The Potential of PI3K/AKT/mTOR Signaling as a Druggable Target for Endometrial and Ovarian Carcinomas

Lengyel, Csongor György; Altuna, Sara C.; Habeeb, Baker Shalal; Trapani, Dario; Khan, Shah Zeb

doi:10.2174/1389450120666191120123612

Cited by 19 publications

(14 citation statements)

References 123 publications

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“…Furthermore, pathways analysis showed that ELFN2 and its co-expressed genes were primarily involved in the PI3K-Akt signaling pathway. Lengyel et al [30] reported that the PI3K/Akt/mTOR pathway was common in both EC and ovarian cancer, and genes enriched in this pathway seemed to be involved in critical steps of EC carcinogenesis. Similarly, Zhang et al [31] indicated that the PI3K-Akt signaling pathway was involved in EC cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma

Dong

Zhang

et al. 2022

Gynecol Obstet Invest

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Objectives: Endometrial carcinoma (EC) is one of the leading causes of death from gynecological cancer due to the high recurrence rate. However, the molecular mechanisms of EC progression are not well understood. This study aimed to identify critical genes and miRNAs associated with the progression and prognosis of EC and find the potential mRNA-miRNA regulatory relationship. Design: The mRNA and miRNA data were downloaded from The Cancer Genome Atlas (TCGA) database. Next, differentially expressed genes (DEGs) were identified. Subsequently, prognosis-related genes and miRNAs were identified, followed by co-expression analysis of these mRNAs and miRNAs. Materials, Setting, and Methods: Samples in the mRNA microarray were divided into normal (n = 35), early stage (n = 385), and advanced stage (n = 153). Next, DEGs in normal versus early stage and early stage versus advanced stage were, respectively, identified, followed by Venn analysis to screen overlapping DEGs in 2 comparison groups. Based on the expression level of these DEGs, univariate Cox regression analysis and Kaplan-Meier method were performed to obtain prognosis-related genes. Moreover, genes-related miRNAs were predicted, and miRNA-mRNA co-expressed pairs were identified. Then, survival analysis of co-expressed miRNA was performed. Finally, co-expressed genes of key genes were identified, and then functional enrichment analysis was conducted. Results: After integrating analysis, 326 overlapping (309 upregulated and 17 downregulated) DEGs were obtained. Univariate Cox regression analysis showed that 44 mRNAs and 8 miRNAs were associated with the prognosis of EC. Combined with the co-expressed analysis, only one prognosis-related hsa-miR-326/ELFN2 axis was obtained. In addition, functional enrichment analysis showed that co-expressed genes of ELFN2 were mainly involved in the PI3K-Akt signaling pathway. Limitations: These findings were obtained via bioinformatics analysis, and thus further experimental studies are urgently demanded to validate our results. Conclusions: One key miRNA-mRNA regulatory pair (hsa-miR-326-ELFN2) was screened. This study provided a bioinformatics basis for the molecular mechanism of EC progression and might contribute to the identification of novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma

Dong

Zhang

et al. 2022

Gynecol Obstet Invest

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“…This pattern of activation of AKT and enhancement by FF correlated well with the levels of AIG of the cell panel. Thus, AKT signaling is one of the most important transforming niche of HGSC and serves as a key target for prevention and treatment [46,47]. Normally, cells rely on integrins to sense and interact with the extracellular matrix (ECM) to maintain a healthy state [48].…”

Section: Discussionmentioning

confidence: 99%

Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma

Hsu

Chen

Seenan

et al. 2021

Cancers

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Background: High-grade serous carcinoma (HGSC) is mainly derived from the stepwise accumulation of driver mutations in the fallopian tube epithelium (FTE), and it subsequently metastasizes to the ovary and peritoneum that develops into a clinically evident ovarian carcinoma. The developmental process involves cell proliferation/clonal expansion, cell migration, anoikis resistance, anchorage-independent growth (AIG), peritoneum attachment, and cell invasion. Previously, we discovered FTE could be transformed by follicular fluid (FF) released from ovulation, the most crucial risk factor of ovarian cancer, and IGF axis proteins in FF confers stemness activation and clonal expansion via IGF-1R/AKT pathway. However, whether other phenotypes in advanced cancer development are involved is unknown. Methods: A panel of FTE and ovarian HGSC cell lines with different severity of transformation were treated with FF with or without IGF-1R and AKT inhibitors and analyzed for the transformation phenotypes in vitro, ex vivo, and in vivo. Results: FF largely promotes (by order of magnitude) cell migration, AIG, cell invasion, peritoneum attachment, anoikis resistance, and cell proliferation. Most of these activities worked in the full panel of cell lines. The AIG activity largely depends on IGF-1R/AKT phosphorylation, and the proliferation activity depends on an AKT phosphorylation not mediated by IGF-1R. In contrast, both AKT- and non-AKT-mediated signals are responsible for the other transformation activities. Conclusions: Our data demonstrate an extensive transformation activity of FF in the full journey of carcinogenesis, and endorsed ovulation-inhibition for the prevention and AKT-inhibition for the treatment of ovarian HGSC.

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“…CDH1 interacts with BCAR1 indirectly via ARHGAP32 [88] or PIK3R1 [89], which both dock at BCAR1's SD. If PIK3R1 also binds to ERBB2 [90], the loss of CDH1 is induced [91]. In FTC-133 cells, CDH2, ITGB3 and MET are linked to BCAR1 via tensin-1 (TNS1).…”

Section: Bcar1 a Chain Link Between Focal Adhesion And Cytoskeletal Proteinsmentioning

confidence: 99%

Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity

Bauer¹,

Gombocz²,

Schulz

et al. 2021

Computation

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When culturing cells in space or under altered gravity conditions on Earth to investigate the impact of gravity, their adhesion and organoid formation capabilities change. In search of a target where the alteration of gravity force could have this impact, we investigated p130cas/BCAR1 and its interactions more thoroughly, particularly as its activity is sensitive to applied forces. This protein is well characterized regarding its role in growth stimulation and adhesion processes. To better understand BCAR1′s force-dependent scaffolding of other proteins, we studied its interactions with proteins we had detected by proteome analyses of MCF-7 breast cancer and FTC-133 thyroid cancer cells, which are both sensitive to exposure to microgravity and express BCAR1. Using linked open data resources and our experiments, we collected comprehensive information to establish a semantic knowledgebase and analyzed identified proteins belonging to signaling pathways and their networks. The results show that the force-dependent phosphorylation and scaffolding of BCAR1 influence the structure, function, and degradation of intracellular proteins as well as the growth, adhesion and apoptosis of cells similarly to exposure of whole cells to altered gravity. As BCAR1 evidently plays a significant role in cell responses to gravity changes, this study reveals a clear path to future research performing phosphorylation experiments on BCAR1.

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The Potential of PI3K/AKT/mTOR Signaling as a Druggable Target for Endometrial and Ovarian Carcinomas

Cited by 19 publications

References 123 publications

Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma

Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma

Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma

Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity

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