scholarly journals Upregulated hsa_circRNA_100269 inhibits the growth and metastasis of gastric cancer through inactivating PI3K/Akt axis

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250603
Author(s):  
Zhongli Wang ◽  
Chao Liu
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Akt Signaling ◽  
Cell Models ◽  
Cycle Arrest ◽  
Histology Grade ◽  
Multiple Signaling

The pathogenesis of GC involves the complex networking of multiple signaling pathways; however, the detailed mechanisms of tumorigenesis of GC remains largely unknown. Therefore, it is necessary to explore novel diagnostic/prognostic biomarkers for GC. In this study, the levels of hsa_circRNA_100269 in gastric cancer (GC) samples and cells were examined, and its effects on the biological functions of GC cells were elucidated. The levels of hsa_circRNA_100269 in specimens/cell lines were examined using RT-qPCR. Cell models with hsa_circRNA_100269 overexpression or knockdown were generated using lentiviral vectors. Cell viability was determined by MTT assay; cell migratory/invasive activity was evaluated using wound healing/Transwell assay. Cell cycle arrest and apoptosis were assessed by flow cytometry; expression of associated markers involved in cell apoptosis, EMT and the PI3K/Akt signaling were determined by RT-qPCR/immunoblotting. In vivo study was also performed using hsa_circRNA_100269 knockout mice. Our findings revealed downregulation of hsa_circRNA_100269 in GC tissues compared to non-cancerous control. Additionally, the levels of PI3K were remarkably elevated in GC tissues, where hsa_circRNA_100269 and PI3K was negatively correlated. Moreover, the expression of hsa_circRNA_100269 was associated with histology grade and occurrence of metastasis in GC patients. In addition, hsa_circRNA_100269 was downregulated in GC cells compared to normal gastric epithelial cells. Overexpressed hsa_circRNA_100269 notably inhibited the proliferation, migration, invasion and EMT of GC cells, whereas cell cycle arrest at G0/G1 phase was promoted and cell apoptosis was enhanced. Moreover, the PI3K/Akt signaling was involved in hsa_circRNA_100269-regulated GC cell proliferation, migration, invasion, EMT and apoptosis. Knockdown of hsa_circRNA_100269 also remarkably induced tumor growth in mouse model. In summary, our findings indicated that the levels of hsa_circRNA_100269 were reduced in GC. Furthermore, hsa_circRNA_100269 could suppress the development of GC by inactivating the PI3K/Akt pathway. More importantly, hsa_circRNA_100269/PI3K/Akt axis may be a novel therapeutic candidate for GC treatment.

scholarly journals Upregulated circRNA_100269 suppresses the growth and metastasis of gastric cancer by inactivating PI3K/Akt signaling pathway

2020 ◽  
Author(s):  
zhongli wang ◽  
chao liu
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Arrest ◽  
Akt Signaling ◽  
Gastric Epithelial Cells ◽  
Akt Signaling Pathway ◽  
Potential Therapeutic Target ◽  
Cycle Arrest

Abstract Background: The expression of circRNA_100269 in gastric cancer (GC) tissues and cells, together with its regulatory roles on GC cells were investigated. Methods: The levels of circRNA_100269 in GC and matched para-carcinoma tissues, as well as in human GC cell lines and normal gastric epithelial cells were evaluated using RT-qPCR. The models with overexpression or knockdown of circRNA_100269 were generated using lentiviral vectors. Cell viability was examined using MTT assay; cell migration and invasive activity were determined by wound healing and Transwell assay. Cell cycle arrest and apoptosis were assessed; molecules involved in PI3K/Akt signaling, apoptosis and EMT were evaluated using RT-qPCR and immunoblotting. Tumour growth and expression of relevant proteins were examined in circRNA_100269 knockout mice.Results: The results indicated the expression of circRNA_100269 was dramatically decreased in GC samples compared with para-carcinoma tissues (p<0.05), while the levels of PI3K were notably increased (p<0.05). Moreover, the level of circRNA_100269 was relevant to histology grade and occurrence of metastasis in GC patients (p<0.05), where circRNA_100269 and PI3K was inversely correlated (p<0.05). Additionally, circRNA_100269 was downregulated in GC cells compared with normal gastric epithelial cells. Overexpressed circRNA_100269 remarkably suppressed the proliferation, migration, invasion and EMT of GC cells (p<0.05), induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis (p<0.05). In addition, PI3K/Akt signaling was involved in circRNA_100269-mediated proliferation, migration, invasion, EMT and apoptosis in GC cells (p<0.05). Knockdown of circRNA_100269 also significantly promoted tumor growth in vivo (p<0.05). Conclusions: the data of the present study suggested that the expression level of circRNA_100269 was decreased in GC tissues and cells. In addition, circRNA_100269 inhibited the progression of GC by suppressing PI3K/Akt signaling. Therefore, circRNA_100269/PI3K/Akt axis may be a potential therapeutic target for GC treatment.

scholarly journals Upregulated circRNA_100269 suppresses the growth and metastasis of gastric cancer by inactivating PI3K/Akt signaling pathway

2020 ◽  
Author(s):  
zhongli wang ◽  
chao liu
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Arrest ◽  
Akt Signaling ◽  
Gastric Epithelial Cells ◽  
Akt Signaling Pathway ◽  
Potential Therapeutic Target ◽  
Cycle Arrest

Abstract Background: The expression of circRNA_100269 in gastric cancer (GC) tissues and cells, together with its regulatory roles on GC cells were investigated. Methods: The levels of circRNA_100269 in GC and matched para-carcinoma tissues, as well as in human GC cell lines and normal gastric epithelial cells were evaluated using RT-qPCR. The models with overexpression or knockdown of circRNA_100269 were generated using lentiviral vectors. Cell viability was examined using MTT assay; cell migration and invasive activity were determined by wound healing and Transwell assay. Cell cycle arrest and apoptosis were assessed; molecules involved in PI3K/Akt signaling, apoptosis and EMT were evaluated using RT-qPCR and immunoblotting. Tumour growth and expression of relevant proteins were examined in circRNA_100269 knockout mice. Results: The results indicated the expression of circRNA_100269 was dramatically decreased in GC samples compared with para-carcinoma tissues (p < 0.05), while the levels of PI3K were notably increased (p < 0.05). Moreover, the level of circRNA_100269 was relevant to histology grade and occurrence of metastasis in GC patients (p < 0.05), where circRNA_100269 and PI3K was inversely correlated (p < 0.05). Additionally, circRNA_100269 was downregulated in GC cells compared with normal gastric epithelial cells. Overexpressed circRNA_100269 remarkably suppressed the proliferation, migration, invasion and EMT of GC cells (p < 0.05), induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis (p < 0.05). In addition, PI3K/Akt signaling was involved in circRNA_100269-mediated proliferation, migration, invasion, EMT and apoptosis in GC cells (p < 0.05). Knockdown of circRNA_100269 also significantly promoted tumor growth in vivo (p < 0.05). Conclusions: the data of the present study suggested that the expression level of circRNA_100269 was decreased in GC tissues and cells. In addition, circRNA_100269 inhibited the progression of GC by suppressing PI3K/Akt signaling. Therefore, circRNA_100269/PI3K/Akt axis may be a potential therapeutic target for GC treatment.

scholarly journals Upregulated circRNA_100269 suppresses the growth and metastasis of gastric cancer by inactivating PI3K/Akt signaling pathway

2020 ◽  
Author(s):  
zhongli wang ◽  
chao liu
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Arrest ◽  
Akt Signaling ◽  
Gastric Epithelial Cells ◽  
Akt Signaling Pathway ◽  
Potential Therapeutic Target ◽  
Cycle Arrest

Abstract Background: The expression of circRNA_100269 in gastric cancer (GC) tissues and cells, together with its regulatory roles on GC cells were investigated. Methods: The levels of circRNA_100269 in GC and matched para-carcinoma tissues, as well as in human GC cell lines and normal gastric epithelial cells were evaluated using RT-qPCR. The models with overexpression or knockdown of circRNA_100269 were generated using lentiviral vectors. Cell viability was examined using MTT assay; cell migration and invasive activity were determined by wound healing and Transwell assay. Cell cycle arrest and apoptosis were assessed; molecules involved in PI3K/Akt signaling, apoptosis and EMT were evaluated using RT-qPCR and immunoblotting. Tumour growth and expression of relevant proteins were examined in circRNA_100269 knockout mice. Results: The results indicated the expression of circRNA_100269 was dramatically decreased in GC samples compared with para-carcinoma tissues (p<0.05), while the levels of PI3K were notably increased (p<0.05). Moreover, the level of circRNA_100269 was relevant to histology grade and occurrence of metastasis in GC patients (p<0.05), where circRNA_100269 and PI3K was inversely correlated (p<0.05). Additionally, circRNA_100269 was downregulated in GC cells compared with normal gastric epithelial cells. Overexpressed circRNA_100269 remarkably suppressed the proliferation, migration, invasion and EMT of GC cells (p<0.05), induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis (p<0.05). In addition, PI3K/Akt signaling was involved in circRNA_100269-mediated proliferation, migration, invasion, EMT and apoptosis in GC cells (p<0.05). Knockdown of circRNA_100269 also significantly promoted tumor growth in vivo (p<0.05). Conclusions: the data of the present study suggested that the expression level of circRNA_100269 was decreased in GC tissues and cells. In addition, circRNA_100269 inhibited the progression of GC by suppressing PI3K/Akt signaling. Therefore, circRNA_100269/PI3K/Akt axis may be a potential therapeutic target for GC treatment.

Piperlongumine induces gastric cancer cell apoptosis and G2/M cell cycle arrest both in vitro and in vivo

Tumor Biology ◽  
2016 ◽  
Vol 37 (8) ◽  
pp. 10793-10804 ◽  
Author(s):  
Chaoqin Duan ◽  
Bin Zhang ◽  
Chao Deng ◽  
Yu Cao ◽  
Fan Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Gastric Cancer Cell ◽  
M Cell ◽  
Cycle Arrest

scholarly journals Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

2020 ◽  
Vol 13 ◽  
pp. 175628481989543
Author(s):  
Amanda Braga Bona ◽  
Danielle Queiroz Calcagno ◽  
Helem Ferreira Ribeiro ◽  
José Augusto Pereira Carneiro Muniz ◽  
Giovanny Rebouças Pinto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Gastric Carcinogenesis ◽  
In Vivo Experiments ◽  
Cycle Arrest

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

DT-13 synergistically potentiates the sensitivity of gastric cancer cells to topotecan via cell cycle arrest in vitro and in vivo

2018 ◽  
Vol 818 ◽  
pp. 124-131 ◽  
Author(s):  
Hongzhi Du ◽  
Yang Liu ◽  
Xudong Chen ◽  
Xiaowen Yu ◽  
Xiaoying Hou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Cycle Arrest

scholarly journals PIM Inhibitor SMI-4a Induces Cell Apoptosis and Cell Cycle Arrest in B-Cell Acute Lymphocytic Leukemia Cells Via the JAK2/STAT3 Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4083-4083 ◽  
Author(s):  
Xingyi Kuang ◽  
Jie Xiong ◽  
Weili Wang ◽  
Xinyao Li ◽  
Tingting Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Stat3 Pathway ◽  
Cycle Arrest ◽  
Molecule Inhibitor

Abstract The serine/threonine PIM protein kinases are critical regulators of turmorigenesis in mutiple hematologic malignancies and solid cancers. We used real-time PCR to detect the expression of PIM in B-cell acute lymphocytic leukemia (B-ALL) patients, and found the expression of PIM in B-ALL patients was significantly higher than that in normal controls. SMI-4a is a pan-PIM small molecule inhibitor, and this agent exhibits demonstrable preclinical antitumour activity in a wide range of hematologic malignant cell lines. To further explore the effect of SMI-4a on B-ALL cells, B-ALL cell lines CCRF-SB and Sup-B15 were treated with this small molecule inhibitor, and the results showed that SMI-4a inhibited B-ALL cell proliferation in a dose- and time-dependent manner. Moreover, SMI-4a significantly promoted B-ALL cell apoptosis and caused cell cycle arrest in the G0/G1 phase. The results of Western blot showed that SMI-4a increased the expression of Caspase-3, Caspase-9, Bax and P21, and decreased the expression of Bcl-2 and CDK4. Furthermore, we found that SMI-4a significantly inhibits the activation of the JAK2/STAT3 pathway and HO-1 interferes with the JAK2/STAT3 pathway to inhibit SMI-4a-induced ALL cell apoptosis. Finally, xenograft experiments in NOD/SCID mice were operated to investigate the potential role of SMI-4a in B-ALL tumorigenesis in vivo. To observe the effect of SMI-4a on tumor growth in vivo, NOD/SCID mice were transplanted with B-ALL devied cells, and the tumor-bearing mice were intraperitoneally injected with saline and SMI-4a, respectively. As a result, tretment with SMI-4a resulted in a significant inhibition on tumor growth. In addition, PIM inhibtor obviously reduced the volume and weight of B-ALL cell-derived tumors. TUNEL assay revealed the proportion of apoptotic cells was higher in the SMI-4a-treated group than in the control group. Taken together, our data showed PIM inhibitor (SMI-4a) significantly inhibits the growth of B-ALL cells in vitro and in vivo and promotes apoptosis and cell cycle arrest. This suppressive effect is mediated partly through inhibiting the JAK2/STAT3 pathway activation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chidamide Combined with Doxorubicin Induced p53-Driven Cell Cycle Arrest and Cell Apoptosis Reverse Multidrug Resistance of Breast Cancer

2020 ◽  
Author(s):  
Lixia CAO ◽  
Shaorong Zhao ◽  
Qianxi Yang ◽  
Zhendong Shi ◽  
Jingjing Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Breast Cancer Cell Lines ◽  
Tunel Staining ◽  
Drug Resistant ◽  
Cycle Arrest ◽  
Resistant Cells

Abstract Background The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aimed to evaluate the resistance of two MDR breast cancer cell lines to the HDAC-selective inhibitor chidamide (CHI). Methods Cell viability, cell cycle and apoptosis were detected by CCK8, crystal violet staining, EDU staining, TUNEL assay, flow cytometry. The expression of HDAC1, H3K9, H3K18, p53, p21, caspase3/7/9 and the Bcl family was analyzed by western blotting and Quantitative real-time PCR. MDR breast cancer growth suppression by CHI and/or doxorubicin (DOX) in vivo was investigated in a tumor xenograft mouse model. Results The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, Annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 as a tumor suppressor was in a silent state in drug-resistant cells. However, p53 was activated in the CHI-treated and combined treatment groups, which, in turn, activated the p53 up-regulated apoptosis regulator recombinant protein (Puma) and pro-apoptotic protein Bax, downregulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis. Conclusion The irreversible cell stress induced by CHI combined with DOX reduced the expression of HDAC1 and activated caspase-dependent apoptosis and p21-mediated growth arrest pathway, which might have been driven by the activation of p53. This provided a strong theoretical basis for exploring the treatment strategy of the combined use of CHI in patients with breast cancer who did not respond to chemotherapy or had cancer progression.

scholarly journals Chidamide Combined With Doxorubicin Induced p53-Driven Cell Cycle Arrest and Cell Apoptosis Reverse Multidrug Resistance of Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Lixia Cao ◽  
Shaorong Zhao ◽  
Qianxi Yang ◽  
Zhendong Shi ◽  
Jingjing Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Combined Treatment ◽  
Tunel Staining ◽  
Cell Cycle Distribution ◽  
Cycle Arrest

The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aim to demonstrate the potential of chidamide (CHI) combined with the chemotherapy drug doxorubicin (DOX) to overcome chemotherapeutic resistance of breast cancer in vitro and in vivo, laying the experimental foundation for the next clinical application. The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 was activated in the CHI-treated group and combined treatment group, and then the activated p53 up-regulated p21, apoptosis regulator recombinant protein (Puma), and pro-apoptotic protein Bax, down-regulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis.

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