scholarly journals TCP1 regulates PI3K/AKT/mTOR signaling pathway to promote proliferation of ovarian cancer cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Huixi Weng ◽  
Xiushan Feng ◽  
Yu Lan ◽  
Zhiqun Zheng
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Cancer Progression ◽  
Ovarian Tissue ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Pi3k Signaling ◽  
Pi3k Signaling Pathway

Abstract Objective TCP1 is one of the eight subunits of the TCP1 ring complex (TRiC) or the multi-protein mammalian cytosolic chaperone complex. TRiC participates in protein folding and regulates the expression of multiple signaling proteins and cytoskeletal components in cells. Although the clinical importance of its subunits has been clarified in various carcinomas, the function of TCP1 in ovarian cancer (OC) remains unclear. We aimed to identify the association between the expression of TCP1 and the development of epithelial OC (EOC) and patient prognosis, and explore the underlying mechanisms of TCP1 on the tumor progression of OC cells. Methods TCP1 protein expression was tested in various ovarian tissues by immunohistochemistry, and the correlation between TCP1 expression and clinical physiologic or pathologic parameters of patients with EOC was analyzed. The relationship between TCP1 expression and the prognosis of patients with OC was investigated and analyzed using the Kaplan–Meier (KM) plotter online database. The expression level of TCP1 was then tested in different OC cell lines by Western blotting. Further, a model using OC cell line A2780 was constructed to study the functions of TCP1 in growth, migration, and invasion of human EOC cells. Finally, the possible regulating signaling pathways were discussed. Results TCP1 protein expression in OC or borderline tissues was significantly higher than that in benign ovarian tumors and normal ovarian tissue. The upregulated expression of TCP1 in OC was positively associated with the differentiation grade and FIGO stage of tumors and predicted poor clinical outcomes. Compared with IOSE-80 cells, TCP1 protein was overexpressed in A2780 cells. TCP1 knockdown using shRNA lentivirus inhibited the viability of A2780 cells. Western blotting showed that the phosphatidylinositol-3 kinase (PI3K) signaling pathway was activated in the tumor invasion in EOC driven by TCP1. Conclusion Upregulated TCP1 is correlated with the poor prognosis of patients with OC. The mechanism of cancer progression promoted by TCP1 upregulation may be linked to the activation of the PI3K signaling pathway, and TCP1 may serve as a novel target for the treatment of OC.

scholarly journals Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4619
Author(s):  
Eun Yeong Lim ◽  
Joon Park ◽  
Yun Tai Kim ◽  
Min Jung Kim
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Monocyte Chemoattractant Protein 1 ◽  
Downstream Signaling ◽  
Castration Resistant

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

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 The Overexpression of Acyl-CoA Medium-Chain Synthetase-3 (ACSM3) Suppresses the Ovarian Cancer Progression via the Inhibition of Integrin β1/AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Limei Yan ◽  
Zeping He ◽  
Wei Li ◽  
Ning Liu ◽  
Song Gao
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Integrin Β1

Ovarian cancer is considered as one of the most fatal gynecologic malignancies. This work aimed to explore the effects and regulatory mechanism of Acyl-CoA medium-chain synthetase-3 (ACSM3, a subunit of CoA ligases) in ovarian cancer progression. As well as employing CCK-8 assay, clone formation assay, and cell cycle analysis were carried out to investigate cell proliferation ability. Wound healing assay and transwell assay were subsequently used to assess cell migration and invasion. Mice xenografts were then conducted to measure the effects of ACSM3 on tumor development in vivo. Our bioinformatics analysis suggested that the expression of ACSM3 was down-regulated in ovarian cancer tissues, and the low expression level of ACSM3 might related with poorer overall survival than high mRNA expression of ACSM3 in ovarian cancer patients. We artificially regulated the expression of ACSM3 to evaluate its effects on ovarian cancer malignant phenotypes. Our data revealed that the overexpression of ACSM3 inhibited cell proliferation, migration, and invasion of ovarian cancer cells. In contrast, the knock-down of ACSM3 received the opposite results. Our western blot results showed that the Integrin β1/AKT signaling pathway was negatively regulated by ACSM3 expression. Moreover, ACSM3 overexpression-induced suppression of cell migration and invasion activities were abolished by the overexpression of ITG β1 (Integrin β1). Additionally, the growth of ovarian cancer xenograft tumors was also repressed by the overexpression of ACSM3. And ACSM3 interference obtained the contrary effects in vivo. In summary, ACSM3 acts as a tumor suppressor gene and may be a potential therapeutic target of ovarian cancer.

scholarly journals UBE2S promotes the progression and Olaparib resistance of ovarian cancer through Wnt/β-catenin signaling pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Wenjing Hu ◽  
Min Li ◽  
Youguo Chen ◽  
Xinxian Gu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Cancer Proliferation ◽  
Skov3 Cells

Abstract Background Ovarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear. Materials and methods In this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model. Results The results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner. Conclusions These data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.

scholarly journals Evodiamine Inhibits Gastric Cancer Cell Proliferation via PTEN-Mediated EGF/PI3K Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Ruichuang Yang ◽  
Jianxia Wen ◽  
Tao Yang ◽  
Chunmei Dai ◽  
Yanling Zhao
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Protein Expression ◽  
Flow Cytometric Analysis ◽  
Migration And Invasion ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Flow Cytometric ◽  
Mrna And Protein Expression ◽  
Pi3k Signaling Pathway

Aims. In this study, the pharmacological effects and potential molecular mechanisms of evodiamine in treating gastric cancer (GC) were investigated. Methods. GC cells lines of AGS and BGC-823 were treated with evodiamine at various concentrations for different times (24, 48, and 72 h). Inhibition of the proliferation of AGS and BGC-823 cells was assessed using a CCK-8 assay. The morphology of gastric cancer cells was detected by high-content screening (HCS). The apoptosis-inducing effect of evodiamine on AGS and BGC-823 cells was detected by flow cytometric analysis. Cell migration and invasion were detected by Transwell assay. The relative mRNA and protein expression levels of PTEN-mediated EGF/PI3K signaling pathways were investigated via RT-qPCR or western blotting, respectively. Results. Evodiamine substantially inhibited AGS and BGC-823 cells proliferation in a dose- and time-dependent manner. Flow cytometric analysis revealed that evodiamine could induce apoptosis of AGS and BGC-823 cells in a dose-dependent manner. In addition, evodiamine inhibited AGS and BGC-823 cell migration and invasion. Mechanistically, the results demonstrated that evodiamine promoted the relative mRNA and protein expression of PTEN and decreased expression of EGF, EGFR, PI3K, AKT, p-AKT, and mTOR. Most importantly, evodiamine could effectively increase the mRNA and protein expression of PTEN and decrease the protein expression of EGF/PI3K pathway, indicating that evodiamine downregulated EGF/PI3K through the activation of PTEN pathway. Conclusion. Evodiamine inhibited the directional migration and invasion of GC cells by inhibiting PTEN-mediated EGF/PI3K signaling pathway. These findings revealed that evodiamine might serve as a potential candidate for the treatment or prevention of GC.

Defining the tumor cell: CA-MSC interactions which mediate ovarian cancer metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18072-e18072
Author(s):  
Ester Goldfeld ◽  
Huda Atiya ◽  
Leonard Frisbie ◽  
Lan Gardner Coffman
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Protein Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Western Blotting ◽  
Normal Tissue ◽  
Ovarian Cancer Cells ◽  
Rna Expression

e18072 Background: Carcinoma-associated mesenchymal stem cells (CA-MSCs) are mesenchymal stem cells (MSCs) within the tumor microenvironment (TME). We demonstrated that CA-MSCs promote ovarian cancer chemotherapy resistance through paracrine signaling with ovarian cancer cells, interact with ovarian cancer cells to form mixed-cellularity complexes which enhance metastasis, and arise from cancer cell and TME reprogramming of normal tissue MSCs. To identify mediators of the CA-MSC:tumor cell interaction, we investigated the role of tetraspanins, which are membrane-spanning proteins that have been implicated in cancer development and metastasis by influencing cell adhesion and cell-cell interactions. The tetraspanins CD9, CD81, CD151, and CD63 were identified as potential mediators of cell surface interactions between ovarian cancer cells and CA-MSCs through homo- and heterodimerization. Methods: Td-labeled OVCAR3 cancer cells were co-cultured with 3 patient-derived MSC (derived from normal tissue) and 3 patient-derived CA-MSC (derived from malignant tissue) cell lines. Flow cytometry was performed to measure surface protein expression of the tetraspanins CD9, CD81, CD151, and CD63, and was compared to control cells (not co-cultured) and their median fluorescence intensity (MFI). We next separated OVCAR3 cells co-cultured with MSCs or CA-MSCs using fluorescent activated cell sorting (FACS) based on Td expression. Following FACS, tetraspanin expression in OVCAR3 cells, MSCs, and CA-MSCs was assessed via qRT-PCR and western blotting, and compared to cell lines that were not co-cultured. Results: Flow cytometric analysis revealed an increase in MFI of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs when compared to non-co-cultured matched cells. Increased RNA expression of CD9, CD151, and CD63 was seen in OVCAR3 cells that were co-cultured with CA-MSCs or MSCs when compared to non-co-cultured OVCAR3 cells. Increased RNA expression of CD81 and CD63 was noted in both co-cultured CA-MSCs and MSCs compared to non-co-cultured cells. Lastly, western blotting demonstrated increased protein expression of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs compared to non-co-cultured matched cells. Conclusions: These results indicate that direct interactions between OVCAR3 cells and CA-MSCs or MSCs lead to overexpression of specific tetraspanins at the RNA and protein levels, implying that they may be facilitating tumor cell:CA-MSC and tumor cell:MSC binding.

scholarly journals Elevated LINC00909 Promotes Tumor Progression of Ovarian Cancer via Regulating the miR-23b-3p/MRC2 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Xu Yang ◽  
Guixia Wu ◽  
Fan Yang ◽  
Lang He ◽  
Xiaohui Xie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Tissue ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Normal Ovarian Tissue ◽  
Gynecology And Obstetrics

Ovarian cancer (OC), the third common gynecologic malignancy, contributes to the most cancer-caused mortality in women. However, 70% of patients with OC are diagnosed at an advanced stage, of which the 5-year survival is less than 30%. Long noncoding RNAs (long ncRNAs or lncRNA), a type of RNA with exceeding 200 nucleotides in length but no protein-coding capability, have been demonstrated to involve the pathogenesis of various cancers and show considerable potential in the diagnosis of OC. In this study, we found that the LINC00909 expression in tumor and serum specimens of OC patients was elevated, determined by real-time quantitative, and droplet digital PCR. In receiver operating characteristic (ROC) analysis, our results revealed that serum LINC00909 distinguished cancers from normal ovarian tissue with 87.8% of sensitivity and 69.6% of specificity (AUC, 81.2%) and distinguished serous ovarian cancer from normal ovarian tissue with 90.0% of sensitivity and 75.9% of specificity (AUC, 84.5%). Furthermore, we observed that the tumor and serum LINC00909 level was positively associated with the International Federation of Gynecology and Obstetrics (FIGO) stage and the Eastern Cooperative Oncology Group (ECOG) score (reflecting patients’ performance status). Also, patients with low serum LINC00909 level showed a longer overall (hazard ratio, HR = 1.874 , p = 0.0004 ) and progression-free ( HR = 1.656 , p = 0.0017 ) survival. Functional assays indicated that the elevation of LINC00909 expression contributes to cell proliferation, migration, and invasion capability of ovarian cancer cells. Besides, we demonstrated that LINC00909 functions as a competing endogenous RNA (ceRNA) of MRC2 mRNA by sponging miR-23-3p, and thereby promotes epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells. Therefore, we highlight that the LINC00909/miR-23b-3p/MRC2 axis is implicated in the pathogenesis of ovarian cancer, and serum LINC00909 may be a promising biomarker for the diagnosis of OC.

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