scholarly journals Exploring the Mechanism of Flaccidoxide-13-Acetate in Suppressing Cell Metastasis of Hepatocellular Carcinoma

Marine Drugs ◽  
2020 ◽  
Vol 18 (6) ◽  
pp. 314
Author(s):  
Yu-Jen Wu ◽  
Wen-Chi Wei ◽  
Guo-Fong Dai ◽  
Jui-Hsin Su ◽  
Yu-Hwei Tseng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Gelatin Zymography ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition ◽  
Cell Metastasis ◽  
Study Results

Hepatocellular carcinoma (HCC) is the most common liver or hepatic cancer, accounting for 80% of all cases. The majority of this cancer mortality is due to metastases, rather than orthotopic tumors. Therefore, the inhibition of tumor metastasis is widely recognized as the key strategy for successful intervention. A cembrane-type diterpene, flaccidoxide-13-acetate, isolated from marine soft coral Sinularia gibberosa, has been reported to have inhibitory effects against RT4 and T24 human bladder cancer invasion and cell migration. In this study, we investigated its suppression effects on tumor growth and metastasis of human HCC, conducting Boyden chamber and Transwell assays using HA22T and HepG2 human HCC cell lines to evaluate invasion and cell migration. We utilized gelatin zymography to determine the enzyme activities of matrix metalloproteinases MMP-2 and MMP-9. We also analyzed the expression levels of MMP-2 and MMP-9. Additionally, assays of tissue inhibitors of metalloproteinase-1/2 (TIMP-1/2), the focal adhesion kinase (FAK)/phosphatidylinositide-3 kinases (PI3K)/Akt/mammalian target of the rapamycin (mTOR) signaling pathway, and the epithelial-mesenchymal transition (EMT) process were performed. We observed that flaccidoxide-13-acetate could potentially inhibit HCC cell migration and invasion. We postulated that, by inhibiting the FAK/PI3K/Akt/mTOR signaling pathway, MMP-2 and MMP-9 expressions were suppressed, resulting in HCC cell metastasis. Flaccidoxide-13-acetate was found to inhibit EMT in HA22T and HepG2 HCC cells. Our study results suggested the potential of flaccidoxide-13-acetate as a chemotherapeutic candidate; however, its clinical application for the management of HCC in humans requires further research.

scholarly journals M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jie Yao ◽  
Zefen Wang ◽  
Yong Cheng ◽  
Chao Ma ◽  
Yahua Zhong ◽  
...  
Keyword(s):  
Cell Migration ◽  
Western Blot ◽  
Signaling Pathway ◽  
Target Gene ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
Mtor Signaling Pathway ◽  
Cell Migration And Invasion

Abstract Background Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. Methods First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. Results The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. Conclusion Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.

T-cadherin deficiency promotes endometriosis progression through the PI3K/AKT/mTOR signaling pathway

2020 ◽  
Author(s):  
yutao guan ◽  
Fu-bin Zhang ◽  
Yan-qing Huang ◽  
Ling-ling Zhou ◽  
Wei-feng Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Benign Disease ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Cell Migration And Invasion ◽  
Female Patients ◽  
Mrna And Protein Expression

Abstract Background: Endometriosis is a progressive and benign disease characterized by the presence of endometrial glands and stroma tissue outside of the uterine cavity. Though endometriosis is a benign disease, it has the characteristics of malignant tumour growth. Abnormal expression of T-cadherin is involved in the occurrence and progression of many tumours. We aimed to investigate whether T-cadherin promotes the migration and invasion of endometriosis cells through the PI3K/AKT/mTOR signaling pathway. Methods: Ectopic and eutopic endometrial samples from 62 female patients with endometriosis and endometrial samples from 51 female patients without endometriosis were collected. The immortalized endometrial stromal cell line hEM15A was cultured. Real-time RT-PCR, immunohistochemistry and Western blot were used to detect the expression of T-cadherin, phospho-PI3K/Akt/mTOR and matrix metalloproteinase 2 (MMP-2). Transfection technology was employed to upregulate T-cadherin expression. The migration and invasion abilities of hEM15A cells were measured by the transwell assay with uncoated or Matrigel-coated membranes. Results: The mRNA and protein expression of T-cadherin was significantly decresed in the ectopic tissues of the patients with endometriosis, while the mRNA and protein expression in the eutopic endometrial tissues of the same patients did not significantly differ from that in the patients without endometriosis. The migration and invasion ability and phospho-PI3K/Akt/mTOR and MMP-2 expression levels were decreased in hEM15A cells with high T-cadherin expression compared with the corresponding parameters in the normal control group. However, everolimus and BEZ235 inhibited cell migration and invasion in cells with low T-cadherin expression, and weakened overexpression of T‑cadherin significantly attenuated MMP-2 protein expression. Conclusion: Loss of T-cadherin promotes cell migration and invasion in endometriosis via the PI3K/AKT/mTOR signalling pathway.

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 Long non-coding RNA LINC00473 acts as a microRNA-29a-3p sponge to promote hepatocellular carcinoma development by activating Robo1-dependent PI3K/AKT/mTOR signaling pathway

2020 ◽  
Vol 12 ◽  
pp. 175883592093789
Author(s):  
Qiqin Song ◽  
Hongyue Zhang ◽  
Jinan He ◽  
Hongyan Kong ◽  
Ran Tao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Progression ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Regulatory Effects

Background: Long non-coding RNAs have suppressive or oncogenic effects in various types of cancers by serving as competing endogenous RNAs for specific microRNAs. In the present study, we aim to delineate the underlying mechanism by which the LINC00473/miR-29a-3p/Robo1 axis affects cell proliferation, migration, invasion, and metastasis in hepatocellular carcinoma (HCC). Methods: The level of Robo1 was examined in HCC tissues and cells, along with its regulatory effects on proliferation, migration, and invasion of HCC cells. Afterwards, the possible involvement of the PI3K/AKT/mTOR signaling pathway was determined. Next, miR-29a-3p expression was overexpressed or inhibited to investigate its regulatory role on HCC cell activities. The interaction among miR-29a-3p, Robo1, and LINC00473 was further characterized. Finally, a xenograft tumor in nude mice was conducted to measure tumorigenesis and metastasis in vivo. Results: miR-29a-3p was downregulated while Robo1 was upregulated in HCC tissues and cells. miR-29a-3p targeted Robo1 and negatively regulated its expression. In response to miR-29a-3p overexpression, Robo1 silencing or LINC00473 silencing, HCC cell proliferation, migration, invasion, tumor progression, and metastasis were impeded, which was involved with the inactivation of the PI3K/AKT/mTOR signaling pathway. Notably, LINC00473 could competitively bind to miR-29a-3p to upregulate Robo1 expression. Conclusion: LINC00473 might be involved in HCC progression by acting as a miR-29a-3p sponge to upregulate the expression of Robo1 that activates the PI3K/AKT/mTOR signaling pathway, which leads to enhanced cell proliferation, migration, invasion, tumor progression, and metastasis in HCC.

scholarly journals YTHDF1 promotes hepatocellular carcinoma progression via activating PI3K/AKT/mTOR signaling pathway and inducing epithelial-mesenchymal transition

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiangyuan Luo ◽  
Mengdie Cao ◽  
Fan Gao ◽  
Xingxing He
Keyword(s):  
Signaling Pathway ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Promoting Effect ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background N6-methyladenosine (m6A) modification, as the most abundant RNA modification, widely participates in the physiological process and is involved in multiple disease progression, especially cancer. YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is a pivotal m6A “reader” protein, which has been reported in multiple cancers. However, the role and molecular mechanism of YTHDF1 in HCC are still not fully elucidated. Methods Based on various bioinformatics databases, q-RT PCR, western blot, and a tissue microarray containing 90 HCC samples, we examined the expression of YTHDF1 in HCC. Then, we applied the loss-of-function experiments to explore the role of YTHDF1 in HCC by in vitro and in vivo assays. Finally, we performed the gene set enrichment analysis (GSEA) to predict the potential signaling pathway of YTHDF1 involved in HCC and further verified this prediction. Results YTHDF1 was overexpressed in HCC and associated with HCC grade. Depletion of YTHDF1 markedly impaired the proliferation, migration, invasion, and cell cycle process of HCC cells. Mechanistically, YTHDF1 promoted the growth of HCC cells via activating the PI3K/AKT/mTOR signaling pathway. Moreover, we also demonstrated that the epithelial-mesenchymal transition (EMT) mediated the promoting effect of YTHDF1 on the migration and invasion of HCC cells. Conclusions YTHDF1 contributes to the progression of HCC by activating PI3K/AKT/mTOR signaling pathway and inducing EMT.

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.

Sign in / Sign up

Export Citation Format

Share Document