HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial-mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/β-catenin signaling activation.
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ABSTRACT:
SUBMITTER: Tian W
PROVIDER: S-EPMC8245914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundmiRNAs are confirmed to play essential roles in tumorigenesis and progression of cancers, including Ewing's sarcoma. miR-185 has been reported to be downregulated in some tumors, whereas the role of miR-185 in Ewing's sarcoma remains unclear.PurposeThe objective of this study was to investigate the role of miR-185 in the progression and metastasis of Ewing's sarcoma and explore the associated mechanism.Materials and methodsEwing's sarcoma cell line RD-ES was transfected with pCMV-MIR-miR185 vector to upregulate the expression of miR-185. Cell Counting Kit 8 and colony formation assays were used to assess the effect of miR-185 on cell proliferation. The effect of miR-185 on cell migration and invasion was detected by transwell assay. Flow cytometry assay was performed to detect apoptosis rate of RD-ES cells. The protein levels of apoptosis-related proteins was determined using Western blot assay or immunohistochemistry assay. Dual-luciferase reporter assay was used to validate the regulation between miR-185 and its target gene.ResultsUpregulation of miR-185 caused significant inhibition on cell growth capacity, migration and invasion of Ewing's sarcoma cell RD-ES. Besides, upregulation of miR-185 was observed to accelerate cell apoptosis in a mitochondrial pathway through regulating Bcl-2/Bax, Caspase 3, and Caspase 9 in Ewing's sarcoma in vitro. Moreover, upregulation of miR-185 was found to suppress the PI3K/Akt/mTOR and Wnt/β-catenin pathways in RD-ES cells. Furthermore, we identified that E2F6 was a target gene for miR-185, and the suppression on cell proliferation caused by overexpression of miR-185 was significantly rescued by the upregulation of E2F6 in RD-ES cells.ConclusionmiR-185 is involved in cell growth, motility and survival of Ewing's sarcoma as a tumor suppressor via suppressing PI3K/Akt/mTOR and Wnt/β-catenin pathways and targeting E2F6.
| S-EPMC6235341 | biostudies-literature
Project description:BackgroundZinc-finger protein 471 (ZNF471) is a member of the Krüppel-associated box domain zinc finger protein (KRAB-ZFP) family. ZNF471 is methylated in squamous cell carcinomas of tongue, stomach and esophageal. However, its role in breast carcinogenesis remains elusive. Here, we studied its expression, functions, and molecular mechanisms in breast cancer.MethodsWe examined ZNF471 expression by RT-PCR and qPCR. Methylation-specific PCR determined its promoter methylation. Its biological functions and related molecular mechanisms were assessed by CCK-8, clonogenicity, wound healing, Transwell, nude mice tumorigenicity, flow cytometry, BrdU-ELISA, immunohistochemistry and Western blot assays.ResultsZNF471 was significantly downregulated in breast cell lines and tissues due to its promoter CpG methylation, compared with normal mammary epithelial cells and paired surgical-margin tissues. Ectopic expression of ZNF471 substantially inhibited breast tumor cell growth in vitro and in vivo, arrested cell cycle at S phase, and promoted cell apoptosis, as well as suppressed metastasis. Further knockdown of ZNF471 verified its tumor-suppressive effects. We also found that ZNF471 exerted its tumor-suppressive functions through suppressing epithelial-mesenchymal transition, tumor cell stemness and AKT and Wnt/β-catenin signaling.ConclusionsZNF471 functions as a tumor suppressor that was epigenetically inactivated in breast cancer. Its inhibition of AKT and Wnt/β-catenin signaling pathways is one of the mechanisms underlying its anti-cancer effects.
| S-EPMC7672945 | biostudies-literature
Project description:MicroRNAs (miRNAs) inhibit or improve the malignant progression of hepatocellular carcinoma (HCC). We previously reported that compared to health controls, patients with liver cirrhosis present the highest levels of circulating miR-885-5p, followed by those with chronic hepatitis B and those with HCC. However, the molecular involvement of miR-885-5p in HCC metastasis is presently unclear. Here, we demonstrated that the expression of miR-885-5p negatively correlated with the invasive and metastatic capabilities of human HCC tissue samples and cell lines. We found that miR-885-5p expression levels correlated with the survival of patients with HCC. Overexpression of miR-885-5p decreased metastasis of HCC cells in vitro and in vivo. Inhibition of miR-885-5p improved proliferation of non-metastatic HCC cells. Furthermore, we disclosed that miR-885-5p targeted gene encoding ?-catenin CTNNB1, leading to decreased activity of the Wnt/?-catenin signaling pathway. The present study indicates that miR-885-5p suppresses the metastasis of HCC and inhibits Wnt/?-catenin signaling pathway by its CTNNB1 target, which suggests that miR-885-5p to be a promising negative regulator of HCC progression and as a novel therapeutic agent to treat HCC.
| S-EPMC5342721 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) poses a serious threat to human health worldwide. lncRNA dysregulation is frequently observed in various cancers, including HCC. However, the function of LINC01370 in HCC progression and its underlying mechanisms remain unclear. LINC01370 expression in HCC tissues with cells was analyzed by applying the GEO and GEPIA databases and qRT-PCR. CCK-8 and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. The PI3K, AKT, with p-AKT protein expression were analyzed by western blotting. Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) showed that LINC01370 expression was significantly lower in HCC tissues than in normal tissues. LINC01370 overexpression markedly repressed HepG2 SMMC-7721 cells proliferation, migration, and invasion. To understand the downstream mechanism of LINC01370 regulation, we further analyzed the genes co-expressed with LINC01370 in GSE136247 and GSE132037 and then performed KEGG analysis. The PA pathway was found to be a downstream pathway regulated by LINC01370 in GSE136247 and GSE132037 via gene co-expression and KEGG analysis. Furthermore, PI3K and p-AKT protein levels decreased after LINC01370 overexpression. Importantly, rescue experiments showed that activation of the PI3K/AKT pathway disrupted the repressive effect of LINC01370 overexpression on the proliferation, migration, and invasion of HepG2 of SMMC-7721 cells. This study verified that LINC01370 suppresses HCC proliferation with metastasis by regulating the PI3K/AKT pathway.
| S-EPMC11294307 | biostudies-literature
Project description:Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/?-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.
| S-EPMC6753380 | biostudies-literature
Project description:The identification of cancer stem cells (CSCs) represents an important milestone in the understanding of chemodrug resistance and cancer recurrence. More specifically, some studies have suggested that potential metastasis-initiating cells (MICs) might be present within small CSC populations. The targeting and eradication of these cells represents a potential strategy for significantly improving clinical outcomes. A number of studies have suggested that dysregulation of Wnt/β-catenin signaling occurs in human breast cancer. Consistent with these findings, our previous data have shown that the relative level of Wnt/β-catenin signaling activity in breast cancer stem cells (BCSCs) is significantly higher than that in bulk cancer cells. These results suggest that BCSCs could be sensitive to therapeutic approaches targeting Wnt/β-catenin signaling pathway. In this context, abnormal Wnt/β-catenin signaling activity may be an important clinical feature of breast cancer and a predictor of poor survival. We therefore hypothesized that Wnt/β-catenin signaling might regulate self-renewal and CSC migration, thereby enabling metastasis and systemic tumor dissemination in breast cancer. Here, we investigated the effects of inhibiting Wnt/β-catenin signaling on cancer cell migratory potential by examining the expression of CSC-related genes, and we examined how this pathway links metastatic potential with tumor formation in vitro and in vivo.
| S-EPMC5378883 | biostudies-literature
Project description:β-Sitosterol is a natural compound with demonstrated anti-cancer properties against various cancers. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms are not well understood. This study aims to investigate the impact of β-sitosterol on HCC. In this study, we investigated the effects of β-sitosterol on HCC tumour growth and metastasis using a xenograft mouse model and a range of molecular analyses, including bioinformatics, real-time PCR, western blotting, lentivirus transfection, CCK8, scratch and transwell assays. The results found that β-sitosterol significantly inhibits HepG2 cell proliferation, migration and invasion both in vitro and in vivo. Bioinformatics analysis identifies forkhead box M1 (FOXM1) as a potential target for β-sitosterol in HCC treatment. FOXM1 is upregulated in HCC tissues and cell lines, correlating with poor prognosis in patients. β-Sitosterol downregulates FOXM1 expression in vitro and in vivo. FOXM1 overexpression mitigates β-sitosterol's inhibitory effects on HepG2 cells. Additionally, β-sitosterol suppresses epithelial-mesenchymal transition (EMT) in HepG2 cells, while FOXM1 overexpression promotes EMT. Mechanistically, β-sitosterol inhibits Wnt/β-catenin signalling by downregulating FOXM1, regulating target gene transcription related to HepG2 cell proliferation and metastasis. β-Sitosterol shows promising potential as a therapeutic candidate for inhibiting HCC growth and metastasis through FOXM1 downregulation and Wnt/β-catenin signalling inhibition.
| S-EPMC10844700 | biostudies-literature
Project description:Cyclin-dependent kinase 3 (CDK3), a member of CDK family, is involved in G0/G1 and G1/S cell cycle transitions. Although several researchers discovered that CDK3 related to cell growth in some kinds of cancer, the functions of CDK3 during tumor development remains unclear. Here, we first found that the expression of CDK3 was higher in primary tumors of non-metastatic breast cancer compared with those in metastatic breast cancer. Overexpression of CDK3 suppressed cell migration and invasion of breast cancer cells, and decreased the metastasis in nude mice. We further identified miR-4469 was a negative regulator of CDK3 by directly targeting its 3'-untranslated region (UTR). The increase of motility induced by miR-4469 could be abolished by CDK3 overexpression. Moreover, RNA-seq analysis revealed that Wnt pathway may be inhibited by CDK3 expression, which was subsequently confirmed by western blot. Moreover, Wnt3a treatment abolished the inhibitory role of CDK3 in cell motility, suggesting that Wnt signaling is the potential downstream of CDK3. In conclusion, these results support that CDK3 which is targeted by miR-4469 suppresses breast cancer metastasis by inhibiting Wnt/β-catenin pathway.
| S-EPMC5689583 | biostudies-literature
Project description:NOP14, which is functionally conserved among eukaryotes, has been implicated in cancer development. Here, we show that NOP14 is poorly expressed in breast cancer cells and invasive breast cancer tissues. In vivo and in vitro studies indicated that NOP14 suppressed the tumorigenesis and metastasis of breast cancer cells. Further investigations revealed that NOP14 enhanced ER? expression and inhibited the Wnt/?-catenin pathway by up-regulating NRIP1 expression. Survival analysis indicated that low NOP14 expression was significantly associated with poor overall survival (P = 0.0006) and disease-free survival (P = 0.0007), suggesting that NOP14 is a potential prognostic factor in breast cancer. Taken together, our findings reveal that NOP14 may suppress breast cancer progression and provide new insights into the development of targeted therapeutic agents for breast cancer.
| S-EPMC4694860 | biostudies-other
Project description:BackgroundNasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated.MethodsThe methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC.ResultsCompared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5-Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/β-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC.ConclusionsTaken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC.
| S-EPMC5689643 | biostudies-literature