BACKGROUND:The SUMOylation modification is closely linked to the progression of fibrotic diseases, yet its role in hepatic fibrosis associated with cystic echinococcosis (CE) remains unclear. This study aimed to investigate the function of SUMOylation in CE-related hepatic fibrosis and evaluate the anti-fibrotic effects and mechanisms of ginkgolic acid (GA) via regulation of the SUMOylation pathway. METHODOLOGY:Peri-lesional (PL) and adjacent normal (AN) liver tissues from CE patients were collected to examine histopathology and SUMO pathway proteins. A CE-infected mouse model was established and treated with GA to assess cyst burden, serum TGF-β1 levels, hepatic fibrosis markers, and SUMO-related proteins. In vitro, macrophages and hepatic stellate cells (HSCs, LX-2 line) were stimulated with Echinococcus granulosus cyst fluid (EgCF) or TGF-β1 to evaluate GA's effects on macrophage polarization (CD206/CD86), HSC activation (α-SMA/PCNA), Smad4 SUMOylation, and nuclear translocation. Macrophage-HSC crosstalk was investigated via conditioned medium co-culture assays. RESULT:Fibrosis was exacerbated in peri-lesional liver tissues of CE patients, accompanied by SUMO pathway activation. GA significantly alleviated hepatic fibrosis in CE mice and reversed SUMO pathway dysregulation. Mechanistically, GA inhibited EgCF-induced pro-fibrotic M2 macrophage polarization and blocked Smad4 SUMOylation and nuclear translocation by modulating SUMOylation. Furthermore, GA directly suppressed HSC activation and bidirectionally disrupted the pro-fibrotic crosstalk between macrophages and HSCs under EgCF stimulation, ultimately alleviating fibrosis. CONCLUSION:This study reveals the critical role of SUMOylation modification in CE-associated hepatic fibrosis and elucidates a novel anti-fibrotic mechanism whereby GA targets the SUMOylation-Smad4 axis to regulate the immune microenvironment.

BACKGROUND:Although TP53 and RB1 co-alterations play critical roles in promoting malignant development and progression, specific inhibitors targeting this co-alteration are lacking. We performed a pan-cancer analysis to characterize the biology of TP53/RB1 co-alterations and identify therapeutic strategies. METHODS:We analyzed mutation data and copy number variation (CNV) data from 42 371 pan-cancer samples across 26 cancer types from the cBioPortal database. Among them, 2417 tumors with TP53/RB1 co-alterations were used for further analysis. We characterized their epidemiology and molecular biology. Therapeutic vulnerabilities of co-altered tumors were examined using Cancer Cell Line Encyclopedia drug screening datasets. RESULTS:TP53/RB1 co-alterations occurred in 5.70% of pan-cancer cases but exhibit striking heterogeneity across cancer types. Patients harboring co-alterations had significantly shorter overall survival (OS) in both primary and metastatic settings and poorer response to immune checkpoint inhibitors. Co-altered tumors displayed frequent alterations in chromatin remodeling genes (CREBBP, ARID1A, and KMT2D) and PI3K pathway (PIK3CA and PTEN), but with distinct tissue-specific mutational patterns: EGFR mutations dominated in lung adenocarcinoma (52%), KRAS in pancreatic cancer (88%), and APC in colorectal cancer (77%). Moreover, upregulated genes in co-altered tumors enriched in cell cycle pathways, DNA repair, and neuronal development, whereas immune/inflammatory signaling was suppressed. Critically, drug screening revealed that co-altered tumors showed increased sensitivity to CDK, AURKA, and PI3K/mTOR inhibitors, but resistance to MAPK/ERK pathway inhibitors. CONCLUSIONS:TP53/RB1 co-alterations define an aggressive cancer subset with dysregulated cell cycle/chromatin pathways and reduced immunotherapy response. Targeting CDK, AURKA, or PI3K signaling offers promising therapeutic strategies.

SHANK2 is crucial for neuronal synapse development and has been implicated in certain tumors; however, its role in esophageal squamous cell carcinoma (ESCC) remains underexplored. In this study, the expression and prognostic significance of SHANK2 in ESCC were assessed through bioinformatics analyses and immunohistochemical staining. We examined the relationship between SHANK2 expression and genetic alterations across multiple ESCC datasets. The effects of SHANK2 on cell proliferation, migration, and invasion were evaluated using cell-based assays. Potential SHANK2-interacting proteins were identified via co-immunoprecipitation followed by mass spectrometry and further validated using immunoprecipitation and immunoblotting. Additionally, we investigated the in vivo role of SHANK2 in ESCC progression using tumor xenograft mouse models. Our findings demonstrated that SHANK2 expression was significantly elevated in ESCC tissues, with high levels correlating with poor patient prognosis. Genetic amplification of SHANK2 was frequently observed in ESCC samples. SHANK2 promoted the proliferation, motility, and epithelial-mesenchymal transition of ESCC cells. Mechanistically, SHANK2 may activate the YAP signaling through competitive binding with DVL2, thereby facilitating malignant progression. In vivo studies indicated that targeting YAP signaling can mitigate SHANK2-induced ESCC growth. Taken together, SHANK2 is upregulated in ESCC and activates YAP signaling by interacting with DVL2, contributing to tumor progression. The SHANK2/DVL/YAP axis presents a potential therapeutic target for ESCC.

Immunosuppression and extensive fibrosis around the lesions are important features of alveolar echinococcosis (AE) caused by E. multilocularis. Recent studies have suggested that TREM2 is involved in tumor immunosuppression and tissue fibrosis. However, the function and mechanism of TREM2 in AE remain to be determined. Here, TREM2 expression was assessed in human and mouse lesions by immunostaining. A variety of E. multilocularis infection models were established in wild-type and Trem2-/- mice. RNA sequencing, ATAC sequencing, and in vitro assays were conducted to explore the underlying roles of TREM2+ macrophages. Potential drugs were screened and tested in vivo. We show that TREM2+ macrophages accumulated at the periparasitic borders of human and mouse metacestode lesions in the liver. Trem2 deficiency exacerbated the parasitic burden and weakened the fibrous shells surrounding the lesions, whereas Trem2 overexpression enhanced peri-lesional fibrosis in mouse models. E. multilocularis vesicle fluid (EmVF) can induce TREM2 expression via TGF-β/Smad signaling. Trem2 deficiency abolished the macrophage migration and fibroblast proliferation induced by EmVF. Drug screening revealed that resiquimod promoted periparasitic fibrosis, whereas SB431542, a TGF-β signaling inhibitor, had the opposite effect. Thus, TREM2-mediated fibrous shell formation plays a protective role in patients with AE. Activation of TREM2 signaling represents a novel potential therapeutic strategy for AE.

Lung cancer in young patients shows a rising incidence and distinct disease biology but remains understudied. We obtained clinical information and somatic mutation data for two large non-small-cell lung cancer (NSCLC) patient cohorts from the cBioPortal database-the China cohort (N = 1948) and the MSK cohort (N = 6220). Additionally, we extracted clinical data from an internal, real-world NSCLC patients (GZSY cohort, N = 3914) spanning the past decade. By comparing clinicopathological and genomic features across age and ethnicities, we systematically characterized the molecular and clinical phenotype of early-onset NSCLC. Young patients were more likely to be female and never smokers, and carried a higher frequency of actionable driver gene mutations, particularly involving EGFR, ALK, ROS1, and ERBB2 genes. In the China cohort, young patients exhibited significantly higher frequencies of EGFR and ERBB2 mutations and a higher rate of concurrent EGFR-TP53 co-mutations. Advanced stage at diagnosis and TP53 mutation status emerged as independent adverse prognostic factors in young patients. Integration of multi-ethnic genomic and clinical data in this study delineates the distinct clinical and molecular landscape of early-onset NSCLC and supports development of age-targeted, precision therapeutic strategies.

Here, we employed human embryonic stem cell spheroid (3D hESCs)-derived exosomes to assess inflammatory responses of macrophages in liver fibrosis, and found that 3D hESC-exosomes promoted the transformation of macrophages from M1 to M2 phenotype in vitro. The transplantation of 3D hESC-exosomes exhibited a notable decrease of pro-inflammatory factors, and significant increase of anti-inflammatory factors, and led to a reduction of CD86+M1 macrophages and an increase of Arg-1+M2 macrophages in the livers of treated fibrotic mice, restricting the advancement of liver fibrosis. hsa_circ_0076798, derived from 3D hESC-exosomes, acts as a molecular sponge that sequesters miR-1184, thereby mitigating miR-1184-mediated repression of DICER1 expression within macrophages. Further investigation revealed that DICER1 ultimately mitigated macrophage inflammation by deactivating TNF/NF-κB signaling pathway. Therefore, our findings demonstrated that 3D hESC-exosomes alleviated inflammatory responses by suppressing TNF/NF-κB pathway through hsa_circ_0076798/miR-1184/DICER1 axis, and offers insights into the targeted treatment of liver fibrosis via exosome-based cell-free therapy.

Chronic obstructive pulmonary disease (COPD) and lung cancer are two leading respiratory disorders that impose substantial morbidity, mortality, and healthcare burdens worldwide. Epidemiological evidence indicates that patients with COPD have a significantly increased risk of developing lung cancer, suggesting potential shared pathophysiological mechanisms between these two conditions. Understanding the underlying molecular mechanisms of these diseases is crucial for the improvement of early detection, diagnosis, and treatment. In recent years, advances in high-throughput technologies have enabled the emergence of metabolomics and metagenomics as powerful tools in biomedical research. Metabolomics allows for the comprehensive profiling of small-molecule metabolites, providing a global snapshot of metabolic dysregulation associated with disease onset and progression. Concurrently, metagenomics facilitates an in-depth analysis of the microbial communities residing in the respiratory and gastrointestinal tracts, shedding light on the crucial roles of the microbiota in modulating host immunity, inflammation, and carcinogenesis. Metabolomics and metagenomics, cutting-edge fields in biomedical research, provide valuable insights into the intricate interplay between host genetics, environmental factors, and microbial communities. These two omics disciplines offer unique but complementary perspectives on the complex biological processes linking COPD and lung cancer. In this review, we delve into the recent research findings on altered metabolomics and metagenomics in COPD and lung cancer, while also exploring the possible associations between these two areas of study.

OBJECTIVE:Hepatocellular carcinoma (HCC) is a prevalent digestive system malignancy with a poor prognosis. Previous studies suggested that elevated CD47 expression, a member of the immunoglobulin superfamily, is correlated with poor outcomes in various cancers. However, the precise mechanisms through which CD47 influences HCC progression remain unclear. METHODS:CD47 expression in tumor and adjacent tissues was assessed using online databases and immunohistochemical staining. The effects of CD47 on tumor cell proliferation were evaluated through cell counting kit-8 and colony formation assays. Bioinformatics analyses, qRT-PCR, and western blotting were employed to investigate the underlying mechanisms by which CD47 regulates tumor progression. RESULTS:CD47 expression was significantly elevated in HCC tissues compared to normal counterparts, and its level was closely associated with tumor stage. Overexpression of CD47 enhanced HCC cell growth, whereas silencing CD47 inhibited proliferation. Mechanistically, HIF-1α directly binds to the CD47 promoter, regulating its transcription. Additionally, CD47 stabilizes HIF-1α protein by inhibiting autophagy-lysosome-mediated degradation, establishing a positive feedback loop that promotes HCC cell proliferation. CONCLUSION:CD47 is upregulated in HCC tissues, and its interaction with HIF-1α accelerates tumor growth through a positive feedback loop. Targeting both CD47 and HIF-1α may offer a promising therapeutic strategy for patients with HCC.

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2), a surface receptor predominantly expressed on myeloid cells, is a major hub gene in pathology-induced immune signaling. However, its function in hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the role of TREM2 in the tumor microenvironment in the context of HCC progression. Methods HCC was experimentally induced in wild-type (WT) and Trem2-deficient (Trem2 −/−) mice, and clinical sample analysis and in vitro studies on macrophages were conducted. HCC cells were treated with conditioned medium from WT or Trem2 −/− macrophages, and their malignant phenotypes and underlying mechanisms were analyzed. Results TREM2 deficiency reduced liver tumor burden in orthotopic and subcutaneous HCC models by altering CD8+ T cell infiltration. Trem2-deficient macrophages presented increased chemokine secretion. TGF-β1 was found to be positively correlated with TREM2 expression in HCC, and TGF-β blockade reversed TREM2 induction. On the other hand, TREM2+ macrophages were found to be associated with glycolysis and PKM2 expression in HCC cells; this association may be related to the secretion of IL-1β, which enhances the malignant phenotypes of HCC cells. Conclusions These results reveal that TREM2+ macrophages play a driving role in HCC progression by suppressing CD8+ T cell infiltration and promoting tumor cell glycolysis, providing a new therapeutic target for HCC.

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-β/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-β1 could enhance the expression of LINC01094, forming a positive feedback loop. TGF-β1-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.

RNA-binding proteins (RBPs) are a class of proteins that primarily function by interacting with different types of RNAs and play a critical role in regulating the transcription and translation of cancer-related genes. However, their role in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed RNA sequencing data and the corresponding clinical information of patients with HCC to screen for prognostic RBPs. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was identified as an independent prognostic factor for liver cancer. It is upregulated in HCC and is associated with a poor prognosis. Elevated IGF2BP3 expression was validated via immunohistochemical analysis using a tissue microarray of patients with HCC. IGF2BP3 knockdown inhibited the proliferation of Hep3B and HepG2 cells, whereas IGF2BP3 overexpression promoted the expansion of HuH-7 and MHCC97H cells. Mechanistically, IGF2BP3 modulates cell proliferation by regulating E2F1 expression. DNA hypomethylation of the IGF2BP3 gene may increase the expression of IGF2BP3, thereby enhancing cell proliferation in HCC. Therefore, IGF2BP3 may act as a novel prognostic biomarker and a potential therapeutic target for HCC.

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.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Chemotherapy using cisplatin, a drug that damages deoxyribonucleic acid (DNA), is not very effective in treating HCC due to its side effects and drug resistance. Manganese (Mn2+), a trace element, has been shown to enhance immune responses, but its ability to improve cisplatin-induced antitumor immunity in HCC remains unclear. The present study found that treatment with Mn2+ in combination with cisplatin promoted cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling activation and C-X-C motif chemokine ligand 10 (CXCL10) production in tumor and dendritic cells. CXCL10 is associated with CD8A levels, and its high expression is linked to better prognosis in patients with HCC. In addition, Mn2+ and cisplatin co-treatment enhanced the recruitment of CD8+ T cells through the CXCL10/CXCR3 axis. Similarly, in an orthotopic transplantation tumor model, STING activation, CD8+ T cell infiltration, and tumor cell killing levels were higher in the combined treatment group. The above findings suggest that utilizing Mn2+ in combination with cisplatin could be a potential treatment option for HCC.

Objective Aberrant expression of CD276 has been reported in malignant tumors. However, the exact role and mechanisms of CD276 influence the progression of esophageal squamous cell carcinoma (ESCC) still need to be understood. Methods Bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus databases, along with immunohistochemistry staining, was used to explore the expression patterns of CD276 in ESCC. Cell counting kit-8 and Transwell assays were employed to evaluate the effects of CD276 expression on tumor cell proliferation and motility. Western blotting and Transwell assays were used to explore the potential pathways through which CD276 mediates the progression of ESCC. Moreover, the in vivo role of CD276 in tumor progression was investigated by establishing a lung metastasis mouse model. Results A significant upregulation of CD276 was observed in ESCC tissues compared to adjacent tissues. The inhibition of CD276 had no evident impact on ESCC cell proliferation but notably hindered their migratory and invasive properties and the expression of epithelial-mesenchymal transition (EMT) markers. Inversely, overexpressing CD276 led to an upregulation of EMT markers, underscoring the capacity of CD276 to amplify the motility of ESCC cells. Furthermore, CD276 was found to enhance the migratory and invasive abilities of ESCC cells by activating the TGF-beta/SMAD signaling but not the PI3K/AKT pathway. In vivo studies demonstrated that CD276 facilitates pulmonary metastasis. Conclusion CD276 is significant upregulation in ESCC tissues and facilitates the EMT process in ESCC cells via the TGF-beta/SMAD signaling, thus promoting the progression of ESCC.

BackgroundCircular 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.MethodsCircRNA 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.ResultsThree 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.ConclusionHsa_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.

Echinococcus granulosus cyst fluid (EgCF) weakens macrophage inflammatory responses, thereby enabling the parasite to evade the immune system. However, the role of histone modification in this process remains to be explored. The levels of IL-6, TNF-α, IL-10, H3K4me3, and KDM5B were detected using quantitative real-time PCR, ELISA, and Western blotting. The enrichment of H3K4me3 and KDM5B at the promoter of inflammatory factors was detected by chromatin immunoprecipitation. Based on EgCF-stimulated macrophage models, we found that EgCF significantly inhibited mRNA expression and protein secretion of IL-6 and TNF-α and upregulated mRNA expression of IL-10 under the influence of TLR4. EgCF lowered the level of H3K4me3 and promoted the transcription and protein stability of histone demethylase KDM5B. Chromatin immunoprecipitation analysis revealed that EgCF suppressed the enrichment of H3K4me3 modification at the promoters of TNF-α and IL-6 and downregulated their expression in macrophages. Additionally, the inhibition of KDM5B activity by CPI-455 weakened the anti-inflammatory effect of EgCF. Our findings demonstrate a novel mechanism through which EgCF promotes KDM5B expression and inhibits the enrichment of H3K4me3 at the promoters of inflammatory cytokines to suppress the inflammatory response.

Background: The impact of hepatitis E virus (HEV) infection on cancer development has been poorly investigated. This study aimed to explore the relationship between HEV seroprevalence and cancer risks and to identify high cancer risk subgroups in HEV-exposed populations. Methods: HEV seroprevalence status was determined in cancer and non-cancer subjects. Logistic regression and sensitivity analyses were used to assess the relationship between HEV antibody seropositivity and cancer risk for 17 cancer types. Additionally, interaction analyses were applied to interpret the association of HEV seroprevalence and other cancer risk factors. Results: Of the enrolled 4948 cancer and 4948 non-cancer subjects, cancer subjects had a higher anti-HEV seropositivity than non-cancer subjects (46.36% vs. 32.50%, p < 0.01). However, this divergency varied in degrees across different cancer types. Additionally, HEV seroprevalence was associated with cancer risk in young males (OR: 1.64, 95% CI: 1.19–2.27, p < 0.01). Remarkably, a significant association between HEV seroprevalence and cancer risk was observed only in gastric cancer patients (OR: 1.82, 95% CI: 1.07–3.09, p = 0.03). Conclusions: HEV seroprevalence was associated with cancer risk selectively in gastric cancer patients and young males, suggesting that cancer screening, particularly gastric cancer, should be regularly performed in young males with a history of HEV exposure.

Background: The primary pathological features of cystic echinococcosis (CE) are the formation of fibrotic pericytes and spaceoccupying lesions in the liver, but fibrogenesis has received little attention in CE. This study aimed to investigate the possible mechanisms underlying CE-induced fibrogenesis from the perspective of competing endogenous RNAs (ceRNAs). Methods: Hydatid fluid was collected from sheep livers infected with Echinococcus granulosus and was used to treat rat hepatic stellate cells (HSC-T6) to establish a fibrotic cell model. Next, RNA sequencing and bioinformatic analyses were conducted. Finally, two important ceRNA axes were chosen for quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Results: After hydatid fluid treatment, the both mRNA and protein expression levels of fibrosis-related factors (anti-alphasmooth muscle actin, type III collagen, and transforming growth factor-beta receptor II) were significantly higher than those in control cells. After sequencing, 569 differentially expressed (DE) mRNAs, 151 DE long non-coding RNAs (lncRNAs), and 14 DE miRNAs were identified in infected cells. Next, ceRNA regulatory networks consisting of 207 mRNAs, 13 miRNAs, and 54 lncRNAs were constructed. Based on the comparative toxicogenomics database, 8 fibrosis-related pathways were identified, including focal adhesion, extracellular matrix-receptor interaction, the hypoxia-inducible factor 1 signaling pathway, and pathways in cancer, as well as disease pathway-related regulatory networks associated with 38 DE lncRNAs, 43 DE mRNAs, 11 DE miRNAs, and 8 pathways. The qRT-PCR results of LNC_003335-novel_559-TNC and LNC_002273-miR-125-2-3p-PDGFD were consistent with the RNA sequencing results. Conclusions: Our study showed that the two ceRNA axes LNC_003335-novel_559-TNC and LNC_002273-miR-125-2-3p-PDGFD may be potential critical targets for CE-induced fibrogenesis.

BackgroundGlutamyl-prolyl-tRNA synthetase 1 (EPRS1) is an aminoacyl-tRNA synthase involved in the pathology of cancer and other diseases. In this study, we investigated the carcinogenic function, potential mechanism, and clinical significance of EPRS1 in human hepatocellular carcinoma (HCC).MethodsThe expression, clinical significance, and prognostic value of EPRS1 in HCC were assessed using the TCGA and GEO databases. The function of EPRS1 in HCC cells was detected by CCK-8, Transwell, and hepatosphere formation assays. Immunohistochemistry was used to explore the difference in EPRS1 levels in HCC tissues and peri-cancerous tissues. The mechanism of EPRS1 was studied using a proteomics method. Finally, cBioportal and MEXEPRSS were used to analyze the variations involved in the differential expression of EPRS1.ResultsEPRS1 was frequently upregulated at the mRNA and protein levels in liver cancer. Increased EPRS1 correlated with shortened patient survival. EPRS1 could promote cancer cell proliferation, characteristics of cell stemness, and mobility. Mechanistically, EPRS1 played a carcinogenic role by upregulating several downstream proline-rich proteins, primarily LAMC1 and CCNB1. In addition, copy number variation could contribute to the high expression of EPRS1 in liver cancer.ConclusionTogether, our data imply that enhanced EPRS1 contributes to the development of HCC by increasing the expression of oncogenes in the tumor microenvironment. EPRS1 may be a successful treatment target.

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.