scholarly journals miR-499 promotes immature porcine Sertoli cell growth through the PI3K/AKT pathway by targeting the PTEN gene

Reproduction ◽  
2020 ◽  
Vol 159 (2) ◽  
pp. 145-157 ◽  
Author(s):  
Hu Gao ◽  
Bin Chen ◽  
Hui Luo ◽  
Bo Weng ◽  
Xiangwei Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Pten Gene ◽  
Seminiferous Tubules ◽  
Akt Signaling Pathway

Sertoli cells are indispensable for normal spermatogenesis, and increasing evidence has shown that miRNAs participate in the regulation of Sertoli cell growth. However, the functions and regulatory mechanisms of miRNAs in Sertoli cells of domestic animals have not been fully investigated. In the present study, we mainly investigated the regulatory roles of miR-499 in immature porcine Sertoli cells. The results showed that miR-499 was mainly located in the basement section of seminiferous tubules of prepubertal porcine testicular tissue. Overexpression of miR-499 promoted cell proliferation and inhibited apoptosis, whereas miR-499 inhibition resulted in the opposite effect. The PTEN gene was directly targeted by miR-499, and the expression of mRNA and protein was also negatively regulated by miR-499 in immature porcine Sertoli cells. siRNA-induced PTEN knockdown resulted in a similar effect as an overexpression of miR-499 and abolished the effects of miR-499 inhibition on immature porcine Sertoli cells. Moreover, both miR-499 overexpression and the PTEN knockdown activated the PI3K/AKT signaling pathway, whereas inhibition of the PI3K/AKT signaling pathway caused immature porcine Sertoli cell apoptosis and inhibited cell proliferation. Overall, miR-499 promotes proliferation and inhibits apoptosis in immature porcine Sertoli cells through the PI3K/AKT pathway by targeting the PTEN gene. This study provides novel insights into the effects of miR-499 in spermatogenesis through the regulation of immature Sertoli cell proliferation and apoptosis.

scholarly journals miR‐130a promotes immature porcine Sertoli cell growth by activating SMAD5 through the TGF‐β‐PI3K/AKT signaling pathway

2020 ◽  
Vol 34 (11) ◽  
pp. 15164-15179
Author(s):  
Hui Luo ◽  
Bin Chen ◽  
Bo Weng ◽  
Xiangwei Tang ◽  
Yao Chen ◽  
...  
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Sertoli Cell ◽  
Akt Signaling ◽  
Akt Signaling Pathway

scholarly journals LINC02085 Regulates Cell Growth and Inflammatory Response in Rheumatoid Arthritis by Regulating PI3K/ AKT Signaling Pathway

2020 ◽  
Author(s):  
Jianting Wen ◽  
Jian Liu ◽  
Xin Wang ◽  
Jie Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Growth ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Arthritis Score ◽  
Akt Signaling Pathway ◽  
Primary Fibroblast

Abstract Background: The present study explored the possible functions and the underlying mechanism of long Non-coding RNA LINC02085 in rheumatoid arthritis (RA). Methods: Primary fibroblast-like synoviocytes (FLS) were separated from synovial tissues and was established cell lines, then cultured for subsequent cell experiments by transfecting different vectors. Rat with AA were injected with sh-LINC02085. The progression of AA was explored by measuring arthritis score and histologic analysis. ELISA analysis was employed to detect the levels of inflammatory cytokines. CCK8 assay, migration and invasion assays were used to evaluate the proliferation, migration and invasion abilities of cells, respectively. Besides, the levels of the the PI3K/AKT pathway-related proteins were measured by WB and IF. Results: The expression level of LINC02085 was significant high in patients with RA, and positively associated with clinical indexes. We found that LINC02085 was upregulated in RA -FLS and TNF-αstimulated. And overexpression of LINC02085 could promote proliferation, migration and invasion induced by TNF-α, through upregulating the levels of TNF-αand TNFAIP2 and promoting the activation of PI3K/AKT pathway. Whereas downexpression of LINC02085 received the opposite results. Knockdown of LINC02085 significantly ameliorated the progression of AA reflected by decreased arthritis score and cartilage destruction. Conclusion: The present study revealed that LINC02085 could regulate cell growth and inflammatory response of RA-FLS by activating the PI3K/ AKT signaling pathway, subsequently playing important roles in promoting the occurrence and development of RA.

Mutational Loss of PTEN Induces Resistance to NOTCH1 Inhibition in T-ALL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5-5
Author(s):  
Adolfo Ferrando ◽  
Teresa Palomero ◽  
Maria Luisa Sulis ◽  
Maria Cortina ◽  
Pedro J. Real ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Notch1 Signaling ◽  
Shrna Knockdown

Abstract Activating mutations in NOTCH1 are common in T-cell lymphoblastic leukemias (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors (GSIs), which block NOTCH1 activation. However, enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by NOTCH1. Here, we identify the loss of the PTEN tumor suppressor gene and activation of the PI3K-AKT signaling pathway as critical factors that determine the resistance of T-ALL cells to inhibition of NOTCH1 signaling with GSIs. Mutational loss of PTEN is found in 17% of T-ALL cases and in the majority of T-ALL cell lines. Importantly, 8/8 T-ALL lines sensitive to NOTCH inhibition with GSIs retain wild type PTEN, while this tumor suppressor is lost in 8/8 GSI-resistant T-ALLs analyzed (P<0.001). Furthermore, both the expression of a constitutively active form of AKT (Myr AKT) and PTEN shRNA knockdown induced resistance to GSIs in T-ALLs and promoted cell growth, proliferation and glucose metabolism. The close association between GSI resistance and PTEN loss prompted us to analyze the interaction between NOTCH1 signaling and the PI3K-AKT pathway. Analysis of normal and leukemic T-cells demonstrated that NOTCH1 signaling regulates PTEN expression and AKT signaling. Thus, inhibition of NOTCH1 with GSIs results in transcriptional upregulation of PTEN and concomitant downregulation of PI3K/AKT signaling in T-ALL. A similar effect -transcriptional upregulation of Pten upon loss of Notch signaling- was observed in primary mouse thymocytes, which are highly dependent on Notch1 to sustain the activity of the Akt signaling pathway. ChIP-on-chip and reporter assays demonstrate that regulation of PTEN is mediated by HES1, a transcriptional repressor directly controlled by NOTCH1. In agreement with these observations, HES1 shRNA knockdown induced transcriptional upregulation of PTEN in T-ALL cells. These results were perfectly recapitulated in a Drosophila model of Notch-induced tumorigenesis. Thus, activation of Notch signaling via expression of Delta and activation of the PI3K-AKT pathway by Akt showed marked synergism in tumor formation in the fly eye. Importantly, also in Drosophila, activation of Akt reverses the growth defect phenotype induced by the loss of Notch signaling, highlighting the importance of the interaction between these two pathways for the control of cell growth. Finally, we proposed that mutational loss of PTEN could induce an oncogene addition switch that makes T-ALL cells resistant to NOTCH inhibitors but enhanced their sensitivity to AKT inhibitors. Treatment with SH-6, a phosphatidylinositol analog inhibitor of AKT, showed a strong antileukemic effect against GSI-resistant/PTEN-null T-ALLs but not against GSI-sensitive/PTEN-positive cells, confirming this hypothesis. These results demonstrate the importance of the interaction of NOTCH1 with the PI3K-AKT pathway in T-cell homeostasis and response to therapy and provide the basis for the design of new therapeutic strategies for T-ALL.

scholarly journals Hypermethylation of DLG3 Promoter Upregulates RAC1 and Activates the PI3K/AKT Signaling Pathway to Promote Breast Cancer Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Bingbing Liu ◽  
Yanning Xu ◽  
Lin Zhang ◽  
Xue Yang ◽  
Ling Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Biological Activities ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition

Objective. This investigation aimed to figure out the relation between discs large homolog 3 (DLG3) expression and the progression and prognosis of breast cancer (BC). Methods. qRT-PCR was utilized for confirming DLG3 expression and RAC1 mRNA expression in BC tissues and cells. Subsequently, after overexpression or interference of DLG3, the changes of the biological activities of BC cells, including cell proliferation, migration, invasion, and apoptosis, were detected through CCK-8, colony formation assay, wound healing assay, transwell assay, and flow cytometry, respectively. Furthermore, western blotting was utilized to measure the protein expression of DLG3 and RAC1, as well as related proteins of epithelial-mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results. At both cellular and tissue level in BC, DLG3 was downregulated and methylation level was upregulated; RAC1 showed an opposite change and was of a negative correlation with DLG3. In MCF-7 and HCC1937, we found that the upregulation of DLG3 could inhibit RAC1 expression as well as cell proliferation, invasion, migration, and EMT, while promoting apoptosis. Also, DLG3 inhibited the activation of the P13K/AKT pathway. Conclusion. Hypermethylation of DLG3 promoter upregulates RAC1 and activates the PI3K/AKT pathway, thus promoting BC progression. This conclusion provides ideas and experimental basis for improving and treating BC patients.

Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation

2021 ◽  
Vol 27 ◽  
Author(s):  
Simin Liang ◽  
Xiaojia Zhou ◽  
Duo Cai ◽  
Fernando Rodrigues-Lima ◽  
Li Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
K562 Cells ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Network Pharmacology ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Antitumor Effects

Background: Chidamide, a novel benzamide-type histone deacetylase (HDAC) inhibitor, exerts antitumor effects on several types of cancer. However, the role of Chidamide in chronic myeloid leukemia (CML) remains elusive. Therefore, the present study aimed to investigate the effects of Chidamide on CML cell proliferation and explore its underlying mechanism. Methods: Cell proliferation was assessed by CCK-8 assay, cell cycle distribution and apoptosis were detected by flow cytometry and the expression of related proteins was evaluated by western blot analysis. The potential mechanisms were systematically explored by the network-based pharmacological methods, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Results: The results revealed that Chidamide inhibited the proliferation of K562 cells in a dose- and time-dependent manner. In addition, Chidamide blocked cells in the G0/G1 phase via downregulating cyclin‑dependent kinase 4, and induced apoptosis via upregulating Bax and downregulating of Bcl-2. Additionally, using network-based pharmacological methods, we found that PI3K/AKT signaling pathway is involved and significantly related to cell proliferation in CML. Intriguingly, cell treatment with Chidamide suppressed the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway via decreasing the levels of phosphorylated (p)-PI3K and p-AKT. Moreover, insulin-like growth factor 1 (IGF-1), a PI3K/AKT activator, reversed the inhibitory effects of Chidamide on K562 cell proliferation. Conclusion: The study demonstrated that Chidamide may inhibit the proliferation of K562 cells by promoting cell cycle arrest and apoptosis via suppressing the PI3K/AKT pathway, suggesting that Chidamide could be a promising approach to the treatment of CML.

scholarly journals circBTBD7 Promotes Immature Porcine Sertoli Cell Growth through Modulating miR-24-3p/MAPK7 Axis to Inactivate p38 MAPK Signaling Pathway

2021 ◽  
Vol 22 (17) ◽  
pp. 9385
Author(s):  
Qiao Bian ◽  
Bin Chen ◽  
Bo Weng ◽  
Dan Chu ◽  
Xiangwei Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Apoptosis ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Normal Spermatogenesis

Sertoli cells are the crucial coordinators to guarantee normal spermatogenesis and male fertility. Although circular RNAs (circRNAs) exhibit developmental-stage-specific expression in porcine testicular tissues and have been thought of as potential regulatory molecules in spermatogenesis, their functions and mechanisms of action remain largely unknown, especially in domestic animals. A novel circBTBD7 was identified from immature porcine Sertoli cells using reverse transcription PCR, Sanger sequencing, and fluorescence in situ hybridization assays. Functional assays illustrated that circBTBD7 overexpression promoted cell cycle progression and cell proliferation, as well as inhibited cell apoptosis in immature porcine Sertoli cells. Mechanistically, circBTBD7 acted as a sponge for the miR-24-3p and further facilitated its target mitogen-activated protein kinase 7 (MAPK7) gene. Overexpression of miR-24-3p impeded cell proliferation and induced cell apoptosis, which further attenuated the effects of circBTBD7 overexpression. siRNA-induced MAPK7 deficiency resulted in a similar effect to miR-24-3p overexpression, and further offset the effects of miR-24-3p inhibition. Both miR-24-3p overexpression and MAPK7 knockdown upregulated the p38 phosphorylation activity. The SB202190 induced the inhibition of p38 MAPK pathway and caused an opposite effect to that of miR-24-3p overexpression and MAPK7 knockdown. Collectively, circBTBD7 promotes immature porcine Sertoli cell growth through modulating the miR-24-3p/MAPK7 axis to inactivate the p38 MAPK signaling pathway. This study expanded our knowledge of noncoding RNAs in porcine normal spermatogenesis through deciding the fate of Sertoli cells.

scholarly journals ERRα promotes gallbladder cancer development via activating PI3K/AKT signaling pathway mediated by Nectin-4

2019 ◽  
Author(s):  
Lei Wang ◽  
Mengmeng Yang ◽  
Xingmei Guo ◽  
Ziyi Yang ◽  
Yuan Ji ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Gallbladder Cancer ◽  
Signaling Pathway ◽  
Ectopic Expression ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition

Abstract Background: Gallbladder cancer (GBC) is the most common malignant tumour of the bile duct with a poor prognosis. The estrogen-related receptor alpha (ERRα) is a nuclear receptor that has been associated with metabolic processes and cancer progression. Increased ERRα has been shown in endocrine-related cancer and non-endocrine-related cancer. Nevertheless, its role in GBC remains unknown. Methods: ERRα expression was analyzed by immunohistochemistry in 59 GBC samples. Its association with clinicopathologic characteristics was evaluated. The effect of ERRα on GBC cell proliferation and invasion was evaluated by loss- or gain-of-function assays in vitro and in vivo. The influence of ERRα on EMT biomarkers, Nectin-4 and PI3K/AKT signaling pathway was detected by western blotting. Inhibition of Nectin-4 was conducted to explore the potential mechanism of ERRα in GBC. Results: Our study reveals increased ERRα expression in GBC tissues vs. non-tumour adjacent tissues. ERRα expression is significantly positively correlated with high TNM stage, high invasion depth and lymph node metastasis, while negatively associated with prognosis. Targeted depletion of ERRα by lentivirus-mediated shRNA decreased cell proliferation in vitro and in vivo. ERRα promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of EMT relevant genes. Ectopic expression of ERRα promoted GBC cell growth and invasion in vitro, while inhibiton of Nectin-4 attenuated cell growth and invasion induced by ERRα. Moreover, ERRα overexpression activated the PI3K/AKT signaling pathway while this effect can be blocked by Nectin-4 depletion. Nectin-4 was involved in the oncogenic function of ERRα to activate PI3K/AKT signaling pathway in GBC. Conclusions: ERRα promotes GBC progression via activating PI3K/AKT signaling pathway mediated by Nectin-4. ERRα may be a potential prognostic factor and molecular therapeutic target for GBC.

Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer

Tumor Biology ◽  
2014 ◽  
Vol 35 (5) ◽  
pp. 4095-4099 ◽  
Author(s):  
Lu Zheng ◽  
Wei Gong ◽  
Ping Liang ◽  
XiaoBing Huang ◽  
Nan You ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Cancer ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Signaling Pathway
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