MiR-214 sensitizes human colon cancer cells to 5-FU by targeting Hsp27.
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC6419349 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
MiR-214 sensitizes human colon cancer cells to 5-FU by targeting Hsp27.
Yang Yong Y Bao Yan Y Yang Guo-Kai GK Wan Jia J Du Ling-Juan LJ Ma Zhen-Huan ZH
Cellular & molecular biology letters 20190314
Overcoming chemorestistance to 5-fluorouracil (5-FU) could offer a new treatment option for highly malignant colon cancer. In our study, differential microRNA expression profiling revealed that miR-214 is downregulated in 5-FU-resistant colon cancer cells compared to normal cells. In vitro, miR-214 could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU. Functionally, miR-214 inhibited cell clone formation and cell growth and enhanced 5-FU-inducing cell apop ...[more]
Similar Datasets
Project description:5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.
| S-EPMC8455313 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is a commonly occurring human malignancy. The 5-fluorouracil (5-Fu) is a first-line anti-gastric cancer agent. However, a large number of GC patients developed 5-Fu resistance. Currently, the roles and molecular mechanisms of the lncRNA-SNHG16-modulated 5-Fu resistance in gastric cancer remain elusive.MethodsExpressions of lncRNA, miRNA, and mRNA were detected by qRT-PCR and Western blot. RNA-RNA interaction was examined by RNA pull-down and luciferase assay. Cell viability and apoptosis rate under 5-Fu treatments were determined by MTT assay and Annexin V assay. The glycolysis rate of GC cells was evaluated by glucose uptake and ECAR.ResultsHere, we report that SNHG16 as well as PTBP1, which is an RNA-binding protein, are positively associated with 5-Fu resistance to gastric cancer. SNHG16 and PTBP1 were significantly upregulated in gastric tumors and cell lines. Silencing SNHG16 or PTBP1 effectively sensitized GC cells to 5-Fu. Furthermore, glucose metabolism was remarkedly elevated in 5-Fu-resistant GC cells. Under low glucose supply, 5-Fu-resistant cells displayed higher vulnerability than parental GC cells. Bioinformatic analysis and luciferase assay demonstrated that SNHG16 downregulated miR-506-3p by sponging it to form a ceRNA network. We identified PTBP1 as a direct target of miR-506-3p in GC cells. RNA-seq results unveiled that PTBP1 positively regulated expressions of multiple glycolysis enzymes, including GLUT1, HK2, and LDHA. Bioinformatic analysis illustrated the 3'UTRs of glycolysis enzymes contained multiple PTBP1 binding sites, which were further verified by RNA pull-down and RNA immunoprecipitation assays. Consequently, we demonstrated that PTBP1 upregulated the mRNAs of glycolysis enzymes via promoting their mRNA stabilities. Finally, in vivo xenograft experiments validated that blocking the SNHG16-mediated miR-506-3p-PTBP1 axis effectively limited 5-Fu-resistant GC cell originated-xenograft tumor growth under 5-Fu treatments.ConclusionsOur study demonstrates molecular mechanisms of the SNHG16-mediated 5-Fu resistance of GC cells through modulating the miR-506-3p-PTBP1-glucose metabolism axis, presenting a promising approach for anti-chemoresistance therapy.
| S-EPMC9707261 | biostudies-literature
Project description:BackgroundDiminished expression or activity of prostate apoptosis response protein 4 (Par-4) has been demonstrated in a number of cancers, although reports on Par-4 expression during colon cancer progression are lacking. An understanding of the molecular events in conjunction with the genetic networks affected by Par-4 is warranted.ResultsColon cancer specimens derived from patients have significantly diminished expression of Par-4 mRNA relative to paired normal colon. Hence, the functional consequences of reintroducing Par-4 into HT29 colon cancer cells were assessed. Overexpression augmented the interaction of Par-4 with NF kappaB in the cytosol but not nucleus, and facilitated apoptosis in the presence of 5-fluorouracil (5-FU). Analogous findings were obtained when AKT1 pro-survival signaling was inhibited. Transcriptome profiling identified approximately 700 genes differentially regulated by Par-4 overexpression in HT29 cells. Nearly all Par-4-regulated genes were shown by promoter analysis to contain cis-binding sequences for NF kappaB, and meta-analysis of patient expression data revealed that one-third of these genes exist as a recurrent co-regulated network in colon cancer specimens. Sets of genes involved in programmed cell death, cell cycle regulation and interestingly the microRNA pathway were found overrepresented in the network. Noteworthy, Par-4 overexpression decreased NF kappaB occupancy at the promoter of one particular network gene DROSHA, encoding a microRNA processing enzyme. The resulting down-regulation of DROSHA was associated with expression changes in a cohort of microRNAs. Many of these microRNAs are predicted to target mRNAs encoding proteins with apoptosis-related functions. Western and functional analyses were employed to validate several predictions. For instance, miR-34a up-regulation corresponded with a down-regulation of BCL2 protein. Treating Par-4-overexpressing HT29 cells with a miR-34a antagomir functionally reversed both BCL2 down-regulation and apoptosis by 5-FU. Conversely, bypassing Par-4 overexpression by direct knockdown of DROSHA expression in native HT29 cells increased miR-34a expression and 5-FU sensitivity.ConclusionOur findings suggest that the initiation of apoptotic sensitivity in colon cancer cells can be mediated by Par-4 binding to NF kappaB in the cytoplasm with consequential changes in the expression of microRNA pathway components.
| S-EPMC2883962 | biostudies-literature
Project description:5-Fluorouracil (5-FU)-based chemotherapy is the first-line option for patients with advanced colorectal cancer (CRC). However, the development of chemoresistance is the primary cause of treatment failure. Halofuginone (HF), a small molecule alkaloid derived from febrifugine, has been demonstrated to exert strong anti-proliferative effects. However, to the best of our knowledge, whether HF inhibits the progression of 5-FU-resistant human CRC HCT-15/FU cells, and the underlying mechanisms, remain unknown. In the present study, the effects of HF on HCT-15/FU cells were assessed in vitro. The results revealed that HF inhibited HCT-15/FU cell viability as demonstrated by the MTT and colony formation assays. Following treatment of HCT-15/FU cells with HF, the migratory and invasive capacities of the cells were significantly decreased. MicroRNA (miRNA/miR)-sequencing data, subsequent miRNA trend analysis and reverse transcription-quantitative PCR all demonstrated that miR-132-3p expression was increased following treatment with HF in a dose-dependent manner. Western blot analysis indicated that following treatment with HF, the expression levels of proteins associated with proliferation, invasion and metastasis in cells were markedly downregulated. These results suggested that HF inhibited the proliferation, invasion and migration of HCT-15/FU cells by upregulating the expression levels of miR-132-3p. Therefore, miR-132-3p may serve as a molecular marker, which may be used to predict CRC resistance to 5-FU, and HF may serve as a novel clinical treatment for 5-FU-resistant CRC.
| S-EPMC7607966 | biostudies-literature
Project description:Breast cancer is the most common cancer type in women. Long non-coding RNAs (lncRNAs) have been reported as potential new diagnostic markers, prognostic factors, and therapeutic targets in cancer. However, the specific roles and mechanisms of lncRNAs in breast cancer remain to be elucidated. Here we demonstrated the downregulation of lncRNA SNORD3A in breast cancer cells and tissues and verified its non-protein-coding property. SNORD3A overexpression had no effect on cell proliferation but specifically sensitized breast cancer cells to 5-fluorouracil (5-FU) in vitro and in vivo. Mechanistically, SNORD3A exerts its effect via enhancing uridine monophosphate synthetase (UMPS) protein expression. SNORD3A acts as a competing endogenous RNA for miR-185-5p, leading to UMPS protein upregulation. miR-185-5p overexpression disrupted the effect of SNORD3A on chemosensitization to 5-FU in vitro and in vivo. Moreover, Meis1 overexpression transcriptionally promotes SNORD3A expression, and Meis1 is downregulated in breast cancer cells and tissues. In breast cancer tissues, SNORD3A level positively correlates with Meis1 and UMPS protein levels, whereas miR-185-5p level negatively correlates with UMPS protein level. High SNORD3A transcript and Meis1 and UMPS protein levels predicts a better outcome, but high miR-185-5p level predicts a worse outcome in breast cancer patients receiving 5-FU-based chemotherapy. Our findings indicate that Meis1-regulated SNORD3A specifically sensitizes breast cancer cells to 5-FU via enhancing UMPS expression. The SNORD3A-UMPS axis may serve as a potential biomarker and therapeutic target to improve the efficacy of 5-FU-based chemotherapy for breast cancer patients.
| S-EPMC7205983 | biostudies-literature
Project description:BackgroundOvarian cancer (OC) is the most lethal gynecological malignancy and the second leading cause of cancer-related death in women. Treatment with PARP inhibitors (PARPi), such as Olaparib, has been recently introduced for OC patients, but resistance may occur and underlying mechanisms are still poorly understood. The aim of this study is to identify target genes within the tumor cells that might cause resistance to Olaparib. We focused on Neuropilin 1 (NRP1), a transmembrane receptor expressed in OC and correlated with poor survival, which has been also proposed as a key molecule in OC multidrug resistance.MethodsUsing three OC cell lines (UWB, UWB-BRCA and SKOV3) as model systems, we evaluated the biological and molecular effects of Olaparib on OC cell growth, cell cycle, DNA damage and apoptosis/autophagy induction, through MTT and colony forming assays, flow cytometry, immunofluorescence and Western blot analyses. We evaluated NRP1 expression in OC specimens and cell lines by Western blot and qRT-PCR, and used RNA interference to selectively inhibit NRP1. To identify miR-200c as a regulator of NRP1, we used miRNA target prediction algorithms and Pearsons' correlation analysis in biopsies from OC patients. Then, we used a stable transfection approach to overexpress miR-200c in Olaparib-resistant cells.ResultsWe observed that NRP1 is expressed at high levels in resistant cells (SKOV3) and is upmodulated in partially sensitive cells (UWB-BRCA) upon prolonged Olaparib treatment, leading to poor drug response. Our results show that the selective inhibition of NRP1 is able to overcome Olaparib resistance in SKOV3 cells. Moreover, we demonstrated that miR-200c can target NRP1 in OC cells, causing its downmodulation, and that miR-200c overexpression is a valid approach to restore Olaparib sensitivity in OC resistant cells.ConclusionsThese data demonstrate that miR-200c significantly enhanced the anti-cancer efficacy of Olaparib in drug-resistant OC cells. Thus, the combination of Olaparib with miRNA-based therapy may represent a promising treatment for drug resistant OC, and our data may help in designing novel precision medicine trials for optimizing the clinical use of PARPi.
| S-EPMC6939329 | biostudies-literature
Project description:Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan. IMPLICATIONS: Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.
| S-EPMC7115128 | biostudies-literature
Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1β converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via O-glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.
| S-EPMC9266755 | biostudies-literature
Project description:Previous studies have shown aberrant expression of miR-214 in human malignancy. Elevated miR-214 is associated with chemoresistance and metastasis. In this study, we identified miR-214 regulation of ovarian cancer stem cell (OCSC) properties by targeting p53/Nanog axis. Enforcing expression of miR-214 increases, whereas knockdown of miR-214 decreases, OCSC population and self-renewal as well as the Nanog level preferentially in wild-type p53 cell lines. Furthermore, we found that p53 is directly repressed by miR-214 and that miR-214 regulates Nanog through p53. Expression of p53 abrogated miR-214-induced OCSC properties. These data suggest the critical role of miR-214 in OCSC via regulation of the p53-Nanog axis and miR-214 as a therapeutic target for ovarian cancer.
| S-EPMC3471722 | biostudies-literature
Project description:This study was aimed at exploring the effect of lncRNA BDNF-AS on cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of oesophageal cancer (EC) cells. The expression of BDNF-AS and miR-214 in tissue samples and cells was measured by qRT-PCR. The targeted relationship between BDNF-AS and miR-214 was analysed by dual-luciferase reporter assay. After cell transfection, the cell proliferation activity was assessed by MTS method, while the migrating and invading abilities were evaluated by transwell assay. LncRNA BDNF-AS was remarkably down-regulated, while miR-214 was up-regulated in EC tissues and cells in comparison with normal tissues and cells. Overexpression of BDNF-AS significantly inhibited the abilities of cell proliferation, migration and invasion as well as the EMT processes of EC cells. The bioinformatics analysis and luciferase assay indicated that BDNF-AS could be directly bound by miR-214. Furthermore, overexpression of miR-214 and BDNF-AS exerted suppressive influence on EC cell multiplication, migration, invasion and EMT processes. LncRNA BDNF-AS restrained cell proliferation, migration, invasion and EMT processes in EC cells by targeting miR-214.
| S-EPMC6050505 | biostudies-literature