USP52 inhibits cell proliferation by stabilizing PTEN protein in non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Zhu M
PROVIDER: S-EPMC8490862 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCyclin D1 (CCND1) is overexpressed in non-small cell lung cancer (NSCLC) and contributes to its tumorigenesis and progression. Accumulating evidence shows that ubiquitin-specific protease 5 (USP5), an important member of the USP family, acts as a tumor promoter by deubiquitinating and stabilizing oncoproteins. However, neither the mechanism for dysregulated turnover of CCND1 protein nor the association of CCND1 with USP5 in NSCLC is well understood.MethodsThe association of USP5 with CCND1 in human NSCLC cells and clinical tissues was determined by immunoprecipitation/immunoblotting, immunohistochemistry (IHC), and The Cancer Genome Atlas database analyses. The effect of USP5 knockdown or overexpression on NSCLC cell proliferation in vitro was assessed by Cell Counting Kit-8, flow cytometry-based cell cycle, and colony formation assays. The effect of the USP5 inhibitor EOAI3402143 (G9) on NSCLC proliferation in vitro was analyzed by CCK-8 assay. The effect of G9 on NSCLC xenograft tumor growth was also examined in vivo, using athymic BALB/c nude mice.ResultsUSP5 physically bound to CCND1 and decreased its polyubiquitination level, thereby stabilizing CCND1 protein. This USP5-CCND1 axis promoted NSCLC cell proliferation and colony formation. Further, knockdown of USP5 led to CCND1 degradation and cell cycle arrest in NSCLC cells. Importantly, this tumor-suppressive effect elicited by USP5 knockdown in NSCLC cells was validated in vitro and in vivo through chemical inhibition of USP5 activity using G9. Consistently, G9 downregulated the protein levels of CCND1 in NSCLC cells and xenograft tumor tissues. Also, the expression level of USP5 was positively associated with the protein level of CCND1 in human clinical NSCLC tissues.ConclusionsThis study has provided the first evidence that CCND1 is a novel substrate of USP5. The USP5-CCND1 axis could be a potential target for the treatment of NSCLC.
| S-EPMC8577967 | biostudies-literature
Project description:In human cancers, dysregulated expression of LIM-homeobox gene 2 (LHX2) and downregulation of miR-1238 has been reported separately. However, the relationship between them remains unclear. We investigated the functional contribution of miR-1238 to the regulation of LHX2 in non-small cell lung cancer (NSCLC). Here, computational algorithms predicted that the 3'-untranslated region (3'-UTR) of LHX2 is a target of miR-1238. Luciferase assays validated that miR-1238 directly bound to 3'-UTR of LHX2. qRT-PCR and western blot analyses further confirmed that overexpression of miR-1238 mimic in NSCLC A549 and LTEP-?-2 cells inhibited endogenous expression of LHX2 mRNA and protein. Moreover, ectopic expression of miR-1238 in NSCLC A549 and LTEP-?-2 cells suppressed cellular viability and proliferation. siRNA-induced knockdown of LHX2 copied the phenotype of miR-1238 overexpression in NSCLC A549 and LTEP-?-2 cells and LHX2 knockdown inhibited cell cycle. In addition, miR-1238 expression was frequently decreased in human NSCLC tissues and reversely correlated with LHX2 expression, which was increased in NSCLC tissues. Collectively, our findings demonstrate that miR-1238 inhibit the proliferation of NSCLC cells at least partly via repression of LHX2, shedding light on the mechanistic interaction of miR-1238 and LHX2 in NSCLC carcinogenesis. Furthermore, our data suggest that expression of miR-1238 could be a promising therapeutic strategy for NSCLC treatment.
| S-EPMC4662474 | biostudies-other
Project description:Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1-interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non-small-cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression-free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation-related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.
| S-EPMC6487700 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is a major pathological type of lung cancer. However, its pathogenesis remains largely unclear. MRPL35 is a regulatory subunit of the mitoribosome, which can regulate the assembly of cytochrome c oxidases and plays an important role in the occurrence of NSCLC.MethodsThe expression of MRPL35 in NSCLC was detected by tissue microarray and immunohistochemistry. H1299 cells were infected with lentivirus to knockdown MRPL35, and the cells were subjected to crystal violet staining to assess the results of colony formation assays. A549 cells were infected by lentiviral particles-expressing shMRPL35 or shControl, and then subcutaneously injected into nude mice. Tumorigenesis in mice was detected by in vivo imaging. The potential pathway of MRPL35 in NSCLC was assessed by Western blotting.ResultsMRPL35 was over-expressed in NSCLC tissue compared to para-cancerous and normal tissues. Knockdown of MRPL35 suppressed cell proliferation and decreased NSCLC progression both in vitro and in vivo. The possible molecular mechanisms were also clarified, which indicated that MRPL35 could be involved in cell apoptosis and proliferation by modulating the expression levels of CDK1, BIRC5, CHEK1, STMN1 and MCM2. Knockdown of MRPL35 activated p53 signaling pathway and inhibited cell cycle regulation.ConclusionsThe oncogenic role of MRPL35 in NSCLC was potentially mediated through the cell cycle regulatory genes such as BIRC5, STMN1, CDK1, CHEK1 and MCM2, as well as activation of P53 signaling pathway.
| S-EPMC10720070 | biostudies-literature
Project description:OBJECTIVE:The primary purpose of this study is to investigate the effect of hedgehog-interacting protein (HHIP) overexpression on the proliferation, migration and invasion of non-small cell lung cancer (NSCLC). METHODS:Firstly, HHIP gene expression data of NSCLC tissues and normal tissues were obtained from GSE18842/GSE19804/GSE43458 databases of the Gene Expression Omnibus (GEO) database and then validated by TCGA NSCLC database in a cohort of 1027 cases of NSCLC patients and 108 cases of normal people. A chi-square test was used to analyze the relationship between HHIP expression and clinicopathological characteristics of NSCLC. The expression levels of HHIP in NSCLC cells were detected by quantitative-real time PCR. The function of HHIP was investigated by a series of in vitro assays. CCK-8, wounding healing, Transwell invasion assay were utilized to explore the mechanisms of HHIP. RESULTS:HHIP mRNA were significantly down-regulated in NSCLC in three GEO databases and TCGA database (P<0.05). This result was confirmed in NSCLC cell lines by qRT-PCR analysis, its expression in normal NSCLC cell line BEAS-2B was significantly higher than that in NSCLC cells. Chi-square test results showed that the low expression of HHIP was correlated with gender, cancer type, TNM stage and tumor size. Functional experimental results showed that over-expressing HHIP significantly decreased the ability of cell proliferation, migration and invasion in NSCLC cells (P<0.05). CONCLUSION:Overall, the above results indicated that HHIP could regulate proliferation, migration and invasion, and could be used as a judging criterion for identifying NSCLC classification and stage.
| S-EPMC6876884 | biostudies-literature
Project description:The deubiquitinase DUB3 is frequently overexpressed in non-small cell lung cancer (NSCLC) and contributes to its malignant phenotype. However, the underlying molecular mechanism of DUB3 in NSCLC is largely unknown. In this study, we report that DUB3 regulates cell cycle progression by deubiquitinating cyclin A that links to proliferation of NSCLC cells. We found that knockdown of DUB3 decreases cyclin A levels, whereas overexpression of DUB3 strongly increases cyclin A levels. Mechanistically, DUB3 interacts with cyclin A, which removes the polyubiquitin chains conjugated onto cyclin A and stabilizes the cyclin A protein. Furthermore, we demonstrate that DUB3 regulates cell cycle progression by stabilizing cyclin A, because ablation of DUB3 arrests cell cycle from G0/G1 to S phase and the resulting effect can be rescued by introducing cyclin A into NSCLC cells. Functionally, we found that the effect of DUB3 on cyclin A mediates proliferation of NSCLC cells. Moreover, a significant correlation between DUB3 abundance and cyclin A expression levels were also found in NSCLC samples. Taken together, these results reveal that DUB3 functions as a novel cyclin A regulator through maintaining cyclin A stability, and that the DUB3-cyclin A signaling axis plays a critical role in cell cycle progression for proliferation of NSCLC.
| S-EPMC6523561 | biostudies-literature
Project description:Background Non-small cell lung cancer (NSCLC) is the most important cause of lung cancer death. Wnt7a is a known tumor suppressor gene which is often downregulated in NSCLC, and restoration of Wnt7a leads to decreased NSCLC cell proliferation. However, the biological role of Wnt7a in the migration and invasion in NSCLC remains unclear. Methods We examined whether overexpression of Wnt7a transfected by pcDNA6-Wnt7a could induce the proliferation, migration and invasion of NSCLC H1650 and A549 cell lines. Wnt7a signaling pathway, such as canonical (β-catenin) or non-canonical (c-Jun N-terminal kinase, JNK) pathways, were also assessed. Results We found that re-expression of Wnt7a led to reduced cell growth in NSCLC cell lines. In spite of the antiproliferative effect, Wnt7a overexpression could affect the migration and invasion of NSCLC cells. In the Wnt7a signaling pathway, the phosphorylation of JNK (Thr-183/Tyr-185) and c-Jun (Ser-63) were increased by re-expression of Wnt7a in both H1650 and A549 cell lines. The phosphorylation of β-catenin (Thr-41/Ser-45, Ser-552, Ser-675, and Ser-45) were not altered by restoration of Wnt7a. In NSCLC cells, Wnt7a overexpression was accompanied by parallel changes in the JNK pathway but not in the β-catenin pathway. Conclusions These results help to understand that Wnt7a may play a two-sided role in NSCLC, suggesting that restoration of Wnt7a expression is not always suitable as therapeutic strategy for NSCLC.
| S-EPMC8797291 | biostudies-literature
Project description:Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer?associated mortality worldwide. In the present study, a novel molecular therapeutic target for lung cancer was investigated. The protein expression level of fidgetin?like 1 (FIGNL1) in human lung cancer tissues was determined and its potential functions in the H1299 and A549 lung cancer cell lines was subsequently studied. In addition, the protein expression level of FIGNL1 in 109 lung cancer samples and corresponding para?cancerous tissues was investigated, using immunohistochemical staining. RNA interference and overexpression of FIGNL1 was used to determine the role of FIGNL1 in regulating cell proliferation, and cDNA microarray analysis was performed to identify the potential regulatory pathways. Lastly, the potential role of FIGNL1 in regulating tumorigenesis in lungs and also the proliferation of lung cancer cells was investigated. Firstly, lung cancer tissues were found to express higher protein levels of FIGNL1 and was significantly associated with decreased cell proliferation, migration and invasion abilities, and enhanced cell death. Overexpression of FIGNL1 significantly promoted cell proliferation, including decreased arrest at the G1 phase of the cell cycle and apoptosis, as well as increased ability for fission and migration. These in vitro findings were consistent with the results of the cell?line derived xenografts in BALB/c nude mice, where tumor growth was decreased when injected with cells transfected with shFIGNL1. Collectively, these results provide suggest that FIGNL1 is involved in cell growth and tumorigenesis.
| S-EPMC7721085 | biostudies-literature
Project description:Coiled-coil domain containing (CCDC) family members enhance tumor cell proliferation, and high CCDC protein levels correlate with unfavorable prognoses. Limited research demonstrated that CCDC106 may promote the degradation of p53/TP53 protein and inhibit its transactivity. The present study demonstrated that CCDC106 expression correlates with advanced TNM stage (P = 0.008), positive regional lymph node metastasis (P < 0.001), and poor overall survival (P < 0.001) in 183 non-small cell lung cancer cases. A549 and H1299 cells were selected as representative of CCDC106-low and CCDC106-high expressing cell lines, respectively. CCDC106 overexpression promoted A549 cell proliferation and xenograft tumor growth in nude mice, while siRNA-mediated CCDC106 knockdown inhibited H1299 cell proliferation. CCDC106 promoted AKT phosphorylation and upregulated the cell cycle-regulating proteins Cyclin A2 and Cyclin B1. Cell proliferation promoted by CCDC106 via Cyclin A2 and Cyclin B1 was rescued by treatment with the AKT inhibitor, LY294002. Our studies revealed that CCDC106 is associated with non-small cell lung cancer progression and unfavorable prognosis. CCDC106 enhanced Cyclin A2 and Cyclin B1 expression and promoted A549 and H1299 cell proliferation, which depended on AKT signaling. These results suggest that CCDC106 may be a novel target for lung cancer treatment.
| S-EPMC5432287 | biostudies-literature
Project description:Peroxiredoxin 2 (PRDX2), a member of the peroxiredoxin family of antioxidant enzymes, has been revealed to be an important player in cancer progression. However, the biological role of PRDX2 in the progression of non-small cell lung cancer (NSCLC) is poor reported. In the present study, the loss-of-function experiments were performed to investigate the specific role of PRDX2 in the growth and invasion of NSCLC. The results revealed that knockdown of PRDX2 by siRNA interference significantly suppressed the proliferation, migration, and invasion of A549 and H1299 cells, as well as diminished the activity of MMP9. Additionally, the decrease in PRDX2 expression significantly promoted apoptosis in NSCLC cells by downregulating expression of Bcl-2 and upregulating the expression of Bax, cleaved caspase 3 and cleaved caspase 9, but had no significant effect on the apoptosis of normal lung epithelial cells BEAS-2B. Moreover, PRDX2 inhibitor also inhibited the proliferation, migration, and invasion of A549 cells and promoted apoptosis. Further, our data demonstrated that silencing of PRDX2 markedly reduced the phosphorylation of Akt and mTOR and expression of downstream proteins Cyclin D1 and p70S6k. In conclusion, our findings indicate that PRDX2 exerts a prooncogenic role in the progression of NSCLC and might be a potential therapeutic target for NSCLC treatment.
| S-EPMC7157786 | biostudies-literature