽  
Xingzhu Ju ◽  
Zhixiang Hu ◽  
Lingfang Xia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Prognostic Indicator ◽  
Mapk Signaling ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Proliferation And Metastasis ◽  
Nuclear Ribonucleoprotein

AbstractNumerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.

scholarly journals Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hongwei Zhao ◽  
Hasaan Hayat ◽  
Xiaohong Ma ◽  
Daguang Fan ◽  
Ping Wang ◽  
...  
Keyword(s):  
Neural Networks ◽  
Ovarian Cancer ◽  
Deep Learning ◽  
Cancer Progression ◽  
In Vivo Imaging ◽  
Near Infrared ◽  
Response To Therapy ◽  
Response To Chemotherapy

Abstract Artificial Intelligence (AI) algorithms including deep learning have recently demonstrated remarkable progress in image-recognition tasks. Here, we utilized AI for monitoring the expression of underglycosylated mucin 1 (uMUC1) tumor antigen, a biomarker for ovarian cancer progression and response to therapy, using contrast-enhanced in vivo imaging. This was done using a dual-modal (magnetic resonance and near infrared optical imaging) uMUC1-specific probe (termed MN-EPPT) consisted of iron-oxide magnetic nanoparticles (MN) conjugated to a uMUC1-specific peptide (EPPT) and labeled with a near-infrared fluorescent dye, Cy5.5. In vitro studies performed in uMUC1-expressing human ovarian cancer cell line SKOV3/Luc and control uMUC1low ES-2 cells showed preferential uptake on the probe by the high expressor (n = 3, p < .05). A decrease in MN-EPPT uptake by SKOV3/Luc cells in vitro due to uMUC1 downregulation after docetaxel therapy was paralleled by in vivo imaging studies that showed a reduction in probe accumulation in the docetaxel treated group (n = 5, p < .05). The imaging data were analyzed using deep learning-enabled segmentation and quantification of the tumor region of interest (ROI) from raw input MRI sequences by applying AI algorithms including a blend of Convolutional Neural Networks (CNN) and Fully Connected Neural Networks. We believe that the algorithms used in this study have the potential to improve studying and monitoring cancer progression, amongst other diseases.

scholarly journals The polypeptide GALNT6 Displays Redundant Functions upon Suppression of its Closest Homolog GALNT3 in Mediating Aberrant O-Glycosylation, Associated with Ovarian Cancer Progression

2019 ◽  
Vol 20 (9) ◽  
pp. 2264 ◽  
Author(s):  
Razan Sheta ◽  
Magdalena Bachvarova ◽  
Elizabeth Macdonald ◽  
Stephane Gobeil ◽  
Barbara Vanderhyden ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Functional Redundancy ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Gene Ablation

Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy; a better understanding of the molecular mechanisms associated with EOC etiology could substantially improve EOC management. Aberrant O-glycosylation in cancer is attributed to alteration of N-acetylgalactosaminyltransferases (GalNAc-Ts). Reports suggest a genetic and functional redundancy between GalNAc-Ts, and our previous data are indicative of an induction of GALNT6 expression upon GALNT3 suppression in EOC cells. We performed single GALNT3 and double GALNT3/T6 suppression in EOC cells, using a combination of the CRISPR-Cas9 system and shRNA-mediated gene silencing. The effect of single GALNT3 and double GALNT3/T6 inhibition was monitored both in vitro (on EOC cells roliferation, migration, and invasion) and in vivo (on tumor formation and survival of experimental animals). We confirmed that GALNT3 gene ablation leads to strong and rather compensatory GALNT6 upregulation in EOC cells. Moreover, double GALNT3/T6 suppression was significantly associated with stronger inhibitory effects on EOC cell proliferation, migration, and invasion, and accordingly displayed a significant increase in animal survival rates compared with GALNT3-ablated and control (Ctrl) EOC cells. Our data suggest a possible functional redundancy of GalNAc-Ts (GALNT3 and T6) in EOC, with the perspective of using both these enzymes as novel EOC biomarkers and/or therapeutic targets.

scholarly journals EPDR1, Which Is Negatively Regulated by miR-429, Suppresses Epithelial Ovarian Cancer Progression via PI3K/AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhendan Zhao ◽  
Zhiling Wang ◽  
Pengling Wang ◽  
Shujie Liu ◽  
Yingwei Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Figo Stage ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Gynecology And Obstetrics

Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future.

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 Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel

2019 ◽  
Vol 20 (5) ◽  
pp. 1042 ◽  
Author(s):  
Apriliana Cahya Khayrani ◽  
Hafizah Mahmud ◽  
Aung Ko Ko Oo ◽  
Maram H. Zahra ◽  
Miharu Oze ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Stem Cell Marker ◽  
Ovarian Cancer Cells ◽  
Cancer Therapies ◽  
Ovarian Cancer Cell Lines ◽  
Tumor Selective

Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15–20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies.

scholarly journals Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

2015 ◽  
Vol 112 (14) ◽  
pp. 4411-4416 ◽  
Author(s):  
Amit Kumar Srivastava ◽  
Chunhua Han ◽  
Ran Zhao ◽  
Tiantian Cui ◽  
Yuntao Dai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Dna Polymerase ◽  
Ovarian Cancer Stem Cells ◽  
Primary Tumors ◽  
Tumor Relapse ◽  
Induced Apoptosis

Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

scholarly journals miR-362-3p acts as a tumor suppressor by targeting SERBP1 in ovarian cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shujun Cao ◽  
Na Li ◽  
Xihong Liao
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Gynecological Cancer ◽  
Luciferase Reporter ◽  
Loss Of Function

Abstract Background Ovarian cancer is the leading lethal gynecological cancer and is generally diagnosed during late-stage presentation. In addition, patients with ovarian cancer still face a low 5-year survival rate. Thus, innovative molecular targeting agents are required to overcome this disease. The present study aimed to explore the function of miR-362-3p and the underlying molecular mechanisms influencing ovarian cancer progression. Methods The expression levels of miR-362-3p were determined using qRT-PCR. Gain-of-function and loss-of-function methods were used to detect the effects of miR-362-3p on cell proliferation, cell migration, and tumor metastasis in ovarian cancer. A luciferase reporter assay was performed to confirm the potential target of miR-362-3p, and a rescue experiment was employed to verify the effect of miR-362-3p on ovarian cancer by regulating its target gene. Results miR-362-3p was significantly downregulated in ovarian cancer tissues and cell lines. In vitro, our data showed that miR-362-3p suppressed cell proliferation and migration. In vivo, miR-362-3p inhibited ovarian cancer growth and metastasis. Mechanistically, SERBP1 was identified as a direct target and functional effector of miR-362-3p in ovarian cancer. Moreover, SERBP1 overexpression rescued the biological function of miR-362-3p. Conclusions Our data reveal that miR-362-3p has an inhibitory effect on ovarian cancer. miR-362-3p inhibits the development and progression of ovarian cancer by directly binding its target gene SERBP1.

scholarly journals CircCRIM1 promotes ovarian cancer progression by working as ceRNAs of CRIM1 and targeting miR-383-5p/ZEB2 axis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuping Du ◽  
Xin Liu ◽  
Song Zhang ◽  
Shuo Chen ◽  
Xue Guan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Gynecologic Cancer ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Reporter System ◽  
Correlation Relationship

Abstract Background Ovarian cancer is the leading cause of death in patients with gynecologic cancer, and circular RNAs (circRNAs) are involved in cancer progression. However, there are limited studies on the roles of circRNAs in ovarian cancer. Methods We designed divergent and convergent primers, used sanger sequencing and RNase R digestion to verify the source of circCRIM1. We detected the expression of circCRIM1 and its parental gene cysteine rich transmembrane BMP regulator 1 (CRIM1) in ovarian cancer and normal ovarian samples via qRT-PCR. MTT viability assay, apoptosis assay, wound healing assay and invasion assay were used to investigate the function of circCRIM1 and CRIM1 in ovarian cancer cell lines OVCAR3 and CAOV3. Mice xenografts experiment was performed. Bioinformatics predicted the microRNAs that bond with circCRIM1 and CRIM1, and dual luciferase reporter system confirmed it. Rescue experiments of microRNAs mimics transfection on the basis of circCRIM1 over-expression were carried out to uncover the mechanism by which circCRIM1 played cancer-promoting roles in ovarian cancer. Results CircCRIM1 was derived from CRIM1 by back-splicing. CircCRIM1 and CRIM1 had higher expression in ovarian cancer than in normal ovarian tissues, and both of them promoted ovarian cancer progression in vitro. In vivo circCRIM1 promoted the growth of tumors. CircCRIM1 and CRIM1 had a positive correlation relationship in the same cohort of ovarian cancer tissues. Bioinformatics predicted and dual luciferase assay confirmed circCRIM1 and CRIM1 bond with miR-145-5p, and circCRIM1 bond with miR-383-5p additionally. CircCRIM1 positively affected the expression of CRIM1. After circCRIM1 was over-expressed, miR-145-5p mimics transfection reversed the expression of CRIM1. Western blot discovered circCRIM1 positively affected the expression of zinc finger E-box binding homeobox 2 (ZEB2). Rescue experiments found miR-383-5p mimics reversed ZEB2 expression and the cancer-promoting effects of circCRIM1. Conclusions CircCRIM1 bond with miR-145-5p to work as competing endogenous RNA (ceRNA) of CRIM1, and circCRIM1 bond with miR-383-5p to improve the expression of ZEB2 in ovarian cancer. CircCRIM1 and CRIM1 promoted the ovarian cancer progression and supplied a novel insight into the researches of ovarian cancer.

scholarly journals Down-regulation of ZNF252P-AS1 alleviates ovarian cancer progression by binding miR-324-3p to downregulate LY6K

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Li Geng ◽  
Zhongqiu Wang ◽  
Yongju Tian
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
In Vivo Experiments ◽  
Cancer Tissues

Abstract Background Ovarian cancer is a common gynecological malignant disease in women. Our work aimed to study the specific functions of ZNF252P antisense RNA 1 (ZNF252P-AS1) in ovarian cancer. Methods ZNF252P-AS1, miR-324-3p, and lymphocyte antigen 6 family member K (LY6K) expression were analyzed by bioinformatics tools in ovarian cancer tissues and was quantified by qRT-PCR in ovarian cancer cells. The effect of ZNF252P-AS1 knockdown, miR-324-3p suppression, and LY6K over-expression on apoptosis, cell viability, invasion, migration, and epithelial to mesenchymal transition (EMT) was determined in vitro by using colony formation and EdU assays, flow cytometry, transwell assay, and Western blot. The interactions between ZNF252P-AS1 and miR-324-3p and between miR-324-3p and LY6K were validated by luciferase assays. The effects of restraining ZNF252P-AS1 in vivo were studied using BALB/c male nude mice. Results ZNF252P-AS1 and LY6K levels were up-regulated, while miR-324-3p was declined in ovarian cancer tissues and cells. ZNF252P-AS1 knockdown reduced ovarian cancer cell proliferation, invasion, migration, and EMT, whereas promoted its apoptosis. Besides, ZNF252P-AS1 interacted with miR-324-3p and reversely regulated its level, and miR-324-3p was directly bound to LY6K and negatively regulated its expression. Moreover, ZNF252P-AS1 knockdown reversed the effect of miR-324-3p on cancer cell apoptosis, growth, migration, invasion, and EMT. Similar results were discovered in the rescue experiments between miR-324-3p and LY6K. Additionally, mouse models in vivo experiments further validated that ZNF252P-AS1 knockdown distinctly inhibited tumor growth. Conclusion ZNF252P-AS1 mediated miR-324-3p/LY6K signaling to facilitate progression of ovarian cancer.

Sign in / Sign up

Export Citation Format

Share Document