scholarly journals Cezanne enhances epithelial mesenchymal transition and prevents anthracycline-induced apoptosis via AKT/mTOR signaling in hepatocellular carcinoma

2021 ◽  
Author(s):  
Xiao-Ping Zhong ◽  
Jiahong Wang ◽  
Jie Mei ◽  
Lianghe Lu ◽  
Yihong Ling ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mtor Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition

Abstract Background Anthracycline resistance have hindered the efficacy of transcatheter arterial chemoembolization (TACE). Translational research is therefore in need to find potential combinations by studying the resistance mechanism of anthracycline. In our published work, we found Cezanne could predict the efficacy of adjuvant TACE (ad-TACE) and induce epithelium mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). We hereby conduct a sequential investigation to reveal the role of Cezanne on EMT and its potential to retard resistance. Methods The response of Cezanne in patients treated with adjuvant TACE after hepatectomy was evaluated. Functional assays were used to examine the resistance function of Cezanne to anthracyclin. In-situ tumorigenesis models and intraperitoneal perfusion chemotherapy experiment were used for in vivo verification. Results High expression of Cezanne correlated to a better outcome. Multivariate analysis showed low expression of Cezanne and the application of postoperative ad-TACE therapy were independent prognostic risk factors. However, patient outcome was significantly shorter in high Cezanne group of ad-TACE patients. In vitro assays revealed that HCC functions were inhibited after overexpressing Cezanne (OE-Cezanne). After treated with epirubicin, however, OE-Cezanne cell lines did not respond to treatment. In vivo experiment was consistent with in vitro assays. Besides, high Cezanne transforms cell morphology and is correlated to the activation of EMT related genes. Gene set analysis showed that Cezanne can regulate PI3K/AKT/mTOR signaling pathway. Therefore, mTOR inhibitor Rapamycin can reverse the resisting effect of Cezanne on HCC cell lines. Conclusions Adjuvant anthracycline-based TACE treatment after curative surgery can reduce the recurrence rate in HCC patients. However, in patients with high Cezanne expression, the efficacy of TACE may be undermined by EMT inducement. We discovered Cezanne modulates EMT by activating the AKT/mTOR signaling pathway and provided evidence for the rationale of combining mTOR inhibitor with TACE to prevent recurrence in HCC patients.

scholarly journals Piezo1 Promoted Hepatocellular Carcinoma Progression and EMT Through Activating TGF-β Signaling by Recruiting Rab5c

2021 ◽  
Author(s):  
Yiming Li ◽  
Cong Xu ◽  
Bo Sun ◽  
Fangjing Zhong ◽  
Momo Cao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Independent Study ◽  
Gene Set Enrichment Analysis ◽  
Mechanism Study ◽  
Mesenchymal Transition

Abstract Background Piezo1 plays critical roles in vascular development during early embryogenesis. However, the function of Piezo1 in hepatocellular carcinoma (HCC) remain elusive. This study aimed to explore the function and mechanisms of Piezo1 in HCC. Methods qRT-PCR, western blot and immunohistochemistry analyses were used to determine Piezo1 expression in HCC samples and cell lines. The clinical significance of Piezo1 was assessed in two independent study cohorts containing 280 patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. A series of in vitro and in vivo experiments were used to determine the role and molecular mechanism of Piezo1 in HCC progression. Results Piezo1 expression was significantly upregulated in HCC tissues and cell lines. High Piezo1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes of HCC patients. Moreover, knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly inhibited proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, EMT and metastasis in vivo. Further mechanism study indicated that these phenotypic and function changes were mediated by TGF-β signaling pathway. Finally, we proved that Piezo1 exerted its tumor promotion effect by recruiting Rab5c to activating TGF-β signaling pathway. Conclusions We proved Piezo1 promotes progression of hepatocellular carcinoma via TGF-β signaling, which may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.

scholarly journals Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K–AKT–mTOR signaling

2019 ◽  
Vol 30 (19) ◽  
pp. 2527-2534 ◽  
Author(s):  
Linsen Shi ◽  
Zhaoying Wu ◽  
Ji Miao ◽  
Shangce Du ◽  
Shichao Ai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition ◽  
Poor Outcomes

The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial–mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K–AKT–mTOR pathway signaling.

MiR-92a-3p promotes the malignant progression of hepatocellular carcinoma by mediating the PI3K/AKT/mTOR signaling pathway

2021 ◽  
Vol 27 ◽  
Author(s):  
Libing Wang ◽  
Mingxin Cui ◽  
Fengzhi Qu ◽  
Daming Cheng ◽  
Jingkun Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Potential Biomarker ◽  
Hcc Cells

Background: As one of the most common cancers in the world, hepatocellular carcinoma (HCC) usually has a poor prognosis. Many HCC patients are usually diagnosed at advanced stages. Therefore, new potential biomarkers for the diagnosis and prognosis of HCC are urgently needed. More and more studies have shown that miR-92a-3p can regulate the occurrence and development of a variety of cancers, but its clinical significance and molecular mechanism in HCC are still elusive. Here, we tried to clarify the regulatory mechanism of miR-92a-3p in HCC. Methods: In this study, we conducted qRT-PCR and revealed that miR-92a-3p was notably upregulated in HCC cells. MTT, flow cytometry, wound healing, Transwell invasion assays and western blot were conducted to uncover that overexpressed miR-92a-3p could boost the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells while inhibiting cell apoptosis. In addition, the proteins associated with PI3K/AKT/mTOR pathway were also detected by western blot. Results: It was suggested that miR-92a-3p could activate the PI3K/AKT/mTOR signaling pathway. Conclusion: These results suggest that miR-92a-3p plays a tumor-promoting role in HCC and may be a potential biomarker for the diagnosis and prognosis of HCC.

scholarly journals YPEL3 suppresses epithelial–mesenchymal transition and metastasis of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway

2016 ◽  
Vol 35 (1) ◽  
Author(s):  
Jian Zhang ◽  
Xin Wen ◽  
Xian-Yue Ren ◽  
Ying-Qin Li ◽  
Xin-Ran Tang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Western Blotting ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Background Metastasis remains the major cause of death in nasopharyngeal carcinoma (NPC). Yippee-like 3 (YPEL3) plays an important role in tumorigenesis. However, its function and mechanism in NPC has not been systematically explored. Methods We evaluated YPEL3 expression in NPC cell lines and tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed YPEL3 and knocked down YPEL3 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of YPEL3 action by identifying the Wnt/β-catenin signaling pathway downstream genes using western blotting. Results YPEL3 was downregulated in NPC cell lines and tissue samples. Ectopic expression of YPEL3 inhibited NPC cell migration and invasion in vitro; while silencing of YPEL3 promoted NPC cell migration and invasion. Further study indicated that overexpression of YPEL3 inhibited NPC cell epithelial–mesenchymal transition (EMT) and that silencing it enhanced EMT. Overexpression of YPEL3 suppressed NPC cell lung metastasis in vivo. The mechanism study determined that YPEL3 suppressed the expression levels of Wnt/β-catenin signaling pathway downstream genes and the nuclear translocation of β-catenin. Conclusions YPEL3 suppresses NPC EMT and metastasis by suppressing the Wnt/β-catenin signaling pathway, which would help better understanding the molecular mechanisms of NPC metastasis and provide novel therapeutic targets for NPC treatment.

scholarly journals Upregulation of Long Noncoding RNA_GAS5 Suppresses Cell Proliferation and Metastasis in Laryngeal Cancer via Regulating PI3K/AKT/mTOR Signaling Pathway

2021 ◽  
Vol 20 ◽  
pp. 153303382199007
Author(s):  
Wenlin Liu ◽  
Jiandong Zhan ◽  
Rong Zhong ◽  
Rui Li ◽  
Xiaoli Sheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Laryngeal Cancer ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Proliferation And Metastasis ◽  
Cancer Tissues ◽  
Lncrna Gas5

Background: Laryngeal cancer is one of the most common malignant tumors among head and neck cancers. Accumulating studies have indicated that long noncoding RNAs (lncRNAs) play an important role in laryngeal cancer occurrence and progression, however, the functional roles and relative regulatory mechanisms of lncRNA growth arrest-specific transcript 5 (GAS5) in laryngeal cancer progression remain unclear. Methods: The expression of lncRNA GAS5 in both laryngeal cancer tissues and cell lines was evaluated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. The relationships between lncRNA GAS5 expression and clinical parameters were also analyzed. To determine the biological function of lncRNA GAS5, a lncRNA GAS5-specific plasmid was first transfected into laryngeal cancer cells using lentiviral technology. Cell counting kit-8 assay, flow cytometry, and Transwell assays were used to detect in vitro cell proliferation, apoptosis, cycle distribution, and metastasis abilities, respectively. Furthermore, in vivo cell growth experiments were also performed using nude mice. Additionally, western blotting was performed to identify the underlying regulatory mechanism. Results: In the current study, lncRNA GAS5 was downregulated in laryngeal cancer tissues and its low expression was closely associated with poor tumor differentiation, advanced TNM stage, lymph node metastasis, and shorter overall survival time. In addition, lncRNA GAS5 upregulation significantly inhibited laryngeal cancer cell proliferation both in vitro and in vivo. Moreover, in response to lncRNA GAS5 overexpression, more laryngeal cancer cells were arrested at the G2/M stage, accompanied by increased cell apoptosis rates and suppressed migration and invasion capacities. Mechanistically, our data showed that the overexpression of lncRNA GAS5 significantly regulated the PI3K/AKT/mTOR signaling pathway. Conclusion: LncRNA GAS5 might act as a suppressor gene during laryngeal cancer development, as it suppressed cell proliferation and metastasis by regulating the PI3K/AKT/mTOR signaling pathway; thus, lncRNA GAS5 is a promising therapeutic biomarker for the treatment of laryngeal cancer.

scholarly journals Long noncoding RNA LINC00941 promotes pancreatic cancer progression by competitively binding miR-335-5p to regulate ROCK1-mediated LIMK1/Cofilin-1 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jie Wang ◽  
Zhiwei He ◽  
Jian Xu ◽  
Peng Chen ◽  
Jianxin Jiang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Loss Of Function ◽  
Mesenchymal Transition

AbstractAn accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial–mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.

MO243STUDY ON THE EFFECT AND MECHANISM OF NOVEL REGULATORY T CELL (CD4+CD126LOWFOXP3+ TREG) IMMUNOTHERAPY IN LUPUS NEPHRITIS*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Zhenjian Xu ◽  
Junzhe Chen ◽  
Anping Xu
Keyword(s):  
T Cell ◽  
Lupus Nephritis ◽  
Signaling Pathway ◽  
B Lymphocytes ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Proliferation And Differentiation ◽  
Inflammatory State

Abstract Background and Aims Our previous study found a new regulatory T cell subpopulation, CD4+CD126lowFoxp3+ regulatory T cells (CD4+CD126lowFoxp3+ Treg). This cell can maintain a stable immune regulatory function in the inflammatory state. Through in vivo and in vitro experiments, we have confirmed that CD4+CD126lowFoxp3+ Treg has an immunotherapeutic effect on T cell-mediated mouse models of autoimmune diseases such as colitis and collagen-induced arthritis (CIA). Further experimental studies showed that CD4+CD126lowFoxp3+ Treg could reduce the kidney injury caused by autoantibodies and prolong the survival time of lupus mice. However, the mechanism of CD4+CD126lowFoxp3+ Treg immunotherapy in lupus nephritis is not clear. The purpose of this study was to explore the mechanism of CD4+CD126lowFoxp3+ Treg immunotherapy in mice with lupus nephritis. Method In vitro experiments CD4+CD126lowFoxp3+ Treg or CD4+CD126lowFoxp3+ Treg pretreated with PD-1 inhibitor were co-cultured with T or B lymphocytes of lupus mice under different in vitro culture condition. The expression levels of Akt and mTOR of Treg in each group were measured under immunoinflammatory conditions. To observe the effects and differences of Treg groups on the activation, proliferation and differentiation of T or B cells and other immunomodulatory effects. In vivo experiments CD4+CD126lowFoxp3+ Treg (2 × 106/mouse) and CD4+CD126lowFoxp3+ Treg (2 × 106/mouse) pretreated with PD-1 inhibitor and PBS were injected into NZM2328 lupus mice, respectively. After cell injection, urine protein was measured weekly. Autoantibody expression in lupus mice was measured every two weeks. The effects of Treg on the proliferation and differentiation of T/B cells in lupus mice were observed. The therapeutic effects of Treg on lupus mice were observed. Results Compared with CD4+CD126lowFoxp3+ Treg, the expression of Akt and mTOR increases in PD-1 inhibitors pretreatment cells. The activation, proliferation and differentiation functions of T or B lymphocytes of lupus mice were significantly weakened by immunosuppression of PD-1 inhibitors pretreated Treg in vitro, indicating that CD4+CD126lowFoxp3+ Treg may inhibit Akt-mTOR signaling pathway through PD-1 in in vitro. Compared with CD4+CD126lowFoxp3+ Treg, the activation, proliferation and differentiation functions of T or B lymphocytes of lupus mice were significantly weakened by immunosuppression of PD-1 inhibitors pretreated Treg in vivo. And its therapeutic effect on lupus mice was ineffective, indicating that CD4+CD126lowFoxp3+ Treg may inhibit Akt-MTOR signaling pathway through PD-1 in vivo. Conclusion CD4+CD126lowFoxp3+ Treg may inhibit the Akt-mTOR signaling pathway by expressing PD-1, and maintain stable immunomodulatory function in the inflammatory state, thus producing immunotherapeutic effect on lupus nephritis mice.

scholarly journals Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

2018 ◽  
Vol 243 (7) ◽  
pp. 645-654 ◽  
Author(s):  
Yi-Quan Yan ◽  
Juan Xie ◽  
Jing-Fu Wang ◽  
Zhao-Feng Shi ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Unfavorable Clinical Outcome ◽  
Metastasis Models ◽  
Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial–mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

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