PDCD4

Gene Summary

Gene:PDCD4; programmed cell death 4
Aliases: H731
Location:10q25.2
Summary:This gene is a tumor suppressor and encodes a protein that binds to the eukaryotic translation initiation factor 4A1 and inhibits its function by preventing RNA binding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:programmed cell death protein 4
Source:NCBIAccessed: 14 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PDCD4 (cancer-related)

Zhou B, Wang J, Zheng G, Qiu Z
Methylated urolithin A, the modified ellagitannin-derived metabolite, suppresses cell viability of DU145 human prostate cancer cells via targeting miR-21.
Food Chem Toxicol. 2016; 97:375-384 [PubMed] Related Publications
Urolithins are bioactive ellagic acid-derived metabolites produced by human colonic microflora. Although previous studies have demonstrated the cytotoxicity of urolithins, the effect of urolithins on miRNAs is still unclear. In this study, the suppressing effects of methylated urolithin A (mUA) on cell viability in human prostate cancer DU145 cells was investigated. mUA induced caspase-dependent cell apoptosis, mitochondrial depolarization and down-regulation of Bcl-2/Bax ratio. The results showed that upon exposure to mUA, miR-21 expression was decreased and the expression of PTEN and Pdcd4 protein was elevated. mUA could further suppress Akt phosphorylation and increase protein expression of FOXO3a, and the effects of mUA on Akt phosphorylation and protein expression of FOXO3a were blocked by PTEN silence. Moreover, mUA suppressed the Wnt/β-catenin-mediated transcriptional activation of MMP-7 and c-Myc, and this function of mUA on MMP-7 and c-Myc was attenuated by over-expression of miR-21. In conclusion, our data suggest that mUA can suppress cell viability in DU145 cells through modulating miR-21 and its downstream series-wound targets, including PTEN, Akt and Wnt/β-catenin signaling.

Gui F, Hong Z, You Z, et al.
MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.
Cell Biol Int. 2016; 40(12):1294-1302 [PubMed] Related Publications
MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

Liao J, Liu R, Shi YJ, et al.
Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer.
Int J Oncol. 2016; 48(6):2567-79 [PubMed] Related Publications
Recent evidence indicates that exosomes can mediate certain microRNAs (miRNAs) involved in a series of biological functions in tumor occurrence and development. Our previous studies showed that microRNA-21 (miR-21) was abundant in both esophageal cancer cells and their corresponding exosomes. The present study explored the function of exosome-shuttling miR-21 involved in esophageal cancer progression. We found that exosomes could be internalized from the extracellular space to the cytoplasm. The exosome-derived Cy3-labeled miR-21 mimics could be transported into recipient cells in a neutral sphingomyelinase 2 (nSMase2)-dependent manner. miR-21 overexpression from donor cells significantly promoted the migration and invasion of recipient cells by targeting programmed cell death 4 (PDCD4) and activating its downstream c-Jun N-terminal kinase (JNK) signaling pathway after co-cultivation. Our population plasma sample analysis indicated that miR-21 was upregulated significantly in plasma from esophageal cancer patients and showed a significant risk association for esophageal cancer. Our data demonstrated that a close correlation existed between exosome-shuttling miR-21 and esophageal cancer recurrence and distant metastasis. Thus, exosome-shuttling miR-21 may become a potential biomarker for prognosis among esophageal cancer patients.

Liang H, Wang F, Chu D, et al.
miR-93 functions as an oncomiR for the downregulation of PDCD4 in gastric carcinoma.
Sci Rep. 2016; 6:23772 [PubMed] Free Access to Full Article Related Publications
Programmed cell death 4 (PDCD4), as a tumor suppressor gene, is frequently reduced in a variety of tumors, including gastric cancer. Previous findings have indicated that PDCD4 participates in tumorigenesis through the regulation of apoptosis, but the molecular basis of this process has not been fully elucidated, and no studies have shown the upstream regulation of this gene in gastric cancer. In this study, we used bioinformatics analysis to search for miRNAs that could potentially target PDCD4 and identified miR-93 as a candidate. Moreover, we observed the inverse correlation between miR-93 and PDCD4 protein levels, but not mRNA levels, in human gastric cancer tissues. We further experimentally validated PDCD4 as the direct target of miR-93 by evaluating PDCD4 expression in gastric cancer cells after the overexpression or knockdown of miR-93. Additionally, the biological consequences of targeting PDCD4 through miR-93 were examined using cell apoptosis assays in vitro. We demonstrated that the repression of PDCD4 through miR-93 suppressed the apoptosis of gastric cancer cells. Finally, we revealed that miR-93 promoted the development of gastric tumor growth in xenograft mice by negatively regulating PDCD4. Taken together, the findings of the present study indicated the oncogenic role of miR-93 in gastric cancer tumorigenesis through targeting PDCD4, particularly in apoptosis.

Li C, Deng L, Zhi Q, et al.
MicroRNA-183 Functions As an Oncogene by Regulating PDCD4 in Gastric Cancer.
Anticancer Agents Med Chem. 2016; 16(4):447-55 [PubMed] Related Publications
MicroRNA-183 (miR-183) has recently been identified to be implicated in a variety of critical processes in multiple human malignancies, and its fuction has been poorly characterized in gastric cancer (GC). Here we reported that miR-183 was markedly over-expressed in GC and its up-regulation was markedly associated with GC clinicopathologicalcharacters. Endogenous miR-183 was inhibited in GC cells, which dramatically attenuated cell proliferation, colony formation, migration, invasion and adhesion and enhancedGC cells apoptosis in vitro. Furthermore, in this study we demonstrated that the tumor suppressor gene PDCD4 was a target of miR-183 in GC. Collectively, these observations showed that miR-183 maybe function as an oncogene by regulating GC cell proliferation, apoptosis and metastasis and the oncogenic effect of miR-183 may relate the direct targeting PDCD4.

De Marchi T, Kuhn E, Dekker LJ, et al.
Targeted MS Assay Predicting Tamoxifen Resistance in Estrogen-Receptor-Positive Breast Cancer Tissues and Sera.
J Proteome Res. 2016; 15(4):1230-42 [PubMed] Related Publications
We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable of predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based on high-resolution MS data. A precise and high-throughput assay to measure these proteins in a multiplexed, targeted fashion would be favorable to measure large numbers of patient samples to move these findings toward a clinical setting. By coupling immunoprecipitation to multiple reaction monitoring (MRM) MS and stable isotope dilution, we developed a high-precision assay to measure the 4-protein signature in 38 primary breast cancer whole tissue lysates (WTLs). Furthermore, we evaluated the presence and patient stratification capabilities of our signature in an independent set of 24 matched (pre- and post-therapy) sera. We compared the performance of immuno-MRM (iMRM) with direct MRM in the absence of fractionation and shotgun proteomics in combination with label-free quantification (LFQ) on both WTL and laser capture microdissected (LCM) tissues. Measurement of the 4-proteins by iMRM showed not only higher accuracy in measuring proteotypic peptides (Spearman r: 0.74 to 0.93) when compared with MRM (Spearman r: 0.0 to 0.76) but also significantly discriminated patient groups based on treatment outcome (hazard ratio [HR]: 10.96; 95% confidence interval [CI]: 4.33 to 27.76; Log-rank P < 0.001) when compared with LCM (HR: 2.85; 95% CI: 1.24 to 6.54; Log-rank P = 0.013) and WTL (HR: 1.16; 95% CI: 0.57 to 2.33; Log-rank P = 0.680) LFQ-based predictors. Serum sample analysis by iMRM confirmed the detection of the four proteins in these samples. We hereby report that iMRM outperformed regular MRM, confirmed our previous high-resolution MS results in tumor tissues, and has shown that the 4-protein signature is measurable in serum samples.

Petrović N
miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development.
Mol Diagn Ther. 2016; 20(2):97-110 [PubMed] Related Publications
Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis.

Ding X, Cheng X, Gong M, et al.
Hypermethylation and Expression Silencing of PDCD4 Gene in Hepatocellular Carcinoma: A Consort Study.
Medicine (Baltimore). 2016; 95(6):e2729 [PubMed] Free Access to Full Article Related Publications
Programmed cell death 4 (PDCD4) is a novel tumor suppressor, which is involved in the initiation and progression of cancers. However, the role of PDCD4 in hepatocellular carcinoma (HCC) has not been reported. The aim of this study was to investigate the molecular mechanism and clinical significance of PDCD4 inactivation in HCC.The mRNA levels of PDCD4 in HCC tissues and adjacent nontumor tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Bisulfite sequencing PCR was performed to determine the methylation status of PDCD4 promoter. Furthermore, the mRNA expression level and the methylated level of PDCD4 were analyzed with the clinical and pathological characteristics.qRT-PCR analysis showed that PDCD4 mRNA levels in tumor tissues were significantly decreased compared with that in adjacent nontumor tissues. The methylation rate of PDCD4 promoter was significantly higher in HCC tissues than that in adjacent nontumor tissues. PDCD4 mRNA levels and promoter methylation levels were both statistically correlated with metastasis and the degree of differentiation in HCC. In addition, the correlation between PDCD4 hypermethylation, mRNA levels, and overall survival (OS) was statistically significant.Our results indicated that PDCD4 may be a novel candidate of tumor suppressor gene in HCC, and that promoter hypermethylation is an important mechanism for its downregulation and is also a good predictor of OS for HCC.

Zhang X, Gee H, Rose B, et al.
Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers.
BMC Cancer. 2016; 16:86 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood.
RESULTS: Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites.
CONCLUSION: This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.

Wei X, Wang W, Wang L, et al.
MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.
Cancer Med. 2016; 5(4):693-702 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21.

Zhen Y, Li D, Li W, et al.
Reduced PDCD4 Expression Promotes Cell Growth Through PI3K/Akt Signaling in Non-Small Cell Lung Cancer.
Oncol Res. 2016; 23(1-2):61-8 [PubMed] Related Publications
It is largely recognized that PDCD4 is frequently lost in tumors of various origins, including lung cancer, and its loss contributes to tumor progression. However, its role and molecular mechanism remain largely unexplored in non-small cell lung cancer (NSCLC). In this study, downregulated PDCD4 mRNA expression was found in NSCLC tissues compared to their corresponding paracarcinoma tissues and distal paracarcinoma tissues. Induced expression of PDCD4 inhibited cell growth and proliferation and cell cycle transition in vitro. Conversely, knocking down PDCD4 expression promoted cell growth and proliferation. Mechanistically, PDCD4 inactivated PI3K/Akt signaling and its downstream cell cycle factors CCND1 and CDK4 to regulate cell growth in NSCLC. Additionally, PI3K-specific inhibitor Ly294002 suppressed the expression of pPI3K (Tyr458), pAkt (Ser473), CCND1, and CDK4 in PC9-shPDCD4 and A549-shPDCD4 cells. Furthermore, Akt-specific inhibitor MK2206 inhibited the expression of pAkt (Ser473), CCND1, and CDK4 in PC9-shPDCD4 and A549-shPDCD4 cells. Taken together, our study provides evidence that PDCD4 inhibits cell growth through PI3K/Akt signaling in NSCLC and may be a potential therapeutic target for NSCLC.

Lu S, Wu J, Gao Y, et al.
MicroRNA-4262 activates the NF-κB and enhances the proliferation of hepatocellular carcinoma cells.
Int J Biol Macromol. 2016; 86:43-9 [PubMed] Related Publications
microRNAs (miRNAs) were known as transcriptional regulators to regulate the repertoires of target genes during the development of hepatocellular carcinoma (HCC). In this study, we investigated the roles of miR-4262 in the process of HCC. Our results showed that miR-4262 is overexpressed in HCC tissues and hepatoma cell lines (HepG2 and Sk-hep-1). We also found that miR-4262 enhanced the process of cell cycle and inhibited the apoptosis leading to promoted cell proliferation and activity. Moreover, the 3'UTR of PDCD4 was complementary to miR-4262 seed region and we confirmed that PDCD4 is the direct target of miR-4262 with 3'UTR luciferase assay. qPCR and WB analysis revealed that the level of PDCD4 was negatively correlated with the expression of miR-4262 in HepG2 cells. Furthermore, our results demonstrated that miR-4262-promoted cell proliferation was mediated by PDCD4 and miR-4262 can activate the NF-κB pathway to promote the accumulation of nuclear NF-κB/P65. All of these findings suggested miR-4262 may play a role in the development of HCC.

Jin YY, Andrade J, Wickstrom E
Non-Specific Blocking of miR-17-5p Guide Strand in Triple Negative Breast Cancer Cells by Amplifying Passenger Strand Activity.
PLoS One. 2015; 10(12):e0142574 [PubMed] Free Access to Full Article Related Publications
Conventional wisdom holds that only one of the two strands in a micro ribonucleic acid (miRNA) precursor duplex is selected as the active miRNA guide strand. The complementary miRNA passenger strand, however, is thought to be inactive. High levels of the oncogenic miRNA (oncomiR) guide strand called miR-17-5p is overexpressed in triple negative breast cancer (TNBC) and can inhibit ribosomal translation of tumor suppressor gene mRNAs, such as programmed cell death 4 (PDCD4) or phosphatase and tensin homolog (PTEN). We hypothesized that knocking down the oncogenic microRNA (oncomiR) miR-17-5p might restore the expression levels of PDCD4 and PTEN tumor suppressor proteins, illustrating a route to oligonucleotide therapy of TNBC. Contrary to conventional wisdom, antisense knockdown of oncomiR miR-17-5p guide strand reduced PDCD4 and PTEN proteins by 1.8±0.3 fold in human TNBC cells instead of raising them. Bioinformatics analysis and folding energy calculations revealed that mRNA targets of miR-17-5p guide strand, such as PDCD4 and PTEN, could also be regulated by miR-17-3p passenger strand. Due to high sequence homology between the antisense molecules and miR-17-3p passenger strand, as well as the excess binding sites for the passenger strand on the 3'UTR of PDCD4 and PTEN mRNAs, introducing a miR-17-3p DNA-LNA mimic to knock down miR-17-5p reduced PDCD4 and PTEN protein expression instead of raising them. Our results imply that therapeutic antisense sequences against miRNAs should be designed to target the miRNA strand with the greatest number of putative binding sites in the target mRNAs, while minimizing affinity for the minor strand.

Lu Y, Li J, Cheng J, Lubahn DB
Genes targeted by the Hedgehog-signaling pathway can be regulated by Estrogen related receptor β.
BMC Mol Biol. 2015; 16:19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nuclear receptor family member, Estrogen related receptor β, and the Hedgehog signal transduction pathway are both reported to relate to tumorigenesis and induced pluripotent stem cell reprogramming. We hypothesize that Estrogen related receptor β can modulate the Hedgehog signaling pathway and affect Hedgehog driven downstream gene expression.
RESULTS: We established an estrogen related receptor β-expressing Hedgehog-responsive NIH3T3 cell line by Esrrb transfection, and performed mRNA profiling using RNA-Seq after Hedgehog ligand conditioned medium treatment. Esrrb expression altered 171 genes, while Hedgehog signaling activation alone altered 339 genes. Additionally, estrogen related receptor β expression in combination with Hedgehog signaling activation affects a group of 109 Hedgehog responsive mRNAs, including Hsd11b1, Ogn, Smoc2, Igf1, Pdcd4, Igfbp4, Stmn1, Hp, Hoxd8, Top2a, Tubb4b, Sfrp2, Saa3, Prl2c3 and Dpt.
CONCLUSIONS: We conclude that Estrogen related receptor β is capable of interacting with Hh-signaling downstream targets. Our results suggest a new level of regulation of Hedgehog signaling by Estrogen related receptor β, and indicate modulation of Estrogen related receptor β can be a new strategy to regulate various functions driven by the Hedgehog signaling pathway.

Liwak-Muir U, Dobson CC, Naing T, et al.
ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism.
Oncotarget. 2016; 7(2):1439-50 [PubMed] Free Access to Full Article Related Publications
Programmed cell death 4 (PDCD4) is a tumour suppressor implicated in cancer development and progression and was recently identified as a repressor of cap-independent translation of specific genes involved in the regulation of apoptosis. We show that the RNA-binding protein HuR binds to the PDCD4 3'UTR to protect it from miR-21-induced silencing. However, following H2O2 treatment, PDCD4 mRNA is degraded via miR-21 binding. Importantly, we identify HuR as a novel substrate of the ERK8 kinase pathway in response to H2O2 treatment. We show that phosphorylation of HuR by ERK8 prevents it from binding to PDCD4 mRNA and allows miR-21-mediated degradation of PDCD4.

Guo Z, Jiang JH, Zhang J, et al.
COX-2 Promotes Migration and Invasion by the Side Population of Cancer Stem Cell-Like Hepatocellular Carcinoma Cells.
Medicine (Baltimore). 2015; 94(44):e1806 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells (CSCs) are thought to be responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to new tumors. Cyclooxygenase-2 (COX-2) is highly expressed in several kinds of CSCs, and it helps promote stem cell renewal, proliferation, and radioresistance. Whether and how COX-2 contributes to CSC migration and invasion is unclear. In this study, COX-2 was overexpressed in the CSC-like side population (SP) of the human hepatocellular carcinoma (HCC) cell line HCCLM3. COX-2 overexpression significantly enhanced migration and invasion of SP cells, while reducing expression of metastasis-related proteins PDCD4 and PTEN. Treating SP cells with the selective COX-2 inhibitor celecoxib down-regulated COX-2 and caused a dose-dependent reduction in cell migration and invasion, which was associated with up-regulation of PDCD4 and PTEN. These results suggest that COX-2 exerts pro-metastatic effects on SP cells, and that these effects are mediated at least partly through regulation of PDCD4 and PTEN expression. These results further suggest that celecoxib may be a promising anti-metastatic agent to reduce migration and invasion by hepatic CSCs.

Göke A, Göke R, Ofner A, et al.
The FGFR Inhibitor NVP-BGJ398 Induces NSCLC Cell Death by Activating Caspase-dependent Pathways as well as Caspase-independent Apoptosis.
Anticancer Res. 2015; 35(11):5873-9 [PubMed] Related Publications
BACKGROUND: Fibroblast growth factor receptors are expressed in diverse cell types. They play a critical role in tumor development. Their activation promotes cell-cycle progression, angiogenesis, and cell survival by induction/suppression of the expression of proteins involved.
MATERIALS AND METHODS: Non-small cell lung cancer (NSCLC) cells (line H1581) were treated with NVP-BGJ398 to evaluate effects on growth by western blot, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay and cell-cycle analysis.
RESULTS: NVP-BGJ398 induced cell death in H1581 cells by activating caspase-dependent mitochondrial and non-mitochondrial pathways. Caspase-independent apoptosis was also activated. Cells were found to be arrested in the G0/G1 phase. Furthermore, the expression of the tumor-suppressor gene programmed cell death 4 (PDCD4) was up-regulated with suppression of angiopoietin 2 (ANG2). This represents an additional mechanism by which NVP-BGJ389 inhibits tumor growth.
CONCLUSION: Various pathways induce apoptosis in NSCLC cells by employing NVP-BGJ398. These data reflect the potential of cancer treatment utilizing small FGFR inhibitors.

Yeomans A, Thirdborough SM, Valle-Argos B, et al.
Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.
Blood. 2016; 127(4):449-57 [PubMed] Related Publications
Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack.

Grozav A, Balacescu O, Balacescu L, et al.
Synthesis, Anticancer Activity, and Genome Profiling of Thiazolo Arene Ruthenium Complexes.
J Med Chem. 2015; 58(21):8475-90 [PubMed] Related Publications
Sixteen hydrazinyl-thiazolo arene ruthenium complexes of the general formula [(η(6)-p-cymene)Ru(N,N'-hydrazinyl-thiazolo)Cl]Cl were synthesized. All complexes were tested in vitro for their antiproliferative activity on three tumor cell lines (HeLa, A2780, and A2780cisR) and on a noncancerous cell line (HFL-1). A superior cytotoxic activity of the ruthenium complexes as compared to cisplatin and oxaliplatin, on both cisplatin-sensitive and cisplatin resistant ovarian cancer cells, was observed. In addition, the biological activity of two selected derivatives was evaluated using microarray gene expression assay and ingenuity pathway analysis. p53 signaling was identified as an important pathway modulated by both arene ruthenium compounds. New activated molecules such as FAS, ZMAT3, PRMT2, BBC3/PUMA, and PDCD4, whose overexpressions are correlated with overcoming resistance to cisplatin therapy, were also identified as potential targets. Moreover, the arene ruthenium complexes can be used in association with cisplatin to prevent cisplatin resistance development and synergistically to induce cell death in ovarian cancer cells.

De Mattos-Arruda L, Bottai G, Nuciforo PG, et al.
MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients.
Oncotarget. 2015; 6(35):37269-80 [PubMed] Free Access to Full Article Related Publications
Patients with primary HER2-positive breast cancer benefit from HER2-targeted therapies. Nevertheless, a significant proportion of these patients die of disease progression due to mechanisms of drug resistance. MicroRNAs (miRNAs) are emerging as critical core regulators of drug resistance that act by modulating the epithelial-to-mesenchymal transition (EMT) and cancer-related immune responses. In this study, we investigated the association between the expression of a specific subset of 14 miRNAs involved in EMT processes and immune functions and the response to neoadjuvant trastuzumab and chemotherapy in 52 patients with HER2-overexpressing breast tumors. The expression of only a single miRNA, miR-21, was significantly associated with residual disease (p = 0.030) and increased after trastuzumab-chemotherapy (p = 0.012). A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN (rs = -0.502; p = 0.005) and PDCD4 (rs = -0.426; p = 0.019), which differentially influenced the drug sensitivity of HER2-positive breast cancer cells. However, PTEN expression was only marginally associated with residual disease. We further demonstrated that miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-κB-mediated signaling loop and activating the PI3K pathway. Our findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer. Collectively, these data provide a rationale for using miR-21 expression as a biomarker to select trastuzumab-chemotherapy-resistant HER2-positive breast cancer patients who may benefit from treatments containing PI3K inhibitors or immunomodulatory drugs.

Wu L, Li S, Peng R, et al.
[Drug resistance of colon cancer cells to 5-fluorouracil mediated by microRNA-21].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015; 32(5):620-4 [PubMed] Related Publications
OBJECTIVE To explore downstream regulatory pathway of microRNA-21 (miR-21) in colon cancer cells (RKO) through detecting miR-21 and its target PDCD4, and the influence of miR-21 regulation on the sensitivity of RKO cells to 5-fluorouracil (5-FU). METHODS 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the effect of 5-FU on the viability of RKO cells with knockout of miR-21 or high expression of PDCD4. Real-time was used to determine the expression of PDCD4, ABCC5 and CD44 in RKO cell after knockout of miR-21. RESULTS MTT assay reveals that the IC50 of 5-FU in RKO-WT cells (52.82 ± 0.06 umol/L) was about 67% higher than in miR-21 knockout cells (32.23 ± 0.05 umol/L) (P < 0.05), and the apoptosis ratio elevated after knockout of miR-21. High expression of PDCD4, a target gene of miR-21, can negatively regulate the expression of ABC transporter ABCC5 and the stem cell marker CD44. CONCLUSION MiR-21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes.

Hu L, Ye H, Huang G, et al.
Long noncoding RNA GAS5 suppresses the migration and invasion of hepatocellular carcinoma cells via miR-21.
Tumour Biol. 2016; 37(2):2691-702 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are aberrantly expressed in various cancers. Although lncRNA GAS5 (growth arrest-specific transcript 5) has been characterized as a tumor suppressor in some kinds of cancer, its role and function in hepatocellular carcinoma (HCC) remain unknown. The present report demonstrates that there are lower levels of GAS5, PDCD4, and PTEN and higher levels of microRNA-21 (miR-21) in HCC tissues than in adjacent normal tissues. Moreover, the levels of GAS5 and miR-21 were correlated with the clinicopathological characteristics of HCC. HCC patients with higher levels of GAS5 or with the lower levels of miR-21 have longer survival times. There are lower levels of GAS5 and higher levels of miR-21 in HCC cell lines (Be7402, SMMC-7721, and HCCLM3) than in normal liver L-02 cells, and the levels correlate with the aggression of the HCC cell lines. Knockdown of GAS5 upregulates miR-21 levels in Bel-7402 cells (weakly aggressive); in contrast, there are opposite changes in HCCLM3 cells (highly aggressive). Moreover, GAS5 that upregulated or downregulated the expression of PDCD4 and PTEN was reversed by inhibiting or overexpressing miR-21 level in Bel-7402 and HCCLM3 cells. Then, overexpression of GAS5 suppresses the migration and invasion of HCC cells and high expression of miR-21 largely eliminates GAS5-mediated suppression of HCC cell migration and invasion. Thus, GAS5 acts as a tumor suppressor in HCCs through negative regulation of miR-21 and its targets and proteins about migration and invasion in cancer cells, which may be a target for treating HCC.

Jiang LH, Ge MH, Hou XX, et al.
miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma.
Lab Invest. 2015; 95(12):1398-408 [PubMed] Related Publications
miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients.

Wen SW, Zhang YF, Li Y, et al.
Characterization and effects of miR-21 expression in esophageal cancer.
Genet Mol Res. 2015; 14(3):8810-8 [PubMed] Related Publications
The aim of this study was to investigate the expression of miR-21 in esophageal cancer and the impact of miR-21 on apoptosis, invasion, and the expression of target genes in esophageal cancer cells. Fluorescence quantitative polymerase chain reaction analysis was used to detect the expression of miR-21 in human esophageal tissues, adjacent tissues, and an esophageal cancer cell line (TE-13). The antisense miR-21 oligonucleotide was generated commercially using the solid-phase chemical synthesis method. Transient transfection was used to transfect esophageal cancer cells (TE-13 antisense and TE-13 control cells). Flow cytometry and Transwell cell assays were used to detect the apoptosis and invasion of esophageal cancer cells, respectively. The western blot method was used to detect the expression of PTEN, PDCD4, and K-ras proteins. These analyses determined that mir-21 expression significantly increased in esophageal cancer tissues and in TE-13 cells, and that this phenomenon was not associated with staging or lymph node metastasis. The apoptosis rate of TE-13 control cells was lower than that of antisense TE-13 cells indicating an enhanced invasive ability. In tissues adjacent to esophageal cancer and in TE-13 antisense cells, the expression of PTEN and PDCD4 was found to be higher than that in the control group, whereas the expression of K-ras showed the opposite pattern. Together, these results suggest that miR- 21 might be involved in the development and metastasis of esophageal cancer, through interaction with its PDCD4 and K-ras target genes.

Thomsen KG, Terp MG, Lund RR, et al.
miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations.
Oncotarget. 2015; 6(30):29224-39 [PubMed] Free Access to Full Article Related Publications
To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression between isogenic metastasizing and non-metastasizing cancer cells, with miR-155 being the most differentially expressed. Highly metastatic mesenchymal-like CL16 cancer cells showed very low miR-155 expression, and miR-155 overexpression in these cells lead to significantly decreased tumor burden in lungs when injected intravenously in immunodeficient mice. Our experiments addressing the underlying mechanism of the altered tumor burden revealed that miR-155-overexpressing CL16 cells were less invasive than CL16 control cells in vitro, while miR-155 overexpression had no effect on cancer cell proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis-associated proteins ALDH1A1, PIR and PDCD4 in miR-155-overexpressing tumors was validated by immunohistochemistry. Our results demonstrate that miR-155 inhibits the ability of cancer cells to extravasate and/or colonize at distant organs and brings additional insight into the complexity of miR-155 regulation in metastatic seeding.

Aster JC
Dicing up T-ALL.
Blood. 2015; 126(8):929-30 [PubMed] Related Publications
In this issue of Blood, Junker et al delineate a novel signaling axis involving miR-21 and the tumor suppressor Pdcd4 that is essential for Notch-mediated induction of T-cell acute lymphoblastic leukemia (T-ALL).

Haghpanah V, Fallah P, Tavakoli R, et al.
Antisense-miR-21 enhances differentiation/apoptosis and reduces cancer stemness state on anaplastic thyroid cancer.
Tumour Biol. 2016; 37(1):1299-308 [PubMed] Related Publications
Anaplastic thyroid carcinoma (ATC) is the most aggressive malignancy in thyroid cancers. Resistance to current therapies is still a challenge. MicroRNAs are a class of small non-coding RNAs, regulating gene expression. MiR-21 is an oncomiR that is overexpressed in nearly all cancers including ATC. Accumulating evidence suggested that miR-21 has a role in cancer stemness state, apoptosis, cell cycle progression, and differentiation. Therefore, we evaluated the application of Off-miR-21 to sequester the microRNA for therapeutic purposes on ATC cell lines. In this study, C643 and SW1736 were transducted by hsa-miR-21 antagomir (Off-miR-21). PTEN gene expression was performed as a known target of miR-21. Stemness state in cancer stem cells (CSCs) was evaluated by the changes of CSC biomarkers including Oct-4 and ABCG2. Apoptosis was assessed by PDCD4 and Mcl-1 gene expression and flow cytometry. Sodium/iodide symporter (NIS) and thyroglobulin (TG) were measured as ATC differentiation markers. In addition, cell cycle progression was investigated via the alterations of p21 gene expression and flow cytometry. Specific downregulation of miR-21 induced the differentiation and apoptosis in C643 and SW1736. Inversely, the treatment inhibited stemness state and cell cycle progression. Knockdown of miR-21 significantly increased the expression of PDCD4, p21, NIS, and TG while leading to decreased expression of Oct-4, ABCG2, and Mcl-1.Taken together, the results suggest that miR-21, as an oncomiR, has a role not only in stemness state but also in tumor growth, differentiation, and apoptosis. Hence, suppression of miR-21 could pave the way for ATC therapy.

Shi R, Wang PY, Li XY, et al.
Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients.
Oncotarget. 2015; 6(29):26971-81 [PubMed] Free Access to Full Article Related Publications
Glioma is a most common type of primary brain tumors. Extracellular vesicles, in the form of exosomes, are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we examined the cerebrospinal fluid (CSF) from patients with recurrent glioma for the levels of cancer-related miRNAs, and evaluated the values for prognosis by comparing the measures of CSF-, serum-, and exosome-contained miR-21 levels. Samples from seventy glioma patients following surgery were compared with those from brain trauma patients as a non-tumor control group. Exosomal miR-21 levels in the CSF of glioma patients were found significantly higher than in the controls; whereas no difference was detected in serum-derived exosomal miR-21 expression. The CSF-derived exosomal miR-21 levels correlated with tumor spinal/ventricle metastasis and the recurrence with anatomical site preference. From additional 198 glioma tissue samples, we verified that miR-21 levels associated with tumor grade of diagnosis and negatively correlated with the median values of patient overall survival time. We further used a lentiviral inhibitor to suppress miR-21 expression in U251 cells. The results showed that the levels of miR-21 target genes of PTEN, RECK and PDCD4 were up-regulated at protein levels. Therefore, we concluded that the exosomal miR-21 levels could be demonstrated as a promising indicator for glioma diagnosis and prognosis, particularly with values to predict tumor recurrence or metastasis.

Lin Z, Song D, Wei H, et al.
TGF-β1-induced miR-202 mediates drug resistance by inhibiting apoptosis in human osteosarcoma.
J Cancer Res Clin Oncol. 2016; 142(1):239-46 [PubMed] Related Publications
PURPOSE: A number of studies have demonstrated that microRNAs play a critical role in osteosarcoma progression, therapy and drug resistance. MicroRNA-202 has proven to be dysregulated in many human cancer studies. This study aimed to explore miR-202 contributions to drug resistance in osteosarcoma.
METHODS: miR-202 expression was measured by real-time PCR in patient tissues, cell lines or cells treated with TGF-β1, using siRNA to knock down the expression of Smad2, Smad3 and Smad4. miR-202 mimics, inhibitor and scramble siRNA were transfected into osteosarcoma cells to observe effects on cell apoptosis and drug resistance. Moreover, relationships of miR-202 level with PDCD4 were investigated by luciferase reporter assay, real-time PCR and Western blotting.
RESULTS: We found that miR-202 is overexpressed in osteosarcoma tissues when compared with normal human osteoblasts and TGF-β1 can induce the expression of miR-202. Transfection of miR-202 mimics into osteosarcoma cell lines significantly promotes chemotherapy resistance by targeting PDCD4, a tumor suppressor which is involved in apoptosis. In contrast, transfection of miR-202 inhibitor enhances the drug sensitivity and apoptosis.
CONCLUSIONS: This study provides new insights into miRNA-202 in osteosarcoma as a potential molecular target for chemotherapy.

Mulens-Arias V, Rojas JM, Pérez-Yagüe S, et al.
Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.
J Control Release. 2015; 216:78-92 [PubMed] Related Publications
Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.

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