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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. [ABSTRACT FROM AUTHOR]

The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA‐binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5′ UTR of the apoptosis‐related genes PIK3CB, Cathepsin Z (CTSZ), and X‐chromosome‐linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5′ UTRs of PIK3CB and CTSZ. An RNA pull‐down assay confirmed binding of the 5′ UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5′ UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment. [ABSTRACT FROM AUTHOR]

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. Significance statement: The present review discusses the potential role of programmed cell death 4 (PDCD4) in the pathogenesis of polycystic ovary syndrome (PCOS) by providing a link between its altered expression in granulosa cells (GCs) and the apoptosis of these cells. PDCD4 is a protein expressed ubiquitously and plays a significant role in regulating different cellular processes, such as apoptosis. The arrest of antral follicle development, as a leading disruption of follicular growth in PCOS, can result from the apoptosis of GCs. Hyperandrogenism‐induced PDCD4 dysregulation leads to upregulated PDCD4 expression, elevated GC apoptosis, and ultimately PCOS development. Accordingly, PDCD4 may serve as a possible target for the prognosis and alleviation of PCOS complications. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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-1β), and anti-inflammatory cytokines (IL-10 and TGF-β) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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.

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-1β 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-1β), which were induced by ICH in vivo. In in vitro study, levels of TNF-α, IL-6, and IL-1β 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. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

Background/Aims: This study aimed to analyze the impact of microRNA-499 (miR-499) on the inflammatory damage of endothelial cells during coronary artery disease (CAD) via the targeting of PDCD4 through the NF-kB/ TNF-α signaling pathway. Methods: A total of 216 CAD patients (CAD group) and 90 healthy people (normal group) were enrolled in our study. Endothelial cells were collected and assigned into normal, OX-LDL, negative control (NC), miR-499 inhibitor, miR-499 mimic, PDCD4 siRNA, and miR-499 inhibitor + PDCD4 siRNA groups. The qRT-PCR and western blotting were performed to detect the mRNA and protein expression levels of PDCD4 and miR-499. The MTT assay was performed to determine cell viability, ELISA was performed to determine the expression levels of inflammatory factors, and flow cytometry assay to evaluate cell apoptosis. Results: Increased miR-499 expression and decreased PDCD4 expression in the plasma were observed in the CAD group compared with the normal group, demonstrating a negative correlation between miR-499 and PDCD4. Compared to the normal and miR-499 inhibitor groups, the survival rate of cells and PDCD4 expression were decreased; and the expressions of miR-499, IL-6, IL-8, IL-1β, TNF-α, NF-kB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all elevated in the OX-LDL, NC, miR-499 mimic, PDCD4 siRNA and miR-499 inhibitor + PDCD4 siRNA groups. Compared to the OX-LDL, NC and miR-499 inhibitor + PDCD4 siRNA groups, PDCD4 expression and the survival rate of cells were increased; and the IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1 and MCP-1 expression levels and the apoptosis rate were all reduced in the miR-499 inhibitor group. In the PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were lower, and the expression levels of IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all higher compared with the miR-499 mimic group. In the miR-499 inhibitor + PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were higher, and the expression levels of IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1, and MCP-1 and the apoptosis rate were all lower than those in the PDCD4 siRNA group. Conclusion: Down-regulated miR-499 expression increased PDCD4 expression and protected endothelial cells from inflammatory damage during CAD by inhibiting the NF-κB/TNF-α signaling pathway.

The aim of the present study was to analyze the role of microRNA (miRNA)-21-5p in tongue squamous cell carcinoma (TSCC), predict the target gene of miR-21-5p and provide novel strategies for gene therapy in TSCC treatment. The expression levels of miRNA-21-5p in TSCC tissues were analyzed using reverse transcription quantitative polymerase chain reaction, and the effects of miRNA-21-5p on cell proliferation, invasion and apoptosis and the expression levels of target protein PDCD4 in the Cal 27 and SCC9 cell lines were determined. PI3K/AKT/Forkhead Box O1 (FOXO1) pathway-associated protein expression levels were evaluated by western blot analysis. miRNA-21-5p was consistently upregulated in TSCC tissues compared with normal tissues. Inhibition of miR-21-5p inhibited cell proliferation and invasion, and promoted cell apoptosis. A luciferase reporter assay confirmed that PDCD4 was the target of miR-21-5p. Inhibition of miRNA21-5p suppressed the PI3K/Akt/FOXO1 signaling pathway. The results from the present study indicated that miR-21-5p-targeting PDCD4 suppresses apoptosis in human TSCC cell lines. This anti-apoptotic effect was achieved by regulating the PI3K/Akt/FOXO1 signaling pathway. These data represent the basis for a promising novel strategy for the treatment of TSCC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the most common malignant tumor type and has become resistant to 5‑fluorouracil (5‑FU) in recent decades, which is one of the most popular therapies. Recently, microRNA (miRNA or miR) has been investigated as a potential therapeutic strategy for CRC. However, there has been little investigation of the underlying mechanism of the association between expression of miRNA and chemosensitivity. The present study aimed to investigate the effect of miR‑1260b inhibitor on CRC cells, and their chemosensitivity to 5‑FU, by treating them with the miR‑1260b inhibitor. miR‑1260b inhibitor was demonstrated to significantly promote the proliferation and invasion of the CRC cell line, HCT116, and to increase the apoptotic rate. Furthermore, it was validated that programmed cell death 4 (PDCD4) was a direct target of miR‑1260b inhibitor in CRC with bioinformatics tools and a luciferase assay. Western blot analysis revealed that miR‑1260b inhibitor could significantly decrease PDCD4 expression, and downregulate the expression of phosphorylated‑Akt (p‑Akt) and phosphorylated‑extracellular‑signal‑regulated kinase (p‑ERK). In conclusion, it was confirmed that the anti‑tumor effect of the miR‑1260b inhibitor was conducted by blocking the phosphorylated 3‑kinase/Akt pathway as dysregulated protein expression induced by miR‑1260b inhibitor was rescued by insulin‑like growth factor. Notably, miR‑1260b inhibitor could significantly enhanced the chemoresponse of HCT116 cells to 5‑FU via reduced proliferation, increased apoptosis, and downregulation of PDCD4, p‑Akt and p‑ERK protein expression. In summary, the present study may provide a novel direction for future clinical therapy to enhance the chemosensitivity of tumor cells. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (PDCD4) has been recognized as a novel tumor suppressor gene, which inhibits the activation and translation of activator protein (AP)‑1. Dysregulated expression of PDCD4 is also involved in various human tumors and is linked to tumor progression and development. However, the function and clinical implication of PDCD4 in giant cell tumors of the bone (GCTBs) has not been previously investigated. In the present study, PDCD4 expression was determined in 83 samples of GCTBs at mRNA and protein levels by quantitative reverse transcription‑polymerase chain reaction, western blotting and immunohistochemistry. The results demonstrated that PDCD4 mRNA expression was reduced in 63% of GCTB samples (17/27) and protein expression was decreased in 65% of samples (54/83), compared with adjacent non‑tumor tissues. Furthermore, decreased expression of PDCD4 was significantly associated with certain clinicopathological characteristics, including the Campanacci grade and recurrence. A strong negative correlation was determined between PDCD4 expression and the Ki‑67 positive rate in GCTBs (r=‑0.6392; P<0.001). The results of the present study suggest that PDCD4 may serve a role in the malignant progression of human GCTBs and may be an important prediction factor for prognosis. [ABSTRACT FROM AUTHOR]

Objective To observe the expression changes of miR-21 and programmed cell death 4( PDCD4) in the esophageal squamous-cell carcinoma tissues and to explore the clinical significance. Methods The real-time PCR was employed to detect the mRNA expression of miR-21 and PDCD4 in the esophageal squamous-cell carcinoma tissues and adjacent normal tissues. According to the average of the expression,the patients with the esophageal squamous cell carcinoma were divided into the high-miR-21 group and the low-miR-21 group,or the high-PDCD4 group and the low-PDCD4 group.The correlation between the miR-21 and PDCD4 in the esophageal squamous-cell carcinoma tissues was analyzed by the Spearman. The Kaplan Meier and the Log Rank were employed to detect the influence of miR-21 and PDCD4 expressions on the prognosis. Results The relative expression level of miR-21 in the esophageal squamous-cell carcinoma tissues was higher than that in the adjacent normal tissues,while the mRNA level of PDCD4 in the esophageal squamous-cell carcinoma tissues was lower than that in the adjacent normal tissues,and there were significant difference( both P < 0. 05). The Spearman results showed that the miR-21 and PDCD4 was negatively correlated in the esophageal squamous-cell carcinoma tissues( r =-0. 883,P = 0. 000). The 5-year survival rate in the high-miR-21 group was lower than that in the lowermiR-21 group( χ2= 4. 720,P = 0. 030),the same was the survival time( P = 0. 029). The 5-year survival rate in the high-PDCD4 group was higher than that in the low-PDCD4 group( χ2= 7. 871,P = 0. 005),the same was the survival time( P = 0. 006). Conclusions In the esophageal squamous-cell carcinoma tissues,the miR-21 is highly expressed and the PDCD4 is low expressed,both of which may be involved in the occurrence and development of esophageal squamous-cell carcinoma,and have important influence on the prognosis. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (PDCD4), as a novel tumor suppressor, serves important roles in the pathogenesis of tumors. The expression of PDCD4 is downregulated or lost in various human tumors. However, the expression of PDCD4 in endometrial cancer and the clinicopathological significance remain unclear. The aim of the present study was to investigate the expression of PDCD4 in endometrioid endometrial carcinoma (EEC) and the association with clinicopathological parameters. The expression of PDCD4 in EEC tissues and control endometrium was detected by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. PDCD4 expression was also investigated in control endometrial glandular epithelial cells and the endometrial cancer KLE cell line by immunocytochemistry, and the association between PDCD4 expression and clinicopathological parameters of patients with EEC was analyzed. The results demonstrated that PDCD4‑positive staining was mainly located in the cytoplasm of endometrial glandular epithelial cells and EEC cells. The staining index of PDCD4 in the proliferative phase was significantly increased compared with that in the secretory phase of control endometrium (P<0.001). There was significantly decreased PDCD4 expression in grade (G) 2/3 EEC tissues compared with the proliferative phase of control endometrium (P<0.001). PDCD4 expression was significantly associated with tumor grade. The PDCD4 levels in G1 EEC tissues were higher compared with the G2/3 EEC group (P<0.01). The results indicated that PDCD4 is associated with the histological grade of EEC, and that PDCD4 may be a valuable indicator of the degree of tumor malignancy in patients with EEC. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Berberine is sourced from multiple medicinal herb resources and is easy to extract. With the advantages of low price, safety and convenience, berberine may have potential for wide clinical use. The present study aimed to investigate whether berberine inhibited the viability of colon cancer and whether it regulated the three-gene network microRNA (miR)-21-integrin β4 (ITGβ4)-programmed cell death 4 (PDCD4). It was demonstrated that berberine treatment suppressed colon cancer cell viability, and induced apoptosis and activated caspase-3 activity in the human colon carcinoma HCT116 cell line. Berberine inhibited miR-21 expression and promoted ITGβ4 and PDCD4 protein expression in the HCT116 cell line. Overexpression of miR-21 reduced the anti-cancer effects of berberine on cell viability, apoptosis rate and caspase-3 activity of the HCT116 cell line. However, it was revealed that the overexpression of miR-21 also suppressed ITGβ4 and PDCD4 protein expression in the HCT116 cell line. In conclusion, miR-21, ITGβ4 and PDCD4 are involved in the anti-cancer effects of berberine on cell viability and apoptosis in the HCT116 cell line. [ABSTRACT FROM AUTHOR]

The expression of microRNA-206 (miR-206) is aberrantly induced in steroid-induced avascular necrosis of femoral head (SANFH). Therefore, investigating the function of miR-206 in SANFH and uncovering the functional mechanism associated with the condition will promote the understanding and treatment of the disease. The purpose of the present study was to investigate the pro-osteoclasteogenic effect of miR-206 that occurs through regulation of programmed cell death 4 (PDCD4). The expression of miR-206 and PDCD4 was analyzed in the clinical SANFH specimens. The level of miR-206 and PDCD4 was regulated in human osteoblast lineage hFOB1.19 and the effect of different treatments on cell viability, proliferation, apoptosis and differentiation potential of osteoblasts were analyzed with a Cell Counting kit-8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry and Hoechst staining. The expression of miR-206 was upregulated while PDCD4 was downregulated in the SANFH specimens. Induced expression of miR-206 decreased cell viability and proliferation, while apoptosis was induced. At the molecular level, overexpression of miR-206 inhibited the expression of PDCD4, alkaline phosphatase (ALP) and B-cell lymphoma 2 (Bcl-2), and increased the expression of apoptosis regulator Bcl2-X-associated protein (Bax). Inhibiting the expression of miR-206 increased cell viability and proliferation but had no effect on cell apoptosis, as detected by flow cytometry and Hoechst staining. However, at the molecular level, inhibiting the expression of miR-206 induced expression of PDCD4, ALP and Bcl-2, while it decreased the expression of Bax. Additionally, knockdown of PDCD4 blocked the effect of miR-206 inhibition on hFOB1.19 cells, representing a PDCD4-dependent manner of miR-206 in inducing apoptosis of osteoblasts. Therefore, miR-206 promoted the onset of SANFH by inducing apoptosis and suppressed the proliferation of osteoblasts, which was dependent on the inhibition of PDCD4. [ABSTRACT FROM AUTHOR]

Background/Aims: This study aimed to analyze the impact of microRNA-499 (miR-499) on the inflammatory damage of endothelial cells during coronary artery disease (CAD) via the targeting of PDCD4 through the NF-kB/TNF-α signaling pathway. Methods: A total of 216 CAD patients (CAD group) and 90 healthy people (normal group) were enrolled in our study. Endothelial cells were collected and assigned into normal, OX-LDL, negative control (NC), miR-499 inhibitor, miR-499 mimic, PDCD4 siRNA, and miR-499 inhibitor + PDCD4 siRNA groups. The qRT-PCR and western blotting were performed to detect the mRNA and protein expression levels of PDCD4 and miR-499. The MTT assay was performed to determine cell viability, ELISA was performed to determine the expression levels of inflammatory factors, and flow cytometry assay to evaluate cell apoptosis. Results: Increased miR-499 expression and decreased PDCD4 expression in the plasma were observed in the CAD group compared with the normal group, demonstrating a negative correlation between miR-499 and PDCD4. Compared to the normal and miR-499 inhibitor groups, the survival rate of cells and PDCD4 expression were decreased; and the expressions of miR-499, IL-6, IL-8, IL-1β, TNF-α, NF-kB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all elevated in the OX-LDL, NC, miR-499 mimic, PDCD4 siRNA and miR-499 inhibitor + PDCD4 siRNA groups. Compared to the OX-LDL, NC and miR-499 inhibitor + PDCD4 siRNA groups, PDCD4 expression and the survival rate of cells were increased; and the IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1 and MCP-1 expression levels and the apoptosis rate were all reduced in the miR-499 inhibitor group. In the PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were lower, and the expression levels of IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all higher compared with the miR-499 mimic group. In the miR-49 9inhibitor + PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were higher, and the expression levels of IL-6, IL-8, IL-1β, TNF-α, NF-κB, VCAM-1, ICAM-1, and MCP-1 and the apoptosis rate were all lower than those in the PDCD4 siRNA group. Conclusion: Downregulated miR-499 expression increased PDCD4 expression and protected endothelial cells from inflammatory damage during CAD by inhibiting the NF-κB/TNF-α signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The objective of the present study was to evaluate the role of the TGFß/PDCD4/AP-1 pathway in nasopharyngeal carcinoma (NPC) and its relationship to NPC prognosis. Methods: NPC tissues collected from 66 NPC patients were compared to 17 nasopharyngeal mucosa biopsy specimens collected as normal tissues. Immunohistochemical staining was performed to assess expression of transforming growth factor-ß receptor I (TGFßRI), programmed cell death 4 (PDCD4) and activator protein-1 (AP-1). The Kaplan-Meier method was applied to evaluate NPC patient overall survival (OS) and progression-free-survival (PFS). Cox regression analysis was used to estimate independent prognostic factors for NPC. The human NPC cell line CNE2 was selected and treated with SB431542, an inhibitor of TGFßRI; expression of TGFßRI and PDCD4 in CNE2 cells was determined by western blotting. NPC tissues showed higher expression of TGFßRI and AP-1 but lower expression of PDCD4 than normal tissues (all P < 0.05). Results: The results of Kaplan-Meier analysis showed that TGFßRIpositive patients and AP-1-positive patients had shorter OS and PFS than TGFßRI-negative patients and AP-1-negative patients; additionally, PDCD4-positive patients had higher OS and PFS than PDCD4-negative patients. Cox regression analysis revealed that advanced tumor stage, overexpression of TGFßRI and AP-1, and low expression of PDCD4 were unfavorable factors influencing OS and PFS in NPC patients. Compared with the control group, expression of TGFßRI decreased and that of PDCD4 increased significantly in CNE2 cells treated with the inhibitor (all P < 0.05). These findings indicate that the TGFß/PDCD4/AP-1 pathway may be associated with NPC development and progression. Conclusion: High expression of TGFßRI and AP-1 and low expression of PDCD4 may be unfavorable prognostic factors for NPC. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap-dependent translation from mRNAs with highly structured 5′-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved. Here we showed that eIF4A1, the eIF4A isoform involved in translation, significantly over-represents Pdcd4 both in cancerous and normal cells. This observation excludes the possibility that cytoplasmic Pdcd4 can efficiently exert its translation suppression function owing to excess of eIF4A, with Pdcd4-free eIF4A being in excess over Pdcd4-bound translation-incompetent eIF4A, thus leaving translation from Pdcd4 mRNA targets unaffected. This contradiction is resumed in the proposed model, which supposes initial complexing between Pdcd4 and its target mRNAs in the nucleus, with subsequent transport of translation-incompetent, Pdcd4-bound target mRNAs into the cytoplasm. Noteworthy, loss of nuclear Pdcd4 in cancer cells was reported to correlate with tumor progression, which supports the proposed model of Pdcd4 functioning. [ABSTRACT FROM PUBLISHER]

Altered expression levels of microRNA‑21 (miRNA‑21) have been observed in a series of pathological processes, including cancer and central nervous system injury; however, the involvement of miRNA‑21 in the molecular pathophysiology of spinal cord injury (SCI) has not been well documented. The present study examined the expression levels of miRNA‑21 and its predicted target genes, programmed cell death 4 (PDCD4) and phosphatase and tensin homolog (PTEN), in rats using quantitative polymerase chain reaction and western blotting to further understand the role of miRNA‑21 and the mechanisms underlying repair following SCI. The present study demonstrated that compared with uninjured spinal cords, miRNA‑21 expression levels were significantly downregulated in injured spinal cords 4 and 8 h, and 1 day post‑SCI, and were significantly upregulated after 3 and 7 days. Conversely, expression levels of PDCD4 and PTEN were significantly decreased at days 3 and 7 post‑SCI compared with the control group. miRNA‑21 overexpression in monolayer‑cultured postnatal rat spinal cord neurons promoted neurite outgrowth and downregulated protein expression levels of PDCD4; however, PTEN protein expression levels were unaltered. To confirm that miRNA‑21 directly targets PDCD4, a pRL‑CMV luciferase reporter construct was used to detect miRNA‑21 interactions with the PDCD4 3'‑untranslated region. The results demonstrated that miRNA‑21 decreased luciferase activity compared with a rat PDCD4 control reporter. The results of the present study suggested that increased miRNA‑21 expression levels following SCI may promote the repair of injured spinal cords by inhibiting the expression of its target gene PDCD4. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (PDCD4) is known to suppress neoplastic transformation, cell proliferation and metastasis, and to be downregulated by microRNA-21 (miR-21) in renal cell carcinoma (RCC) cell lines and tissues. The aim of the present study was to investigate the roles of and association between PDCD4 and miR-21 in a nude mouse renal cancer model. A total of 24 BALB/c male nude mice were randomly assigned into the following three groups: Negative control (NC; n=8), miR-21 inhibitor (n=8) and miR-21 mimic (n=8). Subsequently, renal cell adenocarcinoma 786-O cells were subcutaneously transplanted into the armpits of the mice, which were then injected daily with NC small interfering (si) RNA, precursor-miR-21 (mimic) or anti-miR-21 (inhibitor). Tumors were removed from the mice and weighed 16 days following 786-O cell transplantation. In addition, the expression of miR-21 and PDCD4 mRNA in cancer tissues was analyzed using reverse transcription-quantitative PCR. The expression of PDCD4 protein in cancer tissues was also examined using immunohistochemistry and western blotting. Furthermore, 786-O cells were transfected with PDCD4 siRNA or NC siRNA, and the effects of silencing PDCD4 on tumor cell growth, proliferation and invasion were investigated using soft agar colony formation, EdU cell proliferation assay and Transwell migration and invasion assays. Another 16 BALB/c male nude mice were randomly assigned into two groups as follows: NC (n=8) and PDCD4 siRNA (n=8). The 786-O cells were subcutaneously transplanted into the armpits of the mice, which were subsequently injected daily with NC siRNA or PDCD4 siRNA. The tumors were removed and weighed 16 days following transplantation. Compared with the NC group, tumor weight in the miR-21 mimic group was significantly increased. By contrast, tumor weight in the miR-21 inhibitor group was significantly decreased. Similar to the results observed in human renal cancer tissue and cell lines, miR-21 expression in the nude mouse renal cancer models was significantly upregulated in the miR-21 mimic group compared with the NC group, while it was significantly lower in the miR-21 inhibitor group. Furthermore, there was a significant reduction in PDCD4 protein levels in the miR-21 mimic group and a significant increase in the miR-21 inhibitor group compared with the NC, whereas PDCD4 mRNA expression was not significantly altered. In the EdU proliferation assay, the mean percentage of new cells that incorporated EdU was 28.6% in the NC siRNA group and significantly increased to 44.7% in PDCD4 siRNA transfected cells. In the soft agar colony formation assay, Transwell and migration and invasion assays, a significant increase in colony formation, migration and invasion capacity in PDCD4 siRNA-transfected cells was observed compared with the NC. Furthermore, compared with the NC group, tumor weight in the PDCD4 siRNA group was significantly increased. Similar to the results observed in human renal cancer tissue and cell lines, miR-21 promoted cancer cell hyperplasia and proliferation, and post-transcriptionally downregulated PDCD4 protein expression, in the nude mouse renal cancer model. The results of the present study and previous studies indicate that PDCD4 and miR-21 serve an important role in renal cancer. Thus, increasing PDCD4 expression or inhibiting miR-21 expression may constitute effective novel therapeutic strategies for the treatment of renal cancer. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is the frequently reported cancer of the head and neck. Recent studies are being conducted to evaluate the role of potential markers for diagnosing the stages of development of OSCC from normal cells. Aim: The aim of this study is to evaluate and compare the immunoexpression of programmed cell death 4 (PDCD4) protein in normal oral mucosa, oral epithelial dysplasia (OED) and OSCC. Materials and Methods: Histologically diagnosed, formalin-fixed paraffin-embedded archived cases (n = 100) of normal mucosa (n = 10), OED (n = 60) and OSCC (n = 30) were analyzed immunohistochemically in the present retrospective study using monoclonal rabbit antihuman PDCD4. OED and squamous cell carcinoma were graded according to the World Health Organization and Broder's histological grading criteria, respectively. Clinical parameters and immunohistochemical results were analyzed by Fisher exact test using SPSS software. P <0.05 was indicative of significant differences. Results: PDCD4 expression was observed in the normal oral mucosa, OED and OSCC. The maximum expression was observed in the normal oral mucosa, which reduced significantly in OED and OSCC (P = 0.017). With the increase in the transformation from normal cells to cancer cells, a shift from nuclear to cytoplasmic staining was observed indicating predominant cytoplasmic localization of stain as a feature of altered cells. Conclusion: The present study delineates the molecular difference between the normal, dysplastic and carcinomatous cells; and points toward the role of PDCD4 localization in the proliferation of cells. This study thus highlights the need for further research with inclusion of long follow-up period and other pathological criteria such as inflammation and microenvironment, immune status of patient and tumor stage, which could aid in the development of prospective diagnostic options. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common aggressive sarcoma of the bone in children and adolescents. It is characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. microRNAs (miRNAs) play a key role in cancer initiation, progression and metastasis; however, the potential role of miRNAs in osteosarcoma remains largely unknown. In the present study, miR-433 was shown to be overexpressed in osteosarcoma tissues compared with normal human osteoblasts. Transfection of miR-433 mimics into osteosarcoma cell lines significantly decreased apoptosis by targeting programmed cell death 4, a tumor suppressor that is involved in apoptosis. In contrast, inhibition of miR-433 enhanced apoptosis. Furthermore, in vivo miR-433 overexpression inhibited the apoptosis of tumor cells and increased tumor growth. The results of the present study suggested that miR-433 is a potential molecular target for osteosarcoma therapy. [ABSTRACT FROM AUTHOR]

MicroRNA (miR/miRNA)-21 is a well-known oncogenic miRNA that is overexpressed in various types of tumors. The tumor-suppressor genes programmed cell death 4 (PDCD4) and phosphatase tensin homologue (PTEN), are targets of miR-21, and are underexpressed in several types of cancer. However, the expression of miR-21 and its target genes in neuroblastoma (NB) remains unclear. In the present study, a miR-21 inhibitor oligonucleotide was transfected into the SK-N-SH cell line, and the expression of miR-21, PTEN and PDCD4 was detected through quantitative polymerase chain reaction analysis. Western blotting was used to examine levels of PTEN, PDCD4 and caspase-3 proteins. The expression of PTEN and PDCD4 in the SK-N-SH cell line transfected with the miR-21 inhibitor was significantly increased compared with untransfected SK-N-SH and negative control-transfected cells. Cell proliferation was inhibited and the apoptotic ratio was significantly increased in miR-21 inhibitor-transfected cells compared with untransfected SK-N-SH and negative control-transfected cells. Western blot analysis revealed a significant increase in caspase-3 expression compared with untransfected SK-N-SH and negative control-transfected cells. The results of the present study indicate that miR-21 may serve an oncogenic role in the cellular processes underlying NB development and thus may be a novel therapeutic target for the treatment of patients with NB. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to make clear whether miR-21 was dysregulated in hydatidiform mole (HM) tissues and choriocarcinoma (CCA) cells, to elucidate whether aberrant miR-21 expression would affect the function of CCA cells, and to find out whether there was a relationship between miR-21 and AKT , PDCD4 , and PTEN in CCA cells. Methods: Fresh and formalin-fixed, paraffin-embedded trophoblastic tissues (normal first trimester placentas and HMs) were retrieved from the biobank in the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University. Choriocarcinoma JAR and JEG-3 cells were cultured. Expression of miR-21 in trophoblast cells and tissues was examined by quantitative real-time polymerase chain reaction. Location and distribution of miR-21 in trophoblast tissues were determinated by in situ hybridization and fluorescent in situ hybridization. The effect of miR-21 on JAR and JEG-3 cells was tested by miR-21 mimics and inhibitor transfection, followed by cell viability assay, flow cytometric analysis, and Transwell analysis. Interaction between miR-21 and its target genes in CCA cells was verified by quantitative real-time polymerase chain reaction, Western blot, and luciferase report system. Results: We originally found miR-21 was markedly upregulated in HM tissues compared with normal first trimester placentas. The expression of miR-21 was exclusively confined in trophoblastic layers. Furthermore, we discovered miR-21 was significantly increased in JAR and JEG-3 cells compared with normal primary human trophoblastic cells. Moreover, we demonstrated miR-21 could promote proliferation, migration, and invasion of CCA cells. We furthermore proved miR-21 negatively regulated PDCD4 and PTEN in CCA cells and targeted to PDCD4 3′UTR directly. In addition, we confirmed that miR-21 could activate Akt pathway by phosphorylating Akt at Ser 473. Conclusions: Our results suggested miR-21 was responsible for aggressive phenotype of gestational trophoblastic disease and had the potential diagnostic and therapeutic values for gestational trophoblastic neoplasm. [ABSTRACT FROM AUTHOR]

Previous studies on erythropoiesis revealed that micro RNAs (mi RNAs) play a critical role in erythroid differentiation. Given the abundance of identified mi RNAs and the limited understanding of erythroid mi RNAs, additional examination is required. Here, two sets of erythroid differentiation mi RNome data were analysed to screen for novel erythroid-inhibiting mi RNAs. MIR200A was selected based on its pattern of downregulated expression in the mi RNome datasets during induction of erythroid differentiation. Overexpression of MIR200A in K562 and TF-1 cells confirmed its inhibitory role in erythroid differentiation. Further in vivo study indicated that overexpression of mir200a inhibited primitive erythropoiesis of zebrafish. Transcriptome analyses after MIR200A overexpression in TF-1 cells indicated a significant role in regulating erythroid function and revealed potential regulation networks. Additionally, bioinformatics and experimental analyses confirmed that PDCD4 (programmed cell death 4) and THRB (thyroid hormone receptor, beta) are both targets of MIR200A-3p. Gain- and loss-of-function studies of PDCD4 and THRB revealed that the two targets were capable of promoting erythroid gene expression. Overall, our results revealed that microRNA 200a inhibits erythroid differentiation by targeting PDCD4 and THRB. [ABSTRACT FROM AUTHOR]

The programmed cell death 4 (PDCD4) has recently been recognized as a new and attractive target of acute respiratory distress syndrome. Here, we attempted to discover new and potent PDCD4 mediator ligands from biogenic compounds using a synthetic strategy of statistical virtual screening and experimental affinity assay. In the procedure, a Gaussian process-based quantitative structure-activity relationship regression predictor was developed and validated statistically based on a curated panel of structure-based protein-ligand affinity data. The predictor was integrated with pharmacokinetics analysis, chemical redundancy reduction, and flexible molecular docking to perform high-throughput virtual screening against a distinct library of chemically diverse, drug-like biogenic compounds. Consequently, 6 hits with top scores were selected, and their binding affinities to the recumbent protein of human PDCD4 were identified, 3 out of which were determined to have high or moderate affinity with Kd at micromolar level. Structural analysis of protein-ligand complexes revealed that hydrophobic interactions and van der Waals contacts are the primary chemical forces to stabilize the complex architecture of PDCD4 with these mediator ligands, while few hydrogen bonds, salt bridges, and/or π-π stacking at the complex interfaces confer selectivity and specificity for the protein-ligand recognition. It is suggested that the statistical Gaussian process-based quantitative structure-activity relationship screening strategy can be successfully applied to rational discovery of biologically active compounds. The newly identified molecular entities targeting PDCD4 are considered as promising lead scaffolds to develop novel chemical therapeutics for acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription-quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR-ABL gene expression (r=-0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML. [ABSTRACT FROM AUTHOR]

Programmed cell death 4 (PDCD4) plays a crucial role in modulating cellular signals, mainly via TOLL cascades during the immune response. In the present study, a novel PDCD4 homologue gene (denoted as AjPDCD4 ) was cloned from the sea cucumber Apostichopus japonicus using RACE. The full-length AjPDCD4 cDNA comprised a 366 bp 5ʹ-UTR, a 418 bp 3ʹ-UTR, and a 1353 bp open reading frame encoding a 450 amino acid residue protein with two typical MA3 domains. Phylogenetic analysis revealed that AjPDCD4 belonged to the invertebrate PDCD4 family. Spatial expression analysis indicated that AjPDCD4 mRNA transcripts are expressed at a high level in the tentacles and at a low level in muscle compared with coelomocytes. Vibrio splendidus challenge and LPS exposure could both significantly down-regulate AjPDCD4 mRNA expression. More importantly, we found that ultraviolet (UV)-induced ROS production and DNA damage were greatly repressed in AjPDCD4-knockdown coelomocytes. Meanwhile, the expression levels of the NF-kappa B homologue, p105, were synchronously up-regulated in the same conditions. All of these results indicated that AjPDCD4 is involved in modulating DNA damage and ROS production in sea cucumber, perhaps by affecting the TLR pathway. [ABSTRACT FROM AUTHOR]

Objective To study the inhibition effect of miR-106a inhibitor on tumor growth of ovarian cancer xenografts mice. Methods BALB/c mice were selected as experimental animals, ovarian cancer SKOV-3 cells transfected with miR-106a inhibitor and its negative control were inoculated subcutaneously, intratumoral injection of miR-106a inhibitor and its negative control were continued after tumor formation, and they were enrolled as treatment group and model group, respectively. Tumor volume and weight as well as Ki-67 and programmed cell death 4 (PDCD4) expression were determined; miR-106a inhibitor and its negative control as well as miR-106a mimic and its negative control were transfected into SKOV-3 cells, and expression of PDCD4 in cells was determined. Results Tumor tissue volume and weight as well as mRNA expression and protein expression of Ki-67 in treatment group were significantly lower than those in the model group while mRNA expression and protein expression of PDCD4 were significantly higher than those in the model group; transfection of miR-106a mimic could decrease mRNA expression and protein expression of PDCD4 in SKOV-3 cells, and transfection of miR-106a inhibitor could increase mRNA expression and protein expression of PDCD4 in SKOV-3 cells. Conclusions Transfection of miR-106a inhibitor can inhibit the growth of tumor in ovarian cancer xenografts mice through increasing the expression of PDCD4. [ABSTRACT FROM AUTHOR]

Objective In this study, we explore the effects of pretreatment with atorvastatin on the cardiac function of piglets after coronary microembolization (CME). Methods Twenty Bama miniature pigs were randomized to sham surgery group (sham group), CME Group, conventional dose group and intensive-dose group, with 5 miniature pigs in each group. Pigs in the CME group received a total dosage of 100,000 microspheres (42 μm) suspended in 10 ml normal saline within 40 min, while animals in the sham group received the same dosage of normal saline. In the conventional dose group, atorvastatin (1.5 mg/kg) was given once daily starting 7 d before microembolization. In the intensive-dose group, atorvastatin (1.5 mg/kg) was also given once daily 7 d before intervention, and an additional 3 mg/kg 4 h before percutaneous coronary intervention. Cardiac function indices were determined by echocardiography; and infarct size was determined histopathologically. PDCD4 mRNA and TNF-α mRNA and protein expression were evaluated by quantitative fluorescence-polymerase chain reaction and Western blot, respectively. NF-κB activation was evaluated by electrophoretic mobility shift assay. Results (1) Cardiac function was significantly lower ( P < 0.05) in CME group compared with the sham group. CME reduced myocardial systolic dysfunction and left ventricular dilatation. The conventional and intensive-dose groups showed improved CME-induced cardiac function when compared with the CME Group ( P < 0.05). (2) Compared with the conventional group, the dose-intensive group showed lower PDCD4 and TNF-α expression and NF-κB activation as well as improved cardiac function ( P < 0.05). Conclusions Atorvastatin effectively improved CME-induced cardiac damage with intensive-dose therapy showing better outcome. The protective effects are mediated via suppression of PDCD4/NF-κB/TNF-α signaling in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: The objective of the present study was to evaluate the role of the TGFβ/PDCD4/AP-1 pathway in nasopharyngeal carcinoma (NPC) and its relationship to NPC prognosis. Methods: NPC tissues collected from 66 NPC patients were compared to 17 nasopharyngeal mucosa biopsy specimens collected as normal tissues. Immunohistochemical staining was performed to assess expression of transforming growth factor-β receptor I (TGFβRI), programmed cell death 4 (PDCD4) and activator protein-1 (AP-1). The Kaplan-Meier method was applied to evaluate NPC patient overall survival (OS) and progression-free-survival (PFS). Cox regression analysis was used to estimate independent prognostic factors for NPC. The human NPC cell line CNE2 was selected and treated with SB431542, an inhibitor of TGFβRI; expression of TGFβRI and PDCD4 in CNE2 cells was determined by western blotting. NPC tissues showed higher expression of TGFβRI and AP-1 but lower expression of PDCD4 than normal tissues (all P < 0.05). Results: The results of Kaplan-Meier analysis showed that TGFβRI-positive patients and AP-1-positive patients had shorter OS and PFS than TGFβRI-negative patients and AP-1-negative patients; additionally, PDCD4-positive patients had higher OS and PFS than PDCD4-negative patients. Cox regression analysis revealed that advanced tumor stage, overexpression of TGFβRI and AP-1, and low expression of PDCD4 were unfavorable factors influencing OS and PFS in NPC patients. Compared with the control group, expression of TGFβRI decreased and that of PDCD4 increased significantly in CNE2 cells treated with the inhibitor (all P < 0.05). These findings indicate that the TGFβ/PDCD4/AP-1 pathway may be associated with NPC development and progression. Conclusion: High expression of TGFβRI and AP-1 and low expression of PDCD4 may be unfavorable prognostic factors for NPC.

MicroRNA-21 (miR-21) has been found to promote cell proliferation and survival. It has also been shown to exhibit an increased expression in a number of forms of cardiovascular disease. However, the mechanisms underlying the involvement of miR-21 in atherosclerosis remain to be elucidated. In the present study, it was demonstrated that miR-21 was upregulated in a time-dependent manner in response to high-concentration glucose stimulation in Raw 264.7 macrophages. High concentrations of glucose induce macrophage apoptosis. miR-21-inhibited macrophages treated with a normal concentration of glucose exhibited increased levels of cell apoptosis and augmented levels of activated caspase-3, while cells treated with an miR-21 inhibitor and a high concentration of glucose, revealed significantly increased levels of apoptosis. In addition, inhibition of miR-21 increased mRNA and protein levels of programmed cell death 4 (PDCD4), which, by contrast, were reduced in miR-21-inhibited cells that had been treated with a high concentration of glucose. In conclusion, miR-21 is sensitive to high-concentration glucose treatment in macrophages, and appears to have a protective effect in macrophage apoptosis induced by high concentrations of glucose via PDCD4. [ABSTRACT FROM AUTHOR]

Background: Berberine is a natural alkaloid derived from a traditional Chinese herbal medicine. It is known to modulate microRNA (miRNA) levels, although the mechanism for this action is unknown. Here, we previously demonstrate that the expression of 87 miRNAs is differentially affected by berberine in multiple myeloma cells. Among 49 miRNAs that are down-regulated, nine act as oncomirs, including miR-21. Integrative analysis showed that 28 of the down-regulated miRNAs participate in tumor protein p53 (TP53) signaling and other cancer pathways. miR-21 is involved in all these pathways, and is one of the most important oncomirs to be affected by berberine in multiple myeloma cells. Results: We confirmed that berberine down-regulated miRNA-21 expression and significantly up-regulated the expression of programmed cell death 4 (PDCD4), a predicted miR-21 target. Luciferase reporter assays confirmed that PDCD4 was directly regulated by miR-21. Bioinformatic analysis revealed that the miR-21 promoter can be targeted by signal transducer and activator of transcription 3 (STAT3). Down-regulation of interleukin 6 (IL6) by berberine might lead to inhibition of miR-21 transcription through STAT3 down-regulation in multiple myeloma. Furthermore, both berberine and seed-targeting anti-miR-21 oligonucleotide induced apoptosis, G2-phase cell cycle arrest and colony inhibition in multiple myeloma cell lines. Depletion of PDCD4 by short interfering RNA could rescue berberine-induced cytotoxicity in multiple myeloma cells. Conclusions: Our results suggest that berberine suppresses multiple myeloma cell growth, at least in part, by down-regulating miR-21 levels possibly through IL6/STAT3. This led to increased PDCD4 expression, which is likely to result in suppression of the p53 signaling pathway. These findings may also provide new mechanistic insight into the anti-cancer effects of certain compounds in traditional Chinese herbal medicines. [ABSTRACT FROM AUTHOR]

microRNA-21 (miRNA/miR-21) is a well-known oncogenic miRNA that is overexpressed in various carcinomas. The tumor suppressor genes, programmed cell death 4 (PDCD4) and phosphatase tensin homologue (PTEN), which target miR-21, are underexpressed in several types of cancer. However, the expression of miR-21 and its target genes, PDCD4 and PTEN, has not yet been reported in skin squamous cell carcinoma (SCC). In the present study, anti-miR-21 was transfected into the A431 cell line, and the expression of miR-21, PDCD4 and PTEN and the level of cell apoptosis were detected by quantitative polymerase chain reaction, immunocytochemistry and western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively. The expression levels of PDCD4 and PTEN in the A431 cell line transfected with anti-miR-21 were significantly increased (P<0.05) and the apoptotic ratio was significantly increased (P<0.05). The data indicate that miR-21 may play an oncogenic role in the cellular processes of SCC and represent a novel target for effective therapies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Our recent study has found that microRNA-21 (miRNA-21) was significantly upregulated in papillary thyroid carcinoma (PTC) tissues compared with nontumor tissues by using miRNA microarray chip. However, the function of miRNA-21 is unknown in PTC. The aim of this study was to investigate the roles of miRNA-21 in PTC and the mechanism of gene regulation by it. Methods: We transfected PTC cell line (TPC-1) with pEZX-eGFP-miRNA-21 plasmid to determine the biological functions of miRNA-21. Western blot assay was applied to investigate the correlation between miRNA-21 and programmed cell death 4 (PDCD4) expression in TPC-1 cell line. Results: Overexpression of miRNA-21 could significantly enhance proliferation and invasion and inhibit the apoptosis of TPC-1 cells. In addition, miRNA-21 and PDCD4 expression showed a significantly negative correlation in TPC-1 cells. Conclusions: These data suggest that miRNA-21 may play an oncogenic role by directly targeting PDCD4 in the cellular processes of PTC. In addition, the findings in our present study also may represent new clues for the diagnostic and therapeutic strategies in the treatment of PTC. [Copyright &y& Elsevier]

Objective: To investigate the effects of intensive atorvastatin therapy on programmed cell death 4 (PDCD4) expression by CD4+ T lymphocytes in patients with unstable angina who received percutaneous coronary intervention (PCI). Methods: Patients with unstable angina were randomized to pretreatment with either an intensive dose (80 mg/day, n = 33) or a conventional dose (20 mg/day, n = 33) of atorvastatin. Circulating CD4+ T cells were subsequently obtained prior to PCI, and also 18-24 h after PCI, using a magnetic cell sorting system. Fluorescence-based quantitative real-time PCR was then used to measure levels of PDCD4 mRNA in the isolated CD4+ T lymphocytes, and Western blot analysis was used to detect levels of PDCD4. Serum levels of interleukin (IL)-10 and TNF-α were quantified using enzyme-linked immunosorbent assays. Results: Of the 66 patients with unstable angina that were examined, levels of PDCD4 mRNA and protein were found to dramatically decrease in patients who received an intensive dose of atorvastatin following PCI (p < 0.05). In contrast, serum levels of TNF-α significantly increased following PCI in both the intensive dose group and the conventional dose group, with the latter being higher than the former (p < 0.05). Serum IL-10 levels also markedly increased following PCI for the two groups. However, higher values were associated with the intensive dose group (p < 0.05). Conclusions: Intensive atorvastatin treatment reduced the post-PCI myocardial inflammatory response in patients with unstable angina, possibly by inhibiting PDCD4 expression in CD4+ T lymphocytes. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]