Inhibition of Cell Proliferation and Metastasis by Scutellarein Regulating PI3K/Akt/NF-κB Signaling through PTEN Activation in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Ha SE
PROVIDER: S-EPMC8396260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:Ubiquitin-associated protein 2-like (UBAP2L) is highly expressed in various types of tumors and has been shown to participate in tumor growth and metastasis; however, its role in gastric cancer (GC) remains unknown. In this study, we observed that UBAP2L expression was markedly elevated in GC tissues and five GC cell lines. Higher expression of UBAP2L was associated with poor prognosis as revealed by bioinformatics analysis on online websites and laboratory experiments. Knockdown of UBAP2L impeded the migration and invasion abilities of GC cell lines. In contrast, its overexpression enhanced the migration and invasion abilities of GC cell lines. Overexpression of UBAP2L also increased the number and size of lung metastatic nodules in vivo. According to the results of mass spectrometry and pathway annotation of the identified proteins, the PI3K/AKT pathway was found to be related to UBAP2L regulation. Further exploration and rescue experiments revealed that UBAP2L stimulates the expression and nuclear aggregation of p65 and promotes the expression of SP1 by activating the PI3K/AKT pathway. In summary, our findings indicate that UBAP2L regulates GC metastasis through the PI3K/AKT/SP1/NF-κB axis. Thus, targeting UBAP2L may be a potential therapeutic strategy for GC.
| S-EPMC8933503 | biostudies-literature
Project description:BackgroundExcision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively.MethodsImmunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients' clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting.ResultsERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L.ConclusionThese results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.
| S-EPMC7487553 | biostudies-literature
Project description:BackgroundAberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer.MethodsThe relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan-Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice.ResultsAKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice.ConclusionsAKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.
| S-EPMC8379827 | biostudies-literature
Project description:Phytoestrogens are polyphenol compounds which have similar structure to 17β-estradiol (E2), a kind of main estrogen in women. Thus, phytoestrogens may affect the reproductive and endocrine systems, leading to the development of estrogen-related cancers. The effect of genistein (Gen), one of the most studied phytoestrogens, on human cervical cancer cells (HeLa) was investigated in this study. It was found that Gen at concentrations of 0.001, 0.01, 0.1 and 1 µmol·L-1 promoted the proliferation of HeLa cells in a dose-dependent manner. Gen increased the portion of HeLa cells in S phase and decreased the portion of the cells in G1 phase. Besides, apoptosis rate of the cells was significantly lower when treated with Gen compared with the control group. It was also found that the expression of ERα, Akt or nuclear NF-κB p65 protein was activated by Gen. The correlation between these three proteins may be as following: ERα was the upstream, followed by Akt, and then nuclear NF-κB p65 protein. In addition, the downstream genes of activated nuclear NF-κB p65 were found to be associated with cell cycle and apoptosis of cancer cells. Our results suggested that Gen may stimulate cell proliferation partially through the estrogen receptor-mediated PI3K/Akt-NF-κB pathway and the further activation of the downstream genes of nuclear NF-κB p65.
| S-EPMC5771336 | biostudies-literature
Project description:The highly conserved protease TASP1 not only takes part in critical site-specific proteolysis, but also plays an important role in numerous liquid and solid malignancies. However, the TASP1 expression and its biological regulation function in malignant gallbladder carcinoma (GBC) remain fully unknown. Here we observed that TASP1 levels were substantially overexpressed in GBC samples compared with non-tumor tissues. High TASP1 level was closely associated with T stage and metastasis, and was also correlated with poor prognosis in GBC patients. The depletion of TASP1 inhibited GBC cell proliferation and metastasis in vitro and in vivo. Furthermore, we first revealed that FAM49B had biological function and was positively regulated by TASP1 activating PI3K/AKT signaling pathway in GBC. At the same time, FAM49B also promoted GBC cell proliferation and migration. Inhibition of PI3K/AKT with LY294002 or FAM49B expression abrogated Myc-TASP1/Lv-shTASP1-induced GBC cell proliferation and motility. In conclusion, these findings demonstrate that TASP1 is critical for GBC progression via TASP1-PI3K/AKT-FAM49B axis and it may be a novel prognostic factor. The therapeutic targeting TASP1 may be a potential treatment approach for GBC patients.
| S-EPMC7019140 | biostudies-literature
Project description:Glioma is the most common type of malignant brain tumor. Due to its highly aggressive and metastatic features, glioma is associated with poor prognosis and a lack of effective treatments. Eriodictyol, a natural flavonoid compound, has been reported to possess anti-inflammatory and antioxidant effects. However, the anti-tumor effects of eriodictyol and the underlying mechanisms have rarely been reported. In this study, we found that eriodictyol has anti-tumor activity in lung, colon, breast, pancreas, and liver cancer, and most significantly in glioma cell lines. Eriodictyol dose- and time-dependently suppresses cell proliferation, migration, and invasion in U87MG and CHG-5 glioma cells. In addition, eriodictyol induces apoptosis in U87MG and CHG-5 cells, as evaluated by flow cytometry, immunofluorescence, and Western blot. Furthermore, eriodictyol downregulates the phosphoinositide 3-kinase (PI3K)/Akt/NF-?B signaling pathway in a concentration-dependent manner. Moreover, the effects of eriodictyol on the apoptosis of glioma cells are enhanced by LY294002 (a PI3K inhibitor) and reversed by 740 Y-P (a PI3K agonist). In a mouse xenograft model, eriodictyol not only dramatically suppressed tumor growth but also induced apoptosis in tumor cells. In summary, our data illustrate that eriodictyol effectively inhibits proliferation and metastasis and induces apoptosis of glioma cell lines, which might be a result of the blockade of the PI3K/Akt/NF-?B signaling pathway.
| S-EPMC7052300 | biostudies-literature
Project description:BackgroundChemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown.MethodsChemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin.ResultsChemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN-CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo.ConclusionsOur study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.
| S-EPMC5959946 | biostudies-literature
Project description:As one of the Maillard reaction products, furosine has been widely reported in a variety of heat-processed foods, while the toxicity of furosine on the reproductive system and related mechanisms are unclear. Here, we constructed an intragastric gavage male mice model (42-day administration, 0.1/0.25/0.5 g furosine/Kg body weight per day) to investigate its effects on mice testicle index, hormones in serum, and mice sperm quality. Besides, the lipid metabonomics analysis was performed to screen out the special metabolites and relatively altered pathways in mice testicle tissue. Mice primary sertoli cells were separated from male mice testicle to validate the role of special metabolites in regulating pathways. We found that furosine affected testicle index, hormones expression level and sperm quality, as well as caused pathological damages in testicle tissue. Phosphatidylethanolamine (PE) (18:0/16:1) was upregulated by furosine both in mice testicle tissue and in primary sertoli cells, meanwhile, PE(18:0/16:1) was proved to activate Cep55/NF-κB/PI3K/Akt/FOX01/TNF-α pathway, and as a functional protein in dairy products, lactoferrin could inhibit expression of this pathway when combined with furosine. In conclusion, for the first time we validated that furosine posed toxic effects on mice sperms and testicle tissue through upregulating PE(18:0/16:1) and activating Cep55/NF-κB/PI3K/Akt/FOX01/TNF-α pathway.
| S-EPMC6696181 | biostudies-literature
Project description:Chlorogenic acid (CGA) is a natural polyphenol compound abundant in green plants with antioxidant and anti-inflammatory activities. Here, we explore its protective effects and potential mechanisms of action on intestinal epithelium exposure to oxidative stress (OS). We show that CGA attenuated OS-induced intestinal inflammation and injury in weaned pigs, which is associated with elevated antioxidant capacity and decreases in inflammatory cytokine secretion and cell apoptosis. In vitro study showed that CGA elevated phosphorylation of two critical signaling proteins of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, Akt and nuclear factor erythroid-derived-related factor 2, leading to the elevated expression of intracellular antioxidant enzymes and heme oxygenase-1 (HO-1). Specific inhibition of HO-1 partially abolished its anti-inflammatory effect in IPEC-J2 cells exposure to OS. Interestingly, CGA suppressed the tumor necrosis factor-α (TNF-α) induced inflammatory responses in IPEC-J2 cells by decreasing phosphorylation of two critical inflammatory signaling proteins, NF-kappa-B inhibitor alpha (IκBα) and nuclear factor-κB (NF-κB). Specific inhibition of HO-1 cannot fully abolish its anti-inflammatory effect on the TNF-α-challenged cells. These results strongly suggested that CGA is a natural anti-inflammatory agent that can attenuate OS-induced inflammation and injury of intestinal epithelium via co-regulating the PI3K/Akt and IκBα/NF-κB signaling pathway.
| S-EPMC8750628 | biostudies-literature