Meis homeobox 2 (MEIS2) inhibits the proliferation and promotes apoptosis of thyroid cancer cell and through the NF-κB signaling pathway.
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ABSTRACT:
SUBMITTER: Wen X
PROVIDER: S-EPMC8806259 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGlioma is the most lethal primary brain tumor, the survival rate still isn't improved in the past decades. It's essential to study the regulatory mechanism of glioma progression, hoping to find new therapy targets or methods. The family of tripartite motif (TRIM) containing proteins are E3 ubiquitination ligases, which play critical role in various tumor progression.MethodsCell proliferation and invasion were analyzed by colony formation assay, soft agar growth assay, BrdU incorporation assay and transwell invasion assay. Luciferase reporter analysis was used to analyze NF-κB pathway activity.ResultsWe found TRIM31 was upregulated in glioma cells and tissues, its overexpression significantly promoted glioma cell proliferation and invasion, while its knockdown significantly inhibited glioma cell proliferation and invasion. Mechanism analysis found TRIM31 promoted NF-κB pathway activity and increased its targets expression. NF-κB inhibition reversed the phenotype caused by TRIM31, confirming TRIM31 promoted glioma progression through activating NF-κB pathway. Using clinical specimens found TRIM31 expression was positively correlative with NF-κB activity.ConclusionThis study found TRIM31 promoted glioma proliferation and invasion through activating NF-κB activity.
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Project description:RIPK2 is a 62 kDa protein and a member of the receptor interacting protein kinases (RIPK) family. It was previously demonstrated that RIPK2 might play a role in promoting malignant tumor progression; however, the precise function of RIPK2 in the onset and progression of gastric cancer (GC) remains unclear. In the current study, we investigated the role of RIPK2 in GC. First, we explored the expression levels of RIPK2 in multiple cancers, including GC, using a bioinformatics approach. We constructed the RIPK2-associated protein-protein interaction network using the search tool for the retrieval of interacting genes/proteins for gene ontology and Kyoto encyclopedia of genes and genomes analysis. Next, we compared the RIPK2 expression levels between GC cells and normal gastric mucosal epithelial cell (GES-1) using reverse transcription quantitative PCR analysis. We downregulated the expression of RIPK2 in GC cells to determine the effects of RIPK2 on cell growth, migration, and apoptosis. Finally, we used western blotting to investigate the RIPK2 downstream signaling pathway involved in the regulation of GC progression. Our results showed that RIPK2 was overexpressed in various tumor tissues, including GC, compared to non-cancer tissues. Moreover, RIPK2 expression was significantly upregulated in all four GC cell lines (MGC-803,SGC-7901, HGC-27 and AGS) comparing the GES-1 cells. Silencing of RIPK2 suppressed GC cell growth by inhibiting migration, and inducing apoptosis through the nuclear factor-κB (NF-κB) signaling pathway. In summary, we demonstrate that RIPK2 plays an important role in modulating GC cell proliferation, migration, and apoptosis through the NF-κB signaling pathway. Therefore, RIPK2 functions as a potential oncogene. We believe that RIPK2 can be used as a candidate biomarker, as well as a diagnostic tool, and the therapeutic target for GC.
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Project description:The protein arginine methyltransferases (PRMTs) include a family of proteins with related putative methyltransferase domains that modify chromatin and regulate cellular transcription. Although some family members, PRMT1 and PRMT4, have been implicated in transcriptional modulation or intracellular signaling, the roles of other PRMTs in diverse cellular processes have not been fully established. Here, we report that PRMT2 inhibits NF-kappaB-dependent transcription and promotes apoptosis. PRMT2 exerted this effect by blocking nuclear export of IkappaB-alpha through a leptomycin-sensitive pathway, increasing nuclear IkappaB-alpha and decreasing NF-kappaB DNA binding. The highly conserved S-adenosylmethionine-binding domain of PRMT2 mediated this effect. PRMT2 also rendered cells susceptible to apoptosis by cytokines or cytotoxic drugs, likely due to its effects on NF-kappaB. Mouse embryo fibroblasts from PRMT2 genetic knockouts showed elevated NF-kappaB activity and decreased susceptibility to apoptosis compared to wild-type or complemented cells. Taken together, these data suggest that PRMT2 inhibits cell activation and promotes programmed cell death through this NF-kappaB-dependent mechanism.
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Project description:Tumor Necrosis Factor-α canonically induces the activation of NF-κB and associated gene product cellular FLICE-like inhibitory protein (cFLIPL) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIPL and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-κB signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIPL and inhibition of NF-κB activation, independent of TNF-α stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIPL to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIPL that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.
| S-EPMC4789601 | biostudies-literature
Project description:Previous studies show that mortalin, a HSP70 family member, contributes to the development and progression of ovarian cancer. However, details of the transcriptional regulation of mortalin remain unknown. We aimed to determine whether NF-κB p65 participates in the regulation of mortalin expression in ovarian cancer cells and to elucidate the underlying mechanism. Chromatin immunoprecipitation and luciferase reporter assay were used to identify mortalin gene sequences, to which NF-κB p65 binds. Results indicated that NF-κB p65 binds to the mortalin promoter at a site with the sequence 'CGGGGTTTCA'. Using lentiviral pLVX-NF-κB-puro and Lentivirus-delivered NF-κB short hairpin RNA (shRNA), we created ovarian cancer cell lines in which NF-κB p65 was stably up-regulated and down-regulated. Using these cells, we found that downregulation of NF-κB p65 inhibits the growth and migration of ovarian cancer cells. Further experimental evidence indicated that downregulation of NF-κB p65 reduced mortalin, and upregulation of mortalin rescued the proliferation and migration of ovarian cancer cells reduced by NF-κB p65 knockdown. In conclusion, NF-κB p65 binds to the mortalin promoter and promotes ovarian cancer cells proliferation and migration via regulating mortalin.
| S-EPMC6533498 | biostudies-literature
Project description:microRNA-7-5p (miR-7-5p) is a tumor suppressor in multiple cancer types and inhibits growth and invasion by suppressing expression and activity of the epidermal growth factor receptor (EGFR) signaling pathway. While melanoma is not typically EGFR-driven, expression of miR-7-5p is reduced in metastatic tumors compared to primary melanoma. Here, we investigated the biological and clinical significance of miR-7-5p in melanoma. We found that augmenting miR-7-5p expression in vitro markedly reduced tumor cell viability, colony formation and induced cell cycle arrest. Furthermore, ectopic expression of miR-7-5p reduced migration and invasion of melanoma cells in vitro and reduced metastasis in vivo. We used cDNA microarray analysis to identify a subset of putative miR-7-5p target genes associated with melanoma and metastasis. Of these, we confirmed nuclear factor kappa B (NF-κB) subunit RelA, as a novel direct target of miR-7-5p in melanoma cells, such that miR-7-5p suppresses NF-κB activity to decrease expression of canonical NF-κB target genes, including IL-1β, IL-6 and IL-8. Importantly, the effects of miR-7-5p on melanoma cell growth, cell cycle, migration and invasion were recapitulated by RelA knockdown. Finally, analysis of gene array datasets from multiple melanoma patient cohorts revealed an association between elevated RelA expression and poor survival, further emphasizing the clinical significance of RelA and its downstream signaling effectors. Taken together, our data show that miR-7-5p is a potent inhibitor of melanoma growth and metastasis, in part through its inactivation of RelA/NF-κB signaling. Furthermore, miR-7-5p replacement therapy could have a role in the treatment of this disease.
| S-EPMC5077967 | biostudies-literature
Project description:The vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. The neuroepithelium forms an optic cup in which the spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ)-which possesses both a neurogenic and nonneurogenic potential-and the optic disk (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence, which organize spatial territories in the vertebrate eye.
| S-EPMC7999952 | biostudies-literature
Project description:Background:Rumex dentatus, commonly known as tooth docked, is widely used in traditional system of medicines. Although it is well reported for its biological activities and medicinal value, only few studies have been carried out to assess its anticancer potential. Purpose: This study seeks to evaluate the anticancer activity of leaf extracts of R. dentatus against breast cancer MDA-MB-231 cell line, a triple negative human breast cancer cell line with invasive properties and to identify the molecular targets underlying its mechanism of action. Methods: Cytotoxicity of plant extracts was determined against breast cancer cells, using the MTT assay. Flow cytometry was performed to analyze the changes in cell cycle and apoptotic effect, if any. Cells were also studied for their wound healing and invasive potential as well as for Western blotting of apoptotic genes and nuclear factor-kappaB (NF-κB) pathway. Results: The results revealed that R. dentatus methanol (RM) and chloroform (RC) extracts of R. dentatus had the highest inhibition of cell proliferation in a concentration- and time-dependent manner. This inhibitory effect was found to be linked to arrest of cell cycle at the G0/G1 phase, along with induction of apoptosis and accumulation in the sub-G1 phase. Moreover, it was shown that both RM and RC inhibited the proliferation of the malignant cells and induced apoptosis by repressing the activation of NF-κB and its subsequent transcripts, Bcl-xl, Bcl-2, Cyclin D1, survivin, and XIAP. Apoptosis was also confirmed in the cells as suggested by caspase-3 detection. RM and RC also abrogated IκBa phosphorylation in the malignant cells as well as reduced the invasive and migratory capabilities of these cells. Conclusion: Our findings suggest that the methanol and chloroform extracts of R. dentatus may have anti-cancer compounds that are potentially useful in the treatment of human breast cancer.
| S-EPMC5643984 | biostudies-other
Project description:Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown to investigate the mechanisms underlying the regulation of AML cell growth by SATB1.Genes that displayed two-fold up-regulation or 0.5-fold down-regulation in expression in comparisons were selected for further analyses. Arrays with poor quality according to the manufacturer's recommendations were excluded from further analysis.We found the differentially expressed genes were involved in NF-κB, MAPK and PI3K/Akt signaling pathways. Nuclear NF-κB p65 levels were significantly increased in SATB1 depleted HL-60 cells.
2019-05-16 | GSE131247 | GEO