LncRNA HCG11 suppresses human osteosarcoma growth through upregulating p27 Kip1.
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ABSTRACT:
SUBMITTER: Gu J
PROVIDER: S-EPMC8457558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our previous works revealed that human ribosomal protein S13 (RPS13) was up-regulated in multidrug-resistant gastric cancer cells and overexpression of RPS13 could protect gastric cancer cells from drug-induced apoptosis. The present study was designed to explore the role of RPS13 in tumorigenesis and development of gastric cancer. The expression of RPS13 in gastric cancer tissues and normal gastric mucosa was evaluated by immunohistochemical staining and Western blot analysis. It was found RPS13 was expressed at a higher level in gastric cancer tissues than that in normal gastric mucosa. RPS13 was then genetically overexpressed in gastric cancer cells or knocked down by RNA interference. It was demonstrated that up-regulation of RPS13 accelerated the growth, enhanced in vitro colony forming and soft agar cologenic ability and promoted in vivo tumour formation potential of gastric cancer cells. Meanwhile, down-regulation of RPS13 in gastric cancer cells resulted in complete opposite effects. Moreover, overexpression of RPS13 could promote G1 to S phase transition whereas knocking down of RPS13 led to G1 arrest of gastric cancer cells. It was further demonstrated that RPS13 down-regulated p27(kip1) expression and CDK2 kinase activity but did not change the expression of cyclin D, cyclin E, CDK2, CDK4 and p16(INK4A). Taken together, these data indicate that RPS13 could promote the growth and cell cycle progression of gastric cancer cells at least through inhibiting p27(kip1) expression.
| S-EPMC3822796 | biostudies-literature
Project description:The p27/kip1 (p27) tumor suppressor inhibits cyclin/cyclin-dependent kinase (CDK) complexes and halts cell cycle progression. p27 further regulates invasion and migration in cancer cells, suggesting p27 also functions as an oncoprotein. Using a human osteosarcoma tissue microarray we identified high expression of cytoplasmic p27 in metastatic tumors. We demonstrated a positive correlation between mRNA and protein expression of p27 and expression of key metastatic markers, vimentin, snail-2, β-catenin and stathmin-1 (STMN1) in patient tumors. Our results show that T198 phosphorylation of p27 controls the interaction between p27 and STMN1 that regulates microtubule stabilization and the invasion and migration of osteosarcoma cells. We found that anti-tumoral activity of gemcitabine and the Wee1 kinase inhibitor AZD1775 in osteosarcoma cells, was dependent on drug sequencing that relied on p27 stabilization. Gemcitabine activated caspase-3 and synergized with AZD1775 through caspase-mediated cleavage of p27, that dissociated from STMN1 and effectively induced apoptosis. Further, blockage of nuclear export of p27 by inhibition of Exportin-1 (XPO1) promoted growth arrest, demonstrating that the biological effects of agents relied on the expression and localization of p27. Together, these data provide a rationale for combining chemotherapy with agents that promote p27 tumor suppressor activity for the treatment of osteosarcoma.
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Project description:PURPOSE:Osteosarcoma (OS) is the most common primary bone tumor, with high morbidity in infants and adolescents. Long noncoding RNA LINC00313 has been found to modulate papillary thyroid cancer tumorigenesis and to be dysregulate in lung cancer. However, the role of LINC00313 in OS has not yet been addressed. MATERIALS AND METHODS:We evaluated mRNA and protein expression using real-time quantitative PCR and Western blotting. Cell proliferation was evaluated using MTT; apoptosis and autophagy were assessed with flow cytometry, Western blotting, and/or GFP-LC3 assay. Transwell assay was conducted to measure cell migration and invasion. Potential target sites for LINC00313 and miR-342-3p were predicted with starBase v.2.0 and TargetScan Human, and verified using luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down assay. In vivo, xenogeneic tumors were induced with U2OS and MG-63 cells, separately. RESULTS:LINC00313 was upregulated and miR-342-3p was downregulated in OS tissues and cells. High expression of LINC00313 was associated with shorter overall survival. FOSL2 downregulation and miR-342-3p overexpression suppressed cell proliferation and migratory and invasive abilities while promoting apoptosis and autophagy, all of which were consistent with the effects of LINC00313 knockdown. miR-342-3p, sponged by LINC00313, inversely modulated FOSL2 by targeting MG-63 cells, and FOSL2 expression was positively controlled by LINC00313. LINC00313 knockdown suppressed tumor growth in vivo. CONCLUSION:LINC00313 is upregulated in OS, and LINC00313 knockdown plays a vital anti-tumor role in OS cell progression through a miR-342-3p/FOSL2 axis. Our study suggests that LINC00313 may be a novel, promising biomarker for diagnosis and prognosis of OS.
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Project description:The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G(0)/G(1) phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E-Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor.
| S-EPMC1221955 | biostudies-other
Project description:p27(Kip1) (p27), a CDK inhibitor, migrates into the nucleus, where it controls cyclin-CDK complex activity for proper cell cycle progression. We report here that the classical bipartite-type basic amino-acid cluster and the two downstream amino acids of the C-terminal region of p27 function as a nuclear localization signal (NLS) for its full nuclear import activity. Importin alpha3 and alpha5, but not alpha1, transported p27 into the nucleus in conjunction with importin beta, as evidenced by an in vitro transport assay. It is known that Akt phosphorylates Thr 157 of p27 and this reduces the nuclear import activity of p27. Using a pull-down experiment, 14-3-3 was identified as the Thr157-phosphorylated p27NLS-binding protein. Although importin alpha5 bound to Thr157-phosphorylated p27NLS, 14-3-3 competed with importin alpha5 for binding to it. Thus, 14-3-3 sequestered phosphorylated p27NLS from importin alpha binding, resulting in cytoplasmic localization of NLS-phosphorylated p27. These findings indicate that 14-3-3 suppresses importin alpha/beta-dependent nuclear localization of Thr157-phosphorylated p27, suggesting implications for cell cycle disorder in Akt-activated cancer cells.
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Project description:The r-PTPeta gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPeta (the human homolog of r-PTPeta) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPeta gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Ki oncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPeta caused G(1) growth arrest and increased the cyclin-dependent kinase inhibitor p27(Kip1) protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPeta tumor suppressor activity is mediated by p27(Kip1) protein stabilization, because suppression of p27(Kip1) protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPeta. Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed thyroid cells, the p27(Kip1) protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPeta regulated p27(Kip1) stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.
| S-EPMC102181 | biostudies-literature
Project description:Functional genomics studies have led to the discovery of a large amount of non-coding RNAs from the human genome; among them are long non-coding RNAs (lncRNAs). Emerging evidence indicates that lncRNAs could have a critical role in the regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. As master gene regulators, lncRNAs are capable of forming lncRNA-protein (ribonucleoprotein) complexes to regulate a large number of genes. For example, lincRNA-RoR suppresses p53 in response to DNA damage through interaction with heterogeneous nuclear ribonucleoprotein I (hnRNP I). The present study demonstrates that hnRNP I can also form a functional ribonucleoprotein complex with lncRNA urothelial carcinoma-associated 1 (UCA1) and increase the UCA1 stability. Of interest, the phosphorylated form of hnRNP I, predominantly in the cytoplasm, is responsible for the interaction with UCA1. Moreover, although hnRNP I enhances the translation of p27 (Kip1) through interaction with the 5'-untranslated region (5'-UTR) of p27 mRNAs, the interaction of UCA1 with hnRNP I suppresses the p27 protein level by competitive inhibition. In support of this finding, UCA1 has an oncogenic role in breast cancer both in vitro and in vivo. Finally, we show a negative correlation between p27 and UCA in the breast tumor cancer tissue microarray. Together, our results suggest an important role of UCA1 in breast cancer.
| S-EPMC4040676 | biostudies-literature
Project description:The cyclin-dependent kinase inhibitor, p27(Kip1), which regulates cell cycle progression, is controlled by its subcellular localization and subsequent degradation. p27(Kip1) is phosphorylated on serine 10 (S10) and threonine 187 (T187). Although the role of T187 and its phosphorylation by Cdks is well-known, the kinase that phosphorylates S10 and its effect on cell proliferation has not been defined. Here, we identify the kinase responsible for S10 phosphorylation as human kinase interacting stathmin (hKIS) and show that it regulates cell cycle progression. hKIS is a nuclear protein that binds the C-terminal domain of p27(Kip1) and phosphorylates it on S10 in vitro and in vivo, promoting its nuclear export to the cytoplasm. hKIS is activated by mitogens during G(0)/G(1), and expression of hKIS overcomes growth arrest induced by p27(Kip1). Depletion of KIS using small interfering RNA (siRNA) inhibits S10 phosphorylation and enhances growth arrest. p27(-/-) cells treated with KIS siRNA grow and progress to S/G(2 )similar to control treated cells, implicating p27(Kip1) as the critical target for KIS. Through phosphorylation of p27(Kip1) on S10, hKIS regulates cell cycle progression in response to mitogens.
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Project description:The cytoplasmic element binding protein 1 (CPEB1) regulates many important biological processes ranging from cell cycle control to learning and memory formation, by controlling mRNA translation efficiency via 3' untranslated regions (3'UTR). In the present study, we show that CPEB1 is significantly downregulated in human Glioblastoma Multiforme (GBM) tissues and that the restoration of its expression impairs glioma cell lines growth. We demonstrate that CPEB1 promotes the expression of the cell cycle inhibitor p27(Kip1) by specifically targeting its 3'UTR, and competes with miR-221/222 binding at an overlapping site in the 3'UTR, thus impairing miR-221/222 inhibitory activity. Upon binding to p27(Kip1) 3'UTR, CPEB1 promotes elongation of poly-A tail and the subsequent translation of p27(Kip1) mRNA. This leads to higher levels of p27(Kip1) in the cell, in turn significantly inhibiting cell proliferation, and confers to CPEB1 a potential value as a tumor suppressor in Glioblastoma.
| S-EPMC4855225 | biostudies-literature
Project description:The cyclin-dependent kinase inhibitors are key regulators of cell cycle progression. Although implicated in carcinogenesis, they inhibit the proliferation of a variety of normal cell types, and their role in diverse human diseases is not fully understood. Here, we report that p27(Kip1) plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow-derived (BM-derived) immune cells that migrate into vascular lesions. Lesion formation after mechanical arterial injury was markedly increased in mice with homozygous deletion of p27(Kip1), characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion was substantially increased when BM-derived cells from p27(-/-) mice repopulated vascular lesions induced by mechanical injury in p27(+/+) recipients, in contrast to p27(+/+) BM donors. To determine the contribution of immune cells to vascular injury, transplantation was performed with BM derived from RAG(-/-) and RAG(+/+) mice. RAG(+/+) BM markedly exacerbated vascular proliferative lesions compared with what was found in RAG(-/-) donors. Taken together, these findings suggest that vascular repair and regeneration is regulated by the proliferation of BM-derived hematopoietic and nonhematopoietic cells through a p27(Kip1)-dependent mechanism and that immune cells largely mediate these effects.
| S-EPMC484975 | biostudies-literature