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Flotillin-2 promotes cell proliferation via activating the c-Myc/BCAT1 axis by suppressing miR-33b-5p in nasopharyngeal carcinoma.

ABSTRACT: Previously, we elucidated the function of flotilin-2 (FLOT2) and branched-chain amino acid transaminase 1(BCAT1) in nasopharyngeal carcinoma (NPC). However, the relationship between FLOT2 and BCAT1 in promoting NPC progression remains unknown. Here, we observed that FLOT2 upregulated BCAT1 expression in NPC cells. Ectopic expression of BCAT1 significantly antagonized the inhibitory effects on NPC cell proliferation induced by FLOT2 depletion. Consequently, BCAT1 knockdown markedly inhibited the pro-proliferative effects of FLOT2 overexpression in NPC cells. FLOT2 expression was positively correlated with BCAT1 expression in NPC tissues and was inversely correlated with the prognosis of NPC patients. Mechanistically, FLOT2 maintains the expression level of c-Myc, a positive transcription factor of BCAT1, and subsequently promote BCAT1 transcription. FLOT2 inhibited miR-33b-5p in NPC cells and attenuated its inhibitory effects on c-Myc. Further, experimental validation of the function of the FLOT2/miR-33b-5p/c-Myc/BCAT1 axis in regulating NPC cell proliferation was performed. Our results revealed that FLOT2 promotes NPC cell proliferation by suppressing miR-33b-5p, to maintain proper levels of c-Myc, and upregulate BCAT1trancription. Therefore, the FLOT2/miR-33b-5p/c-Myc/BCAT1 axis is a potential therapeutic target for NPC.

SUBMITTER: Liu R

PROVIDER: S-EPMC8034900 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Long noncoding RNA TMPO-AS1 upregulates BCAT1 expression to promote cell proliferation in nasopharyngeal carcinoma via microRNA let-7c-5p

Project description: Not available

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LncRNA SNHG7 promotes the proliferation of nasopharyngeal carcinoma by miR-514a-5p/ELAVL1 axis.

Project description:BACKGROUND:Nasopharyngeal carcinoma (NPC), with distinct geographical distribution, has gathered public attention. Despite that radiotherapy and chemotherapy are applied to treat NPC, cell metastasis still cannot be avoided. Numerous works have elucidated that lncRNAs are essential players in the development of multiple cancers. LncRNA SNHG7 has been reported as a contributing factor in the occurrence of certain cancers, but its mechanism in NPC deserves further investigation. The purpose of the study is to figure out the role and molecular regulation mechanism of SNHG7 in NPC. METHODS:The role of SNHG7 in NPC was verified by CCK-8, colony formation, EdU staining, western blot and capase-3 assays. The interactions between SNHG7/ELAVL1 and miR-514a-5p were confirmed by RNA pull down, RT-qPCR, RIP and luciferase reporter assays. RESULTS:SNHG7 was upregulated in NPC cells, and absence of SNHG7 suppressed cell proliferation as well as promoted cell apoptosis in NPC. Furthermore, SNHG7 was confirmed to bind with miR-514a-5p and negatively modulate miR-514a-5p expression. Besides, miR-514a-5p was found to be able to bind with ELAVL1 and negatively regulate ELAVL1 mRNA and protein expressions. In the end, rescue assays demonstrated that the miR-514a-5p deficiency restored the NPC progression inhibited by SNHG7 silence, and ELAVL1 partly counteracted the restoration caused by miR-514a-5p inhibitor in HNE1 cells. CONCLUSIONS:LncRNA SNHG7 promotes the proliferation and migration of nasopharyngeal carcinoma by miR-514a-5p/ ELAVL1 axis.

| S-EPMC7202000 | biostudies-literature

Flotillin-2 promotes metastasis of nasopharyngeal carcinoma by activating NF-κB and PI3K/Akt3 signaling pathways.

Project description:Lipid raft proteins have been confirmed to be important in cell signal transduction. Some reports have shown that the aberrant expression of lipid raft proteins is associated with malignant phenotypes in some cancers. However, the role of the lipid raft protein flotillin-2 (Flot-2) in nasopharyngeal carcinoma (NPC) remains to be comprehensively characterized. Here, overexpression of Flot-2 in NPC tissues and cell lines was detected by immunostaining, and Flot-2 expression was found to be positively associated with NPC metastasis. Furthermore, inhibiting Flot-2 expression impaired the malignancy of the highly metastatic NPC cell line 5-8F by constraining its growth and proliferation, mobility and migration, and decreasing the capacity of 5-8F cells to metastasize in nude mice. In contrast, forced overexpression of Flot-2 increased the malignancy of 6-10B, a non-metastatic NPC cell line that weakly expresses Flot-2. Moreover, in 5-8F-shFlot-2 cells, which have inhibited Flot-2 expression, the NF-κB and PI3K/Akt3 pathways were inactivated. Subsequently, MMPs expression were decreased, and Foxo1 activity was increased. In addition, enhanced NF-κB and PI3K/Akt3 activities were observed in Flot-2 overexpressing 6-10B cells. Thus, Flot-2 exerts a pro-neoplastic role in NPC and is involved in tumor progression and metastasis. Moreover, Flot-2 exerts its role through NF-κB and PI3K/Akt3 signaling.

| S-EPMC4648439 | biostudies-literature

Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF-β signaling in nasopharyngeal carcinoma.

Project description:Metastasis is the main cause of cancer-related deaths. Nasopharyngeal carcinoma (NPC) is characterized by severe local invasion and high incidence of regional lymph node metastasis, which represents poor prognosis. However, the underlying mechanism that induces lymph node metastasis of NPC remains largely unknown. Herein, we report that flotillin-1 (FLOT1), a component of lipid raft, which was reported to be involved in tumor progression, was robustly upregulated in the NPC samples with lymph node metastasis. High FLOT1 expression was significantly associated with N classification as well as poorer overall and disease-free survivals in 169 archived clinical NPC samples. Overexpression of FLOT1 enhanced the migratory and invasive abilities of NPC cells in vitro, and more importantly, promoted invasion into the surrounding tissues and metastasis to lymph nodes in vivo. Whereas silencing of endogenous FLOT1 in NPC cells decreased the local invasion and metastasis to lymph nodes. Furthermore, FLOT1 induced the expression and secretion of TGF-β1, facilitated the activation of TGF-β/Smad3 signaling to effectuate epithelial-mesenchymal transition. Our findings present new evidence that FLOT1 plays an important role in promoting aggressive behavior of NPC and provide new insights into the regulatory mechanism of TGF-β signaling.

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Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c-MYC axis in breast cancer.

Project description:Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple-negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi-omic data showed that ERK1/c-MYC axis was identified as a major pivot in PRKD3-mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c-MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c-MYC but did not down-regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c-MYC phosphorylation further led to the lower protein level of c-MYC and then reduced the expression of the c-MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c-MYC in the PRKD3-knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1-c-MYC axis.

| S-EPMC7011155 | biostudies-literature

CDKN2B-AS1 promotes the proliferation, clone formation, and invasion of nasopharyngeal carcinoma cells by regulating miR-98-5p/E2F2 axis.

Project description:ObjectiveTo explore the effect of CDKN2B antisense RNA 1 (CDKN2B-AS1) on the proliferation, clone formation, and invasion of nasopharyngeal carcinoma (NPC) cells by regulating miR-98-5p/E2F transcription factor 2 (E2F2) axis.MethodsThe expressions of CDKN2B-AS1, miR-98-5p, and E2F2 in NPC tissues and cell lines (SUNE-1, 5-8F, 6-10B, and HK-1) as well as in peritumoral normal tissues and cell line NP69 were determined by qRT-PCR. Subcellular localization of CDKN2B-AS1 was detected using the fluorescence in situ hybridization assay. The targeting relationships between CDKN2B-AS1 and miR-98-5p as well as between miR-98-5p and E2F2 were analyzed by the dual-luciferase reporter assay and RNA binding protein immunoprecipitation assay. The proliferation, clone formation and invasion of 5-8F cells were measured using the CCK-8 assay, Clone formation assay, and transwell assay, respectively.ResultsCDKN2B-AS1 was highly expressed in NPC tissues and cells, whereas the expression of miR-98-5p decreased in the NPC tissues and cells. Silencing of CDKN2B-AS1 inhibited the proliferation, clone formation, and invasion of NPC cells (all P<0.05). CDKN2B-AS1 acted asceRNA of miR-98-5p, and miR-98-5p inhibitor could partially reverse the inhibitory effect of silencing CDKN2B-AS1 on NPC cells (all P<0.05). CDKN2B-AS1 upregulated E2F2 by inhibiting miR-98-5p, and the upregulation of E2F2 partially reversed the inhibitory effect of miR-98-5p overexpression on the NPC cells (all P<0.05).ConclusionCDKN2B-AS1, as a lncRNA, can regulate E2F2 by sponging miR-98-5p to promote the proliferation, clone formation, and invasion of NPC cells.

| S-EPMC8748104 | biostudies-literature

LncRNA OIP5-AS1 Knockdown Targets miR-183-5p/GLUL Axis and Inhibits Cell Proliferation, Migration and Metastasis in Nasopharyngeal Carcinoma.

Project description:Nasopharyngeal carcinoma (NPC) is often associated with the infection of Epstein-Barr virus in nasopharynx and is mainly happened in South China and Southeast Asia. Recently, noncoding RNAs have been reported to regulate NPC carcinogenesis. LncRNA OIP5-AS1 participates in tumorigenesis and progression; however, the inherent mechanism of OIP5-AS1-mediated progression of NPC is unclear. In the current study, we aimed to explore the role of OIP5-AS1 in NPC progression. We measured the cell viability, apoptosis, migration, and invasion in NPC cells after OIP5-AS1 modulation. Moreover, we determined whether OIP5-AS1 exerts its oncogenic functions via sponging miR-183-5p in NPC. Furthermore, we determined whether glutamate ammonia ligase (GLUL) was a downstream target of miR-183-5p. We found that OIP5-AS1 downregulation inhibited the viability, migration and invasion of NPC via targeting miR-183-5p. We also identified that GLUL might be a potential downstream target of miR-183-5p in NPC cells. Mechanistically, OIP5-AS1 promotes cell motility via regulating miR-183-5p and GLUL in NPC cells. We concluded that OIP5-AS1 performed its biological functions via targeting miR-183-5p and GLUL in NPC cells.

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microRNA-7-5p inhibits melanoma cell proliferation and metastasis by suppressing RelA

Project description:microRNA-7-5p (miR-7-5p) is an established 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 driven by EGFR signaling, 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. Our results showed 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 melanoma lung colonizationmetastasis in vivo. To investigate the mechanism underlying this effect, 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-ÎºB) subunit RelA, as a novel direct target of miR-7-5p in melanoma cells, such that miR-7-5p suppresses NF-ÎºB activity to decrease expression of canonical NF-ÎºB target genes, including IL-1a, 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 suggest that miR-7-5p replacement therapy might have clinical utility in melanoma to inhibit the metastatic process, in part through its inactivation of RelA/NF-kB signaling. Total RNA was extracted from WM266-4 cells transfected with miR-NC or miR-7-5p precursor molecules (30 nM) for 24 h, using Qiazol reagent (Qiagen).

2016-02-10 | E-GEOD-77196 | biostudies-arrayexpress

LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway.

Project description:BackgroundTongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown.MethodsThe effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2'-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays.ResultsLINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling.ConclusionsOur findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

| S-EPMC7931557 | biostudies-literature

CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression.

Project description:Cellular senescence-inhibited gene (CSIG) protein significantly prolongs the progression of replicative senescence, but its role in tumorigenesis is unclear. To reveal the role of CSIG in HCC, we determined its expression in HCC tissues and surrounding tissues and its functions in tumor cell proliferation in vitro and in vivo. CSIG protein was overexpressed in 86.4% of the human HCC cancerous tissues as compared with matched surrounding tissues, and its protein expression was greater in HCC cells than the non-transformed hepatic cell line L02. Furthermore, upregulation of CSIG significantly increased the colony formation of SMMC7721 and HepG2 cells, and silencing CSIG could induce cell cycle arrest and cell apoptosis. The tumorigenic ability of CSIG was confirmed in vivo in a mouse xenograft model. Our results showed that CSIG promoted the proliferation of HepG2 and SMMC7721 cells in vivo. Finally, CSIG protein directly interacted with c-MYC protein and increased c-MYC protein levels; the ubiquitination and degradation of c-MYC protein was increased with knockdown of CSIG. CSIG could also increase the expression of c-MYC protein in SMMC7721 cells in vivo, and it was noted that the level of c-MYC protein was also elevated in most human cancerous tissues with high level of CSIG.

| S-EPMC4467111 | biostudies-literature

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