Unveiling the role of UPF3B in hepatocellular carcinoma: Potential therapeutic target.

RNA-binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to PPP2R2C, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC.

TGF-ß1-Induced LINC01094 promotes epithelial-mesenchymal transition in hepatocellular carcinoma through the miR-122-5p/TGFBR2-SAMD2-SMAD3 Axis.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. It has been proven that long non-coding RNAs (lncRNAs) play an essential role in regulating HCC progression. However, the involvement of LINC01094 in regulating epithelial-mesenchymal transition (EMT) in HCC remains unclear. LINC01094 expression in HCC patients was retrieved from the Cancer Genome Atlas database. Overexpressing and downregulating LINC01094 were conducted to investigate its biological functions using Hep3B, SNU-387, and HuH-7 cells. Western blotting and morphological observation were performed to study the EMT in HCC cells. Transwell assay was adopted to determine the migration and invasion of HCC cells. The underlying mechanism of competitive endogenous RNAs (ceRNAs) was investigated using bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction, and rescue experiments. Elevated LINC01094 expression was observed in HCC and associated with a poor prognosis. Knockdown of LINC01094 expression in SNU-387 and HuH-7 cells could inhibit migration, invasion, and EMT markers. Overexpression of LINC01094 indicated that LINC01094 promoted EMT via the TGF-ß/SMAD signaling pathway. The bioinformatics analysis revealed that miR-122-5p was a target of LINC01094. The miRWalk database analysis showed that TGFBR2, SMAD2, and SMAD3 were downstream targets of miR-122-5p. Mechanically, LINC01094 acted as a ceRNA that facilitated HCC metastasis by sponging miR-122-5p to regulate the expression of TGFBR2, SMAD2, and SMAD3. Further, TGF-ß1 could enhance the expression of LINC01094, forming a positive feedback loop. TGF-ß1-induced LINC01094 expression promotes HCC cell migration and invasion by targeting the miR-122-5p/TGFBR2-SMAD2-SMAD3 axis. LINC01094 may be a potential prognostic biomarker and therapeutic target for HCC metastasis.

M2 tumor-associated macrophage mediates the maintenance of stemness to promote cisplatin resistance by secreting TGF-ß1 in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly gastrointestinal malignancy, and chemotherapy resistance is a key factor leading to its poor prognosis. M2 tumor-associated macrophages (M2-TAMs) may be an important cause of chemoresistance in ESCC, but its exact mechanism is still unclear. METHODS: In order to study the role of M2-TAMs in ESCC chemoresistance, CCK-8, clone formation assay, flow cytometric apoptosis assay, qRT-PCR, western blotting, and serum-free sphere formation assays were used. In vivo animal experiments and human ESCC tissues were used to confirm the findings. RESULTS: In vitro and in vivo animal experiments, M2-TAMs reduced the sensitivity of ESCC cells to cisplatin. Mechanistically, M2-TAMs highly secreted TGF-ß1 which activated the TGFßR1-smad2/3 pathway to promote and maintain the stemness characteristic of ESCC cells, which could inhibit the sensitivity to cisplatin. Using TGFß signaling inhibitor SB431542 or knockdown of TGFßR1 could reverse the cisplatin resistance of ESCC cells. In 92 cases of human ESCC tissues, individuals with a high density of M2-TAMs had considerably higher levels of TGF-ß1. These patients also had worse prognoses and richer stemness markers. CONCLUSION: TGF-ß1 secreted from M2-TAMs promoted and maintained the stemness characteristic to induce cisplatin resistance in ESCC by activating the TGFß1-Smad2/3 pathway.

Upregulation of hsa_circ_0002003 promotes hepatocellular carcinoma progression.

BACKGROUND: Circular RNAs (circRNAs), which are involved in various human malignancies, have emerged as promising biomarkers. The present study aimed to investigate unique expression profiles of circRNAs in hepatocellular carcinoma (HCC) and identify novel biomarkers associated with HCC development and progression. METHODS: CircRNA expression profiles of HCC tissues were jointly analyzed to identify differentially expressed circRNAs. Overexpression plasmid and siRNA targeting candidate circRNAs were used in functional assays in vitro. CircRNA-miRNA interactions were predicted using miRNAs expressed in the miRNA-seq dataset GSE76903. To further screen downstream genes targeted by the miRNAs, survival analysis and qRT-PCR were conducted to evaluate their prognostic role in HCC and construct a ceRNA regulatory network. RESULTS: Three significantly upregulated circRNAs, hsa_circ_0002003, hsa_circ_0002454, and hsa_circ_0001394, and one significantly downregulated circRNA, hsa_circ_0003239, were identified and validated by qRT-PCR. Our in vitro data indicated that upregulation of hsa_circ_0002003 accelerated cell growth and metastasis. Mechanistically, DTYMK, DAP3, and STMN1, which were targeted by hsa-miR-1343-3p, were significantly downregulated in HCC cells when hsa_circ_0002003 was silenced and were significantly correlated with poor prognosis in patients with HCC. CONCLUSION: Hsa_circ_0002003 may play critical roles in HCC pathogenesis and serve as a potential prognostic biomarker for HCC. Targeting the hsa_circ_0002003/hsa-miR-1343-3p/STMN1 regulatory axis could be an effective therapeutic strategy in patients with HCC.

Corneal deposits and nerve alterations in Bietti Corneoretinal Crystalline Dystrophy imaged using in vivo confocal microscopy.

PURPOSE: To evaluate the imaging features of corneal deposits and nerve alterations in Chinese patients with Bietti Corneoretinal Crystalline Dystrophy (BCD) using in vivo confocal microscopy (IVCM). METHODS: Twenty patients with BCD and 20 age- and sex-matched healthy controls were enrolled in this retrospective, observational study. Corneal deposits and sub-basal nerve plexus (SNP) were observed by IVCM. Parameters of SNP including total nerve density/number, main nerve trunk density/number, and branch nerve density/number were analyzed by Neuron J. RESULTS: Corneal deposits were observed in both eyes of all patients by IVCM. These crystals appeared as dot-shaped, needle-shaped, and rod-shaped hyperreflective bodies and were located not only in the sub-epithelium and stroma of cornea, but in endothelium which were not reported before. There was a decrease of total nerve density (P < 0.001), main nerve trunk density (P = 0.007), and branch nerve density (P = 0.001), in BCD compared to controls. The number of total nerves/frame (P = 0.001), main nerve trunks/frame (P = 0.005), and branch nerves/frame (P = 0.006) in BCD were lower than controls. CONCLUSION: New findings in locations of corneal crystals by IVCM expand the phenotype spectrum of BCD. Corneal deposits may be useful for diagnosis of BCD, especially ones without retinal deposits. Corneal nerve parameters were reduced in BCD, which may provide new insights to be further explored to contribute to our understanding of BCD. IVCM is a promising tool to evaluate corneal deposits and nerve alterations in BCD.

Low expression of PINK1 and PARK2 predicts poor prognosis in patients with esophageal squamous cell carcinoma.

BACKGROUND: The Parkinson's disease (PD) gene family expression is strongly linked to tumor development and progression; PINK1 and PARK2 are essential members of the PD gene family. However, the relationship between PINK1 and PARK2 and esophageal squamous cell carcinoma (ESCC) remains unknown. This research aims to clarify the prognostic value of PINK1 and PARK2 in ESCC. METHODS: PINK1 and PARK2 protein levels in 232 ESCC specimens, and 125 matched adjacent normal tissues were detected by immunohistochemistry. The relationship between PINK1 and PARK2 protein expression and clinicopathological features were analyzed. Kaplan-Meier survival analysis was performed to estimate the prognostic value of the PINK1 and PARK2 proteins in patients. Cox univariate and multivariate analyses were used to assess the risk factors affecting the OS for patients with ESCC. RESULTS: PINK1 and PARK2 had low expression in ESCC. Patients with low PINK1 had worse differentiation and advanced T and TNM stages. Lower PARK2 expression was linked to lymph node metastases and an advanced TNM stage. Furthermore, reduced PINK1 and PARK2 levels were associated with a poor prognosis for ESCC. Cox univariate and multivariate analyses revealed that PINK1, PARK2, and tumor size were closely associated with the prognosis of patients with ESCC, and PARK2 was an independent risk factor for patients with ESCC. Finally, the PINK1 and PARK2 proteins were closely related and shared the same signal pathway. CONCLUSIONS: PINK1 and PARK2 could work as tumor suppressors in ESCC and are likely to become new treatment targets for ESCC.

EgCF mediates macrophage polarisation by influencing the glycolytic pathway.

Human cystic echinococcosis (CE) is a zoonotic disorder triggered by the larval stage of Echinococcus granulosus (E. granulosus) and predominantly occurred in the liver and lungs. The M2 macrophage level is considerably elevated among the liver of patients with hepatic CE and performs an integral function in liver fibrosis. However, the mechanism of CE inducing polarisation of macrophage to an M2 phenotype is unknown. In this study, macrophage was treated with E. granulosus cyst fluid (EgCF) to explore the mechanism of macrophage polarisation. Consequently, the expression of the M2 macrophage and production of anti-inflammatory cytokines increased after 48 h treatment by EgCF. In addition, EgCF promoted polarisation of macrophage to an M2 phenotype by inhibiting the expression of transcriptional factor hypoxia-inducible factor 1-alpha (HIF-1α), which increased the expression of glycolysis-associated genes, including hexokinase 2 (HK2) and pyruvate kinase 2 (PKM2). The HIF-1α agonist ML228 also inhibited the induction of macrophage to an M2 phenotype by EgCF in vitro. Our findings indicate that E. granulosus inhibits glycolysis by suppressing the expression of HIF-1α.

DLEU1 promotes cell survival by preventing DYNLL1 degradation in esophageal squamous cell carcinoma.

BACKGROUND: Emerging evidence has highlighted the critical roles of long noncoding RNAs (lncRNAs) in tumor development and progression. However, the biological functions and underlying mechanisms of DLEU1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: LncRNA expression in ESCC tissues was explored using lncRNA microarray datasets. The functional roles of DLEU1 in ESCC were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down and immunoprecipitation assays were performed to demonstrate the potential mechanisms of DLEU1. RESULTS: In a screen for differentially expressed lncRNAs in ESCC, we determined that DLEU1 was one of the most overexpressed lncRNAs in ESCC tissues and that upregulated DLEU1 expression was associated with a worse prognosis. Functional assays showed that DLEU1 promoted tumor growth by inhibiting cell apoptosis. Mechanistically, DLEU1 could bind and stabilize DYNLL1 by interfering with RNF114-mediated ubiquitination and proteasomal degradation. The DLEU1/DYNLL1 axis subsequently upregulated antiapoptotic BCL2 and promoted cell survival. Furthermore, DLEU1 upregulation was at least partly facilitated by promoter hypomethylation. Notably, targeting DLEU1 sensitized ESCC cells to cisplatin-induced death. CONCLUSIONS: Our findings suggest that DLEU1-mediated stabilization of DYNLL1 is critical for cell survival and that the DLEU1/DYNLL1 axis may be a promising therapeutic target for ESCC.

Long non-coding RNA MIR31HG as a prognostic predictor for malignant cancers: A meta- and bioinformatics analysis.

BACKGROUND: The possible regulatory mechanism of MIR31HG in human cancers remains unclear, and reported results of the prognostic significance of MIR31HG expression are inconsistent. METHODS: The meta-analysis and related bioinformatics analysis were conducted to evaluate the role of MIR31HG in tumor progression. RESULTS: The result showed that high MIR31HG expression was not related to prognosis. However, in the stratified analysis, we found that the overexpression of MIR31HG resulted in worse OS, advanced TNM stage, and tumor differentiation in respiratory system cancers. Moreover, our results also found that MIR31HG overexpression was related to shorter OS in cervical cancer patients and head and neck tumors. In contrast, the MIR31HG was lower in digestive system tumors which contributed to shorter overall survival, advanced TNM stage, and distant metastasis. Furthermore, the bioinformatics analysis showed that MIR31HG was highly expressed in normal urinary bladder, small intestine, esophagus, stomach, and duodenum and low in colon, lung, and ovary. The results obtained from FireBrowse indicated that MIR31HG was highly expressed in LUSC, CESC, HNSC, and LUAD and low in STAD and BLCA. Gene Ontology analysis showed that the co-expressed genes of MIR31HG were most enriched in the biological processes of peptide metabolism and KEGG pathways were most enriched in Ras, Rap1, and PI3K-Akt signaling pathway. CONCLUSION: MIR31HG may serve as a potential biomarker in human cancers.

Defective expression of C20orf54 in esophageal dysplasia: a possible biomarker of esophageal carcinoma for early detection.

BACKGROUND: C20orf54 has been identified as an esophageal squamous cell carcinoma (ESCC) susceptibility gene in previous genome-wide association studies. Here, we attempted to clarify the expression level of C20orf54 in ESCC, non-tumoral esophageal tissues, and esophageal squamous intraepithelial neoplasia (ESIN). METHODS: We assessed C20orf54 expression in 146 ESCC, 108 non-tumoral esophageal tissues, and 148 ESIN using immunohistochemistry on tissue microarrays. We also evaluated the possible correlations of C20orf54 expression with clinicopathological characteristics. The survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: C20orf54 expression was significantly lower in ESCC, high-grade ESIN, and low-grade ESIN than in the non-tumoral esophageal tissues. The level observed for ESCC was also significantly lower than that in low-grade ESIN and high-grade ESIN, whereas no difference was observed between high-grade ESIN and low-grade ESIN. Furthermore, the C20orf54 defective expression correlated significantly with differentiation, lymph node metastasis, and invasion depth. The overall survival time was inversely associated with lymph node metastasis, an advanced TNM stage (III + IV), and deeper invasion. CONCLUSIONS: This study provides the first evidence of C20orf54 defective expression in ESCC and precancerous lesions, demonstrating a potential role in tumor progression and metastasis. C20orf54 could be used as a potential biomarker for the early detection of ESCC.

CCL23 suppresses liver cancer progression through the CCR1/AKT/ESR1 feedback loop.

With the ability to activate certain signaling pathways, chemokines and their receptors may facilitate tumor progression at key steps, including proliferation, immunomodulation, and metastasis. Nevertheless, their prognostic value and regulatory mechanism warrant thorough studies in liver cancer. Here, by screening the expression profiles of all known chemokines in independent liver cancer cohorts, we found that CCL23 was frequently downregulated at mRNA and protein levels in liver cancer. Decreased CCL23 correlated with shortened patient survival, enrichment of signatures related to cancer stem cell property, and metastatic potential. In addition to serving as a tumor suppressor through recruiting CD8+ T cell infiltration in liver cancer, CCL23 could repress cancer cell proliferation, stemness, and mobility. Mechanistically, the expression of CCL23 was transcriptionally regulated by ESR1. On the other hand, CCL23 could suppress the activation of AKT signaling and thus promote the expression of ESR1, forming a feedback loop in liver cancer cells. Collectively, these findings reveal that loss of CCL23 drives liver cancer progression by coordinating immune evasion and metastasis initiation. Targeting the ESR1/CCL23/CCR1/AKT regulatory axis could be an effective therapeutic strategy.

Three novel circRNAs upregulated in tissue and plasma from hepatocellular carcinoma patients and their regulatory network.

BACKGROUND: The regulatory roles of circular RNAs (circRNAs) in tumorigenesis have attracted increasing attention. However, novel circRNAs with the potential to be used as serum/plasma biomarkers and their regulatory mechanism in the pathogenesis of hepatocellular carcinoma (HCC) remain explored. METHODS: CircRNA expression profiles of tumor tissues and plasma samples from HCC patients were compiled and jointly analyzed. CircRNA-miRNA-mRNA interactions were predicted by bioinformatics tools. The expression of interacting miRNAs and mRNA was verified in independent datasets. Survival analysis and pathway enrichment analysis were conducted on hub genes. RESULTS: We identified three significantly up-regulated circRNAs (hsa_circ_0009910, hsa_circ_0049783, and hsa_circ_0089172) both in HCC tissues and plasma samples. Two of them were validated to be indeed circular and could be excreted from hepatoma cells. We further revealed four miRNAs (hsa-miR-455-5p, hsa-miR-615-3p, hsa-miR-18a-3p, hsa-miR-4524a-3p) that targeting circRNAs and expressed in human HCC samples, and 95 mRNAs targeted by miRNAs and significantly up-regulated in two HCC cohorts. A protein-protein interaction network revealed 19 hub genes, 12 of them (MCM6, CCNB1, CDC20, NDC80, ZWINT, ASPM, CENPU, MCM3, MCM5, ECT2, CDC7, and DLGAP5) were associated with reduced survival in two HCC cohorts. KEGG, Reactome, and Wikipathway enrichment analysis indicated that the hub genes mainly functioned in DNA replication and cell cycle. CONCLUSIONS: Our study uncovers three novel deregulated circRNAs in tumor and plasma from HCC patients and provides an insight into the pathogenesis from the circRNA-miRNA-mRNA regulatory network.

A combination of pirfenidone and TGF-ß inhibition mitigates cystic echinococcosis-associated hepatic injury.

Cystic echinococcosis (CE) occurs in the intermediate host's liver, assuming a bladder-like structure surrounded by the host-derived collagen capsule mainly derived from activated hepatic stellate cells (HSCs). However, the effect of CE on liver natural killer (NK) cells and the potential of transforming growth factor-ß (TGF-ß) signalling inhibition on alleviating CE-related liver damage remain to be explored. Here, by using the CE-mouse model, we revealed that the inhibitory receptors on the surface of liver NK cells were up-regulated, whereas the activating receptors were down-regulated over time. TGF-ß1 secretion was elevated in liver tissues and mainly derived from macrophages. A combination of TGF-ß signalling inhibitors SB525334 and pirfenidone could reduce the expression of TGF-ß1 signalling pathway-related proteins and collagen production. Based on the secretion of TGF-ß1, only the pirfenidone group showed a depressing effect. Also, the combination of SB525334 and pirfenidone exhibited a higher potential in effectively alleviating the senescence of the hepatocytes and restoring liver function. Together, TGF-ß1 may be a potential target for the treatment of CE-associated liver fibrosis.

Development of Megaselia spiracularis (Diptera: Phoridae) at different constant temperatures.

Megaselia spiracularis Schmitz, 1938 (Diptera: Phoridae) is a pest that often appears in human living areas where it can spread pathogens. Besides, the species is of forensic value. Currently, studies focusing on the development of this species are limited. Understanding the developmental patterns of M. spiracularis, therefore, is important for controlling populations of this pest and for estimating the minimum postmortem interval (PMImin). Here, we studied the development of M. spiracularis exposed to seven constant temperatures ranging from 16 to 34 °C. The developmental durations, accumulated degree hours and larval body length changes were measured. Three kinds of development models that can be used to estimate the PMImin were established, including isomorphen diagram, isomegalen diagram and thermal summation model. The duration of M. spiracularis development at 16, 19, 22, 25, 28, 31 and 34 °C from egg to adult stage were 1131.1 ± 34.5, 807.3 ± 9.3, 529.6 ± 1.8, 367.0 ± 8.8, 302.4 ± 7.0, 250.0 ± 2.1 and 232.6 ± 1.9 h, respectively. The developmental threshold temperature and the thermal summation constant were estimated as 12.0 ± 0.5 °C and 4989.7 ± 308.9° hours, respectively. A general model represented by a logistic equation describing how larval body length will change with the time after hatching was fit to data. The present study provides basic developmental data of M. spiracularis, which can be used for achieving better control of this noxious insect as well as for estimation of its PMImin at different temperatures.

PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressively malignant tumors with dismal prognosis. Profilin 2 (PFN2) is an actin-binding protein that regulates the dynamics of actin polymerization and plays a key role in cell motility. Recently, PFN2 have emerged as significant regulators of cancer processes. However, the clinical significance and biological function of PFN2 in ESCC remain unclear. METHODS: PFN2 protein expression was validated by immunohistochemistry (IHC) on tissue microarray from Chinese Han and Kazakh populations with ESCC. The associations among PFN2 expression, clinicopathological features, and prognosis of ESCC were analyzed. The effects on cell proliferation, invasion and migration were examined using MTT and Transwell assays. Markers of epithelial-mesenchymal transition (EMT) were detected by Western blot analysis. RESULTS: Compared with normal esophageal epithelium (NEE), PFN2 protein expression was markedly increased in low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and ESCC, increased gradually from LGIN to ESCC, and finally reached high grade in HGIN in the Han population. Similarly, PFN2 protein was more overexpressed in ESCC than in NEE in the Kazakh population. The results of Western blot analysis also showed that PFN2 expression was significantly higher in the ESCC tissue than in a matched adjacent non-cancerous tissue. PFN2 expression was positively correlated with invasion depth and lymph node metastasis. High PFN2 expression was significantly correlated with short overall survival (OS) (P = 0.023). Cox regression analysis revealed that PFN2 expression was an independent prognostic factor for poor OS in ESCC. Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro. CONCLUSIONS: Our findings demonstrate that PFN2 has a novel role in promoting ESCC progression and metastasis and portending a poor prognosis, indicating that PFN2 could act as an early biomarker of high-risk population. Targeting PFN2 may offer a promising therapeutic strategy for ESCC treatment.

Prognostic significance of p53 expression in patients with esophageal cancer: a meta-analysis.

BACKGROUND: The prognostic value of p53 protein expression in esophageal cancer has been evaluated, but the results remain inconclusive and no consensus has yet been achieved. This meta-analysis was conducted to quantitatively assess the prognostic significance of p53 expression in esophageal cancer. METHODS: Publications that assessed the clinical or prognostic significance of p53 expression in esophageal cancer and were published before July 1, 2015 were identified by searching the PubMed and EMBASE databases. A meta-analysis was performed to clarify the association between p53 expression and the clinical outcomes. RESULTS: A total of 36 publications met the criteria and included 4577 cases. Analysis of these data showed that p53 expression in esophageal cancer was significantly associated with poorer 5-year survival (RR = 1.30, 95 % CI: 1.11-1.51, P = 0.0008). Subgroup analyses according to histological type, continent of the patients, and cut-off value revealed the similar results. The results also indicated that p53 expression was highly associated with advanced TNM stages (I/II vs. III/IV, OR = 0.74, 95 % CI: 0.55-0.99, P = 0.04), lymph node metastasis (OR = 0.77, 95 % CI: 0.66-0.90, P = 0.001), and distant metastasis (OR = 0.46, 95 % CI: 0.26-0.80, P = 0.006). However, p53 expression in the included studies was not significantly associated with tumor size (≤ 5 cm vs. > 5 cm, OR = 1.13, 95 % CI: 0.92-1.40, P = 0.24), tumor location (upper + middle vs. lower, OR = 0.91, 95 % CI: 0.70-1.17, P = 0.45), grade of differentiation (well + moderate vs. poor, OR = 1.10, 95 % CI: 0.90-1.34, P = 0.35), and the depth of invasion (T1/T2 vs. T3/T4, OR = 0.86, 95 % CI: 0.71-1.03, P = 0.09). CONCLUSIONS: This meta-analysis showed that p53 expression may be a useful biomarker for predicting poorer prognosis in patients with esophageal cancer.

Highly pathogenic porcine reproductive and respiratory syndrome virus induces prostaglandin E2 production through cyclooxygenase 1, which is dependent on the ERK1/2-p-C/EBP-ß pathway.

UNLABELLED: Atypical porcine reproductive and respiratory syndrome (PRRS) caused by highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is characterized by high fever and high mortality. However, the mechanism underlying the fever induction is still unknown. Prostaglandin E2 (PGE2), synthesized by cyclooxygenase type 1/2 (COX-1/2) enzymes, is essential for inducing fever. In this study, we found that PGE2, together with COX-1, was significantly elevated by HP-PRRSV. We subsequently demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK (p-ERK) were the key nodes to trigger COX-1 expression after HP-PRRSV infection. Furthermore, we proved the direct binding of p-C/EBP-ß to the COX-1 promoter by luciferase reporter and chromatin immunoprecipitation assays. In addition, silencing of C/EBP-ß remarkably impaired the enhancement of COX-1 production induced by HP-PRRSV infection. Taken together, our results indicate that HP-PPRSV elicits the expression of COX-1 through the ERK1/2-p-C/EBP-ß signaling pathway, resulting in the increase of PGE2, which might be the cause of high fever in infected pigs. Our findings might provide new insights into the molecular mechanisms underlying the pathogenesis of HP-PRRSV infection. IMPORTANCE: The atypical PRRS caused by HP-PRRSV was characterized by high fever, high morbidity, and high mortality in pigs of all ages, yet how HP-PRRSV induces high fever in pigs remains unknown. In the present study, we found out that HP-PRRSV infection could increase PGE2 production by upregulation of COX-1, and we subsequently characterized the underlying mechanisms about how HP-PRRSV enhances COX-1 production. PGE2 plays a critical role in inducing high temperature in hosts during pathogen infections. Thus, our findings here could help us have a better understanding of HP-PRRSV pathogenesis.

MicroRNA 181 suppresses porcine reproductive and respiratory syndrome virus (PRRSV) infection by targeting PRRSV receptor CD163.

We previously showed that microRNA 181 (miR-181) can inhibit PRRSV replication by directly targeting its genomic RNA. Here, we report that miR-181 can downregulate the PRRSV receptor CD163 in blood monocytes and porcine alveolar macrophages (PAMs) through targeting the 3' untranslated region (UTR) of CD163 mRNA. Downregulation of CD163 leads to the inhibition of PRRSV entry into PAMs and subsequently suppresses PRRSV infection. Our findings indicate that delivery of miR-181 can be used as antiviral therapy against PRRSV infection.