PDCD4 silencing alleviates KA­induced neurotoxicity of HT22 cells by inhibiting endoplasmic reticulum stress via blocking the MAPK/NF­κB signaling pathway.

Human programmed cell death 4 (PDCD4) has been reported to participate in multiple neurological diseases. However, the role of PDCD4 in epilepsy, as well as its underlying mechanism, remains unclear. To induce excitotoxicity, 100 µM kainic acid (KA) was applied for the stimulation of HT22 cells for 12 h. Initially, the mRNA and protein expression levels of PDCD4 were evaluated using reverse transcription-quantitative PCR and western blotting. A lactate dehydrogenase assay was performed to detect cell injury. Cell apoptosis was assessed using flow cytometry and western blotting was performed to determine the expression levels of apoptosis-related proteins. Oxidative stress was detected using dichlorodihydrofluorescein diacetate staining, and malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) assay kits. Furthermore, the expression levels of MAPK/NF-κB signaling-related proteins and endoplasmic reticulum (ER) stress-related proteins C/EBP homologous protein, glucose-regulated protein 78, activating transcription factor 4 and phosphorylated-eukaryotic initiation factor-2α were assessed by western blotting. It was revealed that PDCD4 expression was markedly elevated in KA-induced HT22 cells, whereas PDCD4 silencing alleviated KA-induced neurotoxicity of HT22 cells by alleviating cell injury and inhibiting apoptosis. In addition, PDCD4 silencing reduced the levels of reactive oxygen species and MDA, but elevated those of SOD and GSH-Px. PDCD4 silencing also suppressed ER stress by blocking the MAPK/NF-κB signaling pathway. By contrast, the MAPK agonist phorbol myristate acetate reversed the effects of PDCD4 silencing on KA-induced neurotoxicity and oxidative stress in HT22 cells. In conclusion, PDCD4 silencing alleviated KA-induced neurotoxicity and oxidative stress in HT22 cells by suppressing ER stress through the inhibition of the MAPK/NF-κB signaling pathway, which may provide novel insights into the treatment of epilepsy.

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

PDCD4 and MIR-21 are promising biomarkers in the follow-up of OED in liquid biopsies.

This research aims to examine the impact of programmed cell death 4 (PDCD4), microRNA-21 (miR-21) and microRNA-208a (miR-208a) transcripts, and protein levels on oral epithelial dysplasia (OED) development in oral squamous cell carcinoma (OSCC). METHODS: The research investigation involved the collection of saliva, blood, and tissue samples from a total of 20 patients diagnosed with OSCC, 15 patients diagnosed with OED, and 15 healthy individuals. PDCD4, miR-21, and miR-208a expression was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). PDCD4 protein levels were assessed using enzyme-linked immunosorbent assay (ELISA) in both saliva and blood samples. For statistical analysis, the Kruskal-Wallis test and the Spearmen rank test were utilised. RESULTS: PDCD4 expression levels were considerably lower in patients with OSCC and OED (p < 0.05) in three biological samples. In contrast, miR-21 expression was higher in OED and OSCC patients. Patients with low PDCD4 mRNA levels and strong miR-21 expression had a significant connection (p < 0.05) with tumor size and depth. CONCLUSIONS: Examining PDCD4 and miR-21 transcript levels may help detect the transition from OED to OSCC. This work suggests that PDCD4 and miR-21 expression levels in liquid biopsies may be biomarkers for OED monitoring in the future.

Exosomal microRNA-342-5p from human umbilical cord mesenchymal stem cells inhibits preeclampsia in rats.

We aimed to investigate the inhibitory effect of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes (hucMSC-Exos) transmitting microRNA-342-5p (miR-342-5p) on the development of preeclampsia (PE) by targeting programmed cell death 4 (PDCD4). The primary hucMSCs were cultured and transfected with miR-342-5p, and the exosomes (Exo) were extracted from the hucMSCs. PE rats were performed with an intraperitoneal injection of L-NAME from days 11 to 19 of gestation, and injection of Exo, Exo-negative control (NC), Exo-miR-342-5p agomir, Exo-miR-342-5p antagomir, and overexpressing PDCD4 (oe-PDCD4) vector into the placenta on the 16th day of pregnancy. HE staining was utilized to observe the pathological changes in placental tissues. TUNEL staining was implemented to evaluate cell apoptosis in placental tissues. Blood pressure and 24-h urinary protein in pregnant rats were measured by a non-invasive rat tail artery blood pressure measurement and protein auto-analyzer. Expressions of miR-342-5p, PDCD4, proinflammatory cytokines (TNF-α and IL-1ß), and anti-inflammatory cytokines (IL-10 and TGF-ß) were detected by RT-qPCR, and PDCD4 protein expression was determined by Western blot. The interaction between miR-342-5p and PDCD4 was analyzed by luciferase activity assay. MiR-342-5p was downregulated while PDCD4 was upregulated in the placental tissues of PE rats. HucMSC-Exo relieved pathology and suppressed inflammatory response, and apoptosis in the placental tissues, as well as reducing blood pressure and 24-h urinary protein of PE rats. Elevated miR-342-5p enhanced the promoting influence of hucMSC-Exo on PE rats, while inhibited miR-342-5p reversed the functions of hucMSC-Exo on PE rats. miR-342-5p targeted PDCD4. Overexpression of PDCD4 worsened the development of PE in rats. HucMSC-Exo conveying elevated miR-342-5p inhibits the development of PE in a rat model through downregulating PDCD4.

Circulating miR-21 Overexpression Correlates with PDCD4 and IL-10 in Systemic Lupus Erythematosus (SLE): A Promising Diagnostic and Prognostic Biomarker.

Background: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune condition that affects multiple organs significantly impacts morbidity and mortality. The development of SLE is influenced by genetic predisposition and dysregulated immune response. Our objective was to investigate miR-21, IL-10, and PDCD4 expression in SLE patient plasma and analyze their correlations and potential diagnostic and prognostic values. Methods: The study included 100 healthy subjects, 50 newly diagnosed (ND), and 50 under-treatment (UT) SLE patients. The patients were observed for 24 weeks to track relapses. miR-21 and PDCD4 gene expression levels were measured using real-time RT-PCR, and IL-10 production was measured using ELISA. Results: miR-21 and IL-10 expression levels were significantly greater in SLE patients than in healthy subjects, with the highest levels observed in ND patients. PDCD4 expression was also significantly greater in SLE patients than in subjects, with the highest levels observed in UT patients. ROC curve analyses and Cox-Mantel Log-rank tests indicated miR-21, PDCD4, and IL-10 as proper diagnostic and prognostic biomarkers for SLE. The study also revealed a significant positive correlation between miR-21 and PDCD4 and IL-10 levels in SLE patients. Conclusions: The studies suggest that dysregulation of miR-21, PDCD4, and IL-10 in patients with SLE may contribute to disease development and provides new diagnostic and prognostic markers. Additionally, the observed correlation between miR-21, PDCD4, and IL-10 levels in SLE patients signifies a potential interplay between these molecules.

Downregulation of PDCD4 by deSUMOylation associates with the progression of gestational trophoblastic disease.

INTRODUCTION: Gestational trophoblastic disease (GTD) encompasses a range of trophoblastic disorders from hydatidiform mole (HM), to malignant gestational trophoblastic neoplasia (GTN). The exact molecular mechanisms of GTN remain unknown. Dysregulation and dysfunction of programmed cell death 4 (PDCD4)have been observed in many cancers. The roles of PDCD4 in GTD have not been previously reported. METHODS: A total of 161 cases of formalin-fixed, paraffin-embedded trophoblast blocks, and 36 cases of fresh trophoblast tissues were collected, including normal first trimester placentas, HM, and invasive HM. Choriocarcinoma cells JAR and JEG-3 were employed. The expressions of PDCD4 and small ubiquitin-like modifier 2/3 (SUMO2/3) were examined by immunohistochemistry, quantitative reverse transcription PCR and Western blotting in trophoblastic tissues and cells. The relationship between SUMOylation and PDCD4 was investigated. The effects of PDCD4 on proliferation, invasion, and migration of choriocarcinoma cells were evaluated by Cell Counting Kit-8 and transwell assays post siRNA transfection. Extracellular Matrix & Adhesion Profiler PCR Array was used to screen the downstream molecules of PDCD4. RESULTS: PDCD4 was significantly repressed in HM tissues. Loss of PDCD4 expression was demonstrated in 90% invasive HMs. Choriocarcinoma cells also displayed with suppressed PDCD4 expression. The varied expression of PDCD4 was paralleled by SUMO2/3. Inhibition of SUMOylation reduced the expression of PDCD4. Silencing of PDCD4promoted proliferation/migration/invasion, upregulatedMMP3/MMP8/ITGB2, and downregulated TIMP1/TIMP2 in choriocarcinoma cells. DISCUSSION: Our results suggest that reduced SUMOylation is one reason for suppressed PDCD4 in GTD. Loss of PDCD4 likely determines the malignant phenotype of GTN by dysregulating some members of the MMPs/TIMPs/integrins complex.

Genistein promotes M1 macrophage apoptosis and reduces inflammatory response by disrupting miR-21/TIPE2 pathway.

Cardiovascular diseases are a major cause of mortality, and vascular injury, a common pathological basis of cardiovascular disease, is deeply correlated with macrophage apoptosis and inflammatory response. Genistein, a type of phytoestrogen, exerts cardiovascular protective activities, but the underlying mechanism has not been fully elucidated. In this study, RAW264.7 cells were treated with genistein, lipopolysaccharide (LPS), nuclear factor-kappa B (NF-κB) inhibitor, and/or protein kinase B (AKT) agonist to determine the role of genistein in apoptosis and inflammation in LPS-stimulated cells. Simultaneously, high fat diet-fed C57BL/6 mice were administered genistein to evaluate the function of genistein on LPS-induced cardiovascular injury mouse model. Here, we demonstrated that LPS obviously increased apoptosis resistance and inflammatory response of macrophages by promoting miR-21 expression, and miR-21 downregulated tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) expression by targeting the coding region. Genistein reduced miR-21 expression by inhibiting NF-κB, then blocked toll-like receptor 4 (TLR4) pathway and AKT phosphorylation dependent on TIPE2, resulting in inhibition of LPS. Our research suggests that miR-21/TIPE2 pathway is involved in M1 macrophage apoptosis and inflammatory response, and genistein inhibits the progression of LPS-induced cardiovascular injury at the epigenetic level via regulating the promoter region of Vmp1 by NF-κB.

miR-21 promotes the fibrotic properties in oral mucosa through targeting PDCD4.

Background/purpose: Oral submucous fibrosis (OSF) has been regarded as a premalignant disorder of oral cancer, and myofibroblasts are the main cells that are responsible for pathological fibrosis. Hence, elucidation of the molecular mechanism underlying myofibroblast activation is important to treat OSF. MicroRNA-21 (miR-21) is a well-known fibrosis non-coding RNA, and its role in the development of OSF remains largely unclear. Materials and methods: Luciferase reporter assay was used to confirm the direct interaction between miR-21 and its target programmed cell death 4 (PDCD4). The expression level of PDCD4 in OSF was examined by qRT-PCR. Myofibroblast activities were assessed by collagen gel contraction and transwell migration assays. Results: Our result validated the direct binding of miR-21 to PDCD4. We showed the expression of PDCD4 was downregulated in OSF specimens and negatively correlated with miR-21. Our results suggested that overexpression of PDCD4 in fibrotic buccal mucosal fibroblasts (fBMFs) mitigated the myofibroblast activities, including collagen gel contractility and migration capacity. Moreover, we showed miR-21 contributed to myofibroblast activation of BMFs through repression of PDCD4. Conclusion: Our results suggest that the miR-21/PDCD4 axis mediates the myofibroblast activation of BMFs, and targeting this axis may exert an anti-fibrosis effect.

TRIM27 regulates the expression of PDCD4 by the ubiquitin­proteasome pathway in ovarian and endometrial cancer cells.

Programmed cell death 4 (PDCD4) is regarded as an important tumor suppressor that is lowly expressed or deleted in numerous human types of cancer, including ovarian and endometrial cancer. Tripartite motif­containing 27 (TRIM27) is closely related to the occurrence and development of tumors and is highly expressed in numerous types of cancer such as ovarian and endometrial cancer. PDCD4 can be degraded through ubiquitination, while TRIM27 has the E3 ubiquitin ligase activity. However, whether TRIM27 may regulate the expression of PDCD4 by ubiquitination effect remains unclear. In the present study, the expression of PDCD4 and TRIM27 in different ovarian and endometrial cancer cell lines was detected by reverse transcription­quantitative PCR (RT­qPCR), western blotting and immunocytochemistry. The impact of TRIM27 overexpression and knockdown on PDCD4 expression and the effective mechanism of TRIM27 regulating PDCD4 expression were also investigated in vitro by RT­qPCR, western blotting, co­immunoprecipitation assay, Transwell migration and Matrigel invasion assays. The results showed that the expression of TRIM27 and PDCD4 had a negative association at the protein level, and the distribution of TRIM27 and PDCD4 proteins had a phenomenon of co­localization in different ovarian and endometrial cancer cell lines. TRIM27 promoted the degradation of PDCD4 through the ubiquitin­proteasome pathway. To sum up, TRIM27 could increase the migration and invasion of ovarian and endometrial cancer cells by promoting the ubiquitination and degradation of PDCD4. The present findings may provide a new target for the treatment of ovarian and endometrial cancer.

MicroRNA-15a-5p plays a role in osteogenic MC3T3-E1 cells differentiation by targeting PDCD4 (programmed cell death 4) via Wnt/ß-catenin dependent signaling pathway.

Osteoporosis is defined as a bone condition characterized by bone mass reduction, bone micro-architectural and quality deterioration, leading to compromised strength and increased chances of fracture. Evidence have shown an essential role of microRNAs (miRNAs) in various osteogenic differentiation processes. However, the function of miR-15a-5p in the differentiation of osteogenic cells and possible mechanisms remains unclear. The present study explored the expression of miR-15a-5p in human osteoporosis specimens and during the osteogenic differentiation of MC3T3-E1 cells. Functions of miR-15a-5p were determined using miR-15a-5p mimics and inhibitors. Luciferase assay was used to verify the binding of miR-15a-5p and PDCD4 3'UTR. Alizarin Red Staining (ARS) and Alkaline phosphatase (ALP) activity were used to determine the miR-15a-5p role in osteogenic differentiation. Finally, Wnt pathway inhibitor was used to determine the miR-15a-5p/PDCD4/Wnt signaling pathway in regulating osteogenic differentiation. We found miR-15a-5p expression was increased in human osteoporosis specimens and during differentiation of MC3T3-E1 cells. PDCD4 was also identified as a target of miR-15a-5p and was found to be involved in osteogenic differentiation. Further, miR-15a-5p mimics attenuated the effects of PDCD4 overexpression. Finally, use of XAV939 (Wnt pathway inhibitor) downregulated osteogenic differentiation in miR-15a5p/PDCD4/Wnt-dependent signaling pathway. In conclusion, miR-15a-5p induced differentiation of osteoblasts and mineralization by modulating osteoblast differentiation factors, mainly OSX, ALP, OCN, and RUNX2, by inhibiting PDCD4 and Wnt signaling pathways. This study provides a modality for the future use of miR-15a-5p in the treatment and prevention of osteoporosis.

Differential data on the responsiveness of multiple cell types to cell death induced by non-thermal atmospheric pressure plasma-activated solutions.

A discovery that cells die of a novel and distinctive process, along with some characteristic events, such as cellular shrinkage and Programmed cell death 4 disappearance, has been done by using non-thermal atmospheric pressure plasma-activated solutions [1]. Data on the responsiveness of multiple cell types to the induction of cellular shrinkage and cell death and the loss of Programmed cell death 4 by exposure to the non-thermal atmospheric pressure plasma-activated solutions were collected. Human neuroblastoma SH-SY5Y cells, murine myoblast C2C12 cells, and murine embryonic fibroblasts were cultured for various periods in each of the non-thermal atmospheric pressure plasma-activated solutions and then examined by light field microscopic observation for their effects on cell morphology, by Trypan blue dye exclusion assay for those on cell death, and by Western blotting for those on Programmed cell death 4 disappearance. The data clarified some differences in the responsiveness to the induction of cellular shrinkage, cell death, and Pdcd4 disappearance by all the non-thermal atmospheric pressure plasma-activated solutions among the cells.

Induction of PDCD4 by albumin in proximal tubule epithelial cells potentiates proteinuria-induced dysfunctional autophagy by negatively targeting Atg5.

Autophagy dysfunction is a hallmark of type 1 diabetes. However, the precise molecular mechanism of proteinuria-induced dysfunctional autophagy remains unclear. Herein, we investigated the role of programmed cell death 4 (PDCD4) in the regulation of autophagy in the pathogenesis of diabetic kidney disease (DKD) in vivo and in vitro. RT-qPCR, immunohistochemistry (IHC), and western blotting demonstrated an upregulation of Pdcd4 mRNA and protein in streptozotocin (STZ)-induced DKD rats, as compared to the control. In addition, IHC and western blotting of a unilateral ureteral obstruction mouse model showed an upregulation of PDCD4 in the disease group, as compared to their respective controls. IHC analysis of kidney biopsy samples of human DKD patients showed an upregulation of PDCD4 compared to the control. Western blotting of the STZ-induced DKD rat tissues displayed a low microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, as compared to the control. It was found that albumin overload in cultured PTECs upregulated the expression of PDCD4 and p62 and decreased the expression of LC3-II and autophagy-related 5 (Atg5) proteins. The knockout of Pdcd4 in cultured PTECs could reduce albumin-induced dysfunctional autophagy, as evidenced by the recovery of Atg5 and LC3-II protein. The forced expression of PDCD4 could further suppress the expression of the crucial autophagy-related gene Atg5. Evidence suggests that endogenous PDCD4 promotes proteinuria-induced dysfunctional autophagy by negatively regulating Atg5. Therefore, PDCD4 may be a potential therapeutic target in DKD.

RNA-binding proteins La and HuR cooperatively modulate translation repression of PDCD4 mRNA.

Posttranscriptional regulation of gene expression plays a critical role in controlling the inflammatory response. An uncontrolled inflammatory response results in chronic inflammation, often leading to tumorigenesis. Programmed cell death 4 (PDCD4) is a proinflammatory tumor-suppressor gene which helps to prevent the transition from chronic inflammation to cancer. PDCD4 mRNA translation is regulated by an interplay between the oncogenic microRNA miR-21 and the RNA-binding protein (RBP) human antigen R (HuR) in response to lipopolysaccharide stimulation, but the role of other regulatory factors remains unknown. Here, we report that the RBP lupus antigen (La) interacts with the 3'-untranslated region of PDCD4 mRNA and prevents miR-21-mediated translation repression. While lipopolysaccharide causes nuclear-cytoplasmic translocation of HuR, it enhances cellular La expression. Remarkably, La and HuR were found to bind cooperatively to the PDCD4 mRNA and mitigate miR-21-mediated translation repression. The cooperative action of La and HuR reduced cell proliferation and enhanced apoptosis, reversing the pro-oncogenic function of miR-21. Together, these observations demonstrate a cooperative interplay between two RBPs, triggered differentially by the same stimulus, which exerts a synergistic effect on PDCD4 expression and thereby helps maintain a balance between inflammation and tumorigenesis.

Expressions and Significance of PDCD4 and Autophagy-related Factors LC3Ⅱ and p62 in Endoscopic Submucosal Dissection Specimens of Early Colorectal Cancer / 胃肠病学

Background: Endoscopic submucosal dissection (ESD) has become the preferred treatment of early colorectal cancer. PDCD4 and autophagy have important clinical significance in the pathogenesis of colorectal cancer. Aims: To explore the expressions and significance of apoptosis factor PDCD4 and autophagy factors LC3Ⅱ and p62 in colorectal cancer. Methods: Fifty-four early colorectal adenocarcinoma patients treated by ESD from Jan. 2015 to Nov. 2020 at Binzhou Medical University Hospital were collected. The expressions of PDCD4, LC3Ⅱ and p62 were detected by immunohistochemistry, and the correlations with clinicopathological factors were analyzed. The differential expression of PDCD4 in pan-cancer was analyzed by bioinformatics analysis. Results: Expression of PDCD4 was associated with the long-diameter of paracancer adenoma (P<0.05), and expressions of LC3Ⅱ and p62 were associated with the long-diameters of adenocarcinoma and paracancer adenoma (P<0.05). The positive expression of PDCD4 in P-NIMM was located in the nucleus, while the positive expression in adenocarcinoma was located in cytoplasm. The nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-NIMM than in P-LGIN, P-HGIN and adenocarcinoma (P<0.05), and the nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-LGIN, P-HGIN than in adenocarcinoma (P<0.05). The positive expression rates of LC3Ⅱ and p62 were significantly higher in adenocarcinoma than in P-NIMM and P-LGIN (P<0.05). In P-LGIN, P-HGIN and adenocarcinoma, the expression of PDCD4 was negatively correlated with the expressions of LC3Ⅱ and p62 (P<0.05). The bioinformatics analysis showed that expression of PDCD4 was significantly reduced in a variety of malignant tumors including colorectal cancer (P<0.05). Conclusions: The inhibition of apoptosis and activation of autophagy may promote the occurrence of colorectal cancer, and its mechanism may be related to the intracellular transposition of PDCD4 that inhibits cell apoptosis and enhances autophagy, and activating cellular autophagy may further accelerate the degradation of PDCD4 and thus reducing its cancer inhibiting effect.

Protective Effect of miR-340-5p against Brain Injury after Intracerebral Hemorrhage by Targeting PDCD4.

OBJECTIVE: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease. Increasing evidence has documented the crucial role of microRNAs in ICH. The present study aimed to investigate the role and underlying mechanism of miR-340-5p in ICH. METHODS: The collagenase-induced ICH rat model was established. The neurological function of rats and the cerebral water content of rat brain tissue were measured to assess the brain injury. BV-2 cells were recruited and treated by LPS to mimic ICH-induced inflammatory response. qRT-PCR was used for the measurement of miR-340-5p. The protein levels of TNF-α, IL-6, and IL-1ß were detected using ELISA. Luciferase reporter gene assay was performed to confirm the target gene. RESULTS: Downregulation of miR-340-5p was detected in the serum of ICH patients and the brain tissues of ICH rats. Overexpression of miR-340-5p reversed the influence of ICH on the neurological function score and cerebral water content and inhibited the production of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), which were induced by ICH in vivo. In in vitro study, levels of TNF-α, IL-6, and IL-1ß were significantly enhanced in cells after LPS treatment, but these increases were eliminated by overexpression of miR-340-5p. PDCD4 was a direct target gene of miR-340-5p. CONCLUSION: miR-340-5p protects against brain injury after ICH. miR-340-5p might exert an anti-inflammatory effect during the occurrence of ICH via targeting PDCD4.

Forkhead box P3 promotes breast cancer cell apoptosis by regulating programmed cell death 4 expression.

Forkhead box P3 (FOXP3), an X-linked tumor suppressor gene, plays an important role in breast cancer. However, the biological functions of FOXP3 in breast cancer apoptosis remain unclear. To investigate the underlying genes and networks regulated by FOXP3 in breast cancer, RNA sequencing was performed to compare FOXP3-overexpressing MDA-MB-231 cells and control MDA-MB-231 cells. Differentially expressed genes were identified, and functional enrichment analysis comparing the two groups was performed. The differentially expressed genes were mainly enriched in phagosomes, oxytocin, serotonergic synapses and the phospholipase D signaling pathway. Furthermore, gene set enrichment analysis revealed the enrichment of a gene signature associated with apoptosis in FOXP3-overexpressing MDA-MB-231 cells compared with wild-type cells. Further analysis showed that programmed cell death 4 (PDCD4), a key molecule involved in apoptosis, was overexpressed in FOXP3-MDA-MB-231 cells. Reverse transcription-quantitative PCR and western blotting showed that FOXP3 upregulated the expression of PDCD4 in breast cancer cells. Clinical sample analysis using a public database showed that the expression level of PDCD4 was associated with breast cancer clinical stages. Overall, the present study suggested that FOXP3 can promote the apoptosis of breast cancer cells by upregulating the expression of PDCD4, thus exerting a tumor suppressive function.

miR-590-5p may regulate colorectal cancer cell viability and migration by targeting PDCD4.

Recent studies have revealed that microRNAs (miRs) are involved in the pathogenesis of colorectal cancer (CRC); however, the roles of miR-590-5p in CRC are not completely understood. Therefore, the present study investigated the expression of miR-590-5p and programmed cell death 4 (PDCD4) in CRC tissues and healthy adjacent tissues via reverse transcription-quantitative PCR. Furthermore, human CRC cells were cultured in vitro and transfected with miR-590-5p inhibitor. CRC cell viability, migration and invasion were evaluated by conducting MTT, wound healing and Transwell assays, respectively. Additionally, the relative expression of PDCD4 and phosphorylated-Smad2/3 was analyzed via western blotting. miR-590-5p was significantly upregulated and PDCD4 was significantly downregulated in CRC tissues compared with healthy adjacent tissues. Moreover, the results indicated that miR-590-5p knockdown inhibited cell viability and migration by altering the expression of PDCD4, transforming growth factor-ß and phosphorylated-Smad2/3. PDCD4 was identified as a direct target of miR-590-5p. In conclusion, the results of the present study suggested that miR-590-5p may regulate CRC cell viability and migration, indicating that miR-590-5p may serve as a potential therapeutic target for CRC.

PDCD4 regulates axonal growth by translational repression of neurite growth-related genes and is modulated during nerve injury responses.

Programmed cell death 4 (PDCD4) protein is a tumor suppressor that inhibits translation through the mTOR-dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons. Using loss- and gain-of-function experiments in cortical and dorsal root ganglia primary neurons, we demonstrated the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome and translatome targets, we used Ribo-seq and uncovered a list of potential targets with known functions as axon/neurite outgrowth regulators. In addition, we observed that PDCD4 can be locally synthesized in adult axons in vivo, and its levels decrease at the site of peripheral nerve injury and before nerve regeneration. Overall, our findings demonstrate that PDCD4 can act as a new regulator of axonal growth via the selective control of translation, providing a target mechanism for axon regeneration and neuronal plasticity processes in neurons.

PDCD4 inhibits lung tumorigenesis by the suppressing p62-Nrf2 signaling pathway and upregulating Keap1 expression.

Programmed cell death 4 (PDCD4) suppresses tumorigenesis, tumor progression, and invasion by inhibiting transcription and translation of oncogenes. However, the role of PDCD4 in lung tumorigenesis is unclear. Sequestosome1/p62 mediates cell proliferation, survival, and death through multiple signaling pathways, including autophagy and cell metabolism. p62/SQSTM1 is transcriptional target of Nrf2 and an important regulator of tumor growth. The aim of this study was to clarify whether and how PDCD4 regulates the p62-Nrf2 pathway, and how this regulation relates to tumorigenesis in human lung cancer cells. We established two stable human lung cancer cell lines, A549 and H460 that each overexpressed PDCD4. We found that PDCD4 overexpression decreased p62 expression levels and inhibited cell proliferation, and also increased the expression levels of cleaved PARP and cleaved caspase 3. Knockdown of p62 markedly increased the apoptotic rate of A549 and H460 cells overexpressing PDCD4. Furthermore levels of the epithelial-mesenchymal transition-related markers Slug, Snail, Twist1 and Vimentin were decreased and expression level of E-cadherin was increased in PDCD4-overexpressing cells. We also found that PDCD4 suppressed transcriptional activation of Nrf2 (an upstream regulator of p62) and increased endogenous levels of Keap1 (a negative regulator of Nrf2). Upregulation of Keap1 induced apoptosis and inhibited cell proliferation by suppressing activity of the p62-Nrf2 pathway in PDCD4-overexpressing cells. As anticipated, results from a mouse xenograft model showed that PDCD4 overexpression in xenografts inhibited cell proliferation and tumorigenesis. Taken together, our results demonstrate that PDCD4 overexpression, which increased Keap1 expression, reduces the levels and activity of the p62-Nrf2 pathway, thereby inhibiting tumorigenesis. Our findings suggest that PDCD4 may be a potential target for lung cancer therapies.

SIRT1 protects against aortic dissection by regulating AP-1/decorin signaling-mediated PDCD4 activation.

Medial degeneration of aorta wall is the principal feature of aortic dissection (AD). Sirtuin 1 (SIRT1) plays essential protective effect on many aortic-associated disease. However, it is still unclear whether SIRT1participates in the process of medial degeneration-mediated AD. The purpose of this study is to explore the association between SIRT1 and AD process. qRT-PCR was used to evaluate the transcriptional level of genes involved in study. Protein levels and acetylation detection were measured by Western blotting. The regulatory relations between AP-1 and decorin was assessed by luciferase reporter gene assay. Acute aortic dissection (AAD) mice model was constructed by feeding with ß-aminopropionitrile monofumarate (BAPN). Haematoxylin and eosin (HE) and Mallory staining were performed for pathological analysis. In clinical aorta tissue of thoracic aortic dissection (TAD), the expression of SIRT1, activator protein 1 (AP-1) and decorin were in accordant trend. AP-1 expression which acts on Decorin promoter region is possibly regulated in a SIRT1-mediated deacetylation dependent manner. Resveratrol or SRT1720-initiated SIRT1 activation ameliorated BAPN-induced AAD symptoms accompanied by the activation of AP-1/decorin signaling and decorin-mediated programmed cell death 4 (PDCD4) expression by inhibiting miR-21 and miR-181b. These data suggest that SIRT1/AP-1/decorin signal cascades possibly play a part role in the process of AD. Our research demonstrate that activation of SIRT1 protects against AAD symptoms by enhancing AP-1-mediated decorin expression and downstream PDCD4 signaling pathway. Possibly, SIRT1 is served as a protective factor of AD and targeting SIRT1 therapy might be an attractive therapeutic approaches for AD treatment.