Platelet count as a predictor of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma: A systematic review and meta-analysis.

Background: Vascular invasion (VI) indicates highly invasive tumor biological behavior and is a major determining factor of poor survival and high risk of metastasis in hepatocellular carcinoma (HCC). Epidemiological evidence of the association between pretherapeutic platelet count (PLT) and the risk of VI and extrahepatic metastasis in HCC remains controversial. Methods: A systematic retrieval was executed in databases of PubMed, Embase, and Web of Science until Dec 2022. Effect size and 95% confidence interval (CI) were extracted or estimated to synthetically investigate the effects of pretherapeutic PLT on VI and extrahepatic metastasis. Meta-analyses were performed by using a random or a fixed effects model. Results: Finally, the current meta-analysis included 15 studies with a total of 12,378 HCC patients. It was shown that, patients with a higher pretherapeutic level of PLT had a significantly increased risk of VI (11 studies,8,759 patients; OR = 1.44, 95%CI: 1.02-2.02) and extrahepatic metastasis (6 studies,8, 951 patients; OR = 2.51, 95% CI: 2.19-2.88) in comparison with patients with a lower PLT. Funnel plots and Begg's tests indicated that there were no significant publication biases. Conclusion: This meta-analysis shows that pretherapeutic elevated PLT is associated with an increased risk of VI and extrahepatic metastasis in HCC.

"Five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in laparoscopic pancreaticoduodenectomy.

BACKGROUND: Although en bloc dissection of hepatic hilum lymph nodes has many advantages in radical tumor treatment, the feasibility and safety of this approach for laparoscopic pancreaticoduodenectomy (LPD) require further clinical evaluation and investigation. AIM: To explore the application value of the "five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in LPD patients. METHODS: A total of 52 patients who underwent LPD via the "five steps four quadrants" modularized en bloc dissection technique for hepatic hilum lymph nodes from April 2021 to July 2023 in our department were analyzed retrospectively. The patients' body mass index (BMI), preoperative laboratory indices, intraoperative variables and postoperative complications were recorded. The relationships between preoperative data and intraoperative lymph node dissection time and blood loss were also analyzed. RESULTS: Among the 52 patients, 36 were males and 16 were females, and the average age was 62.2 ± 11.0 years. There were 26 patients with pancreatic head cancer, 16 patients with periampullary cancer, and 10 patients with distal bile duct cancer. The BMI was 22.3 ± 3.3 kg/m², and the median total bilirubin (TBIL) concentration was 57.7 (16.0-155.7) µmol/L. All patients successfully underwent the "five steps four quadrants" modularized en bloc dissection technique without lymph node clearance-related complications such as postoperative bleeding or lymphatic leakage. Correlation analysis revealed significant associations between preoperative BMI (r = 0.3581, P = 0.0091), TBIL level (r = 0.2988, P = 0.0341), prothrombin time (r = 0.3018, P = 0.0297) and lymph node dissection time. Moreover, dissection time was significantly correlated with intraoperative blood loss (r = 0.7744, P < 0.0001). Further stratified analysis demonstrated that patients with a preoperative BMI ≥ 21.9 kg/m² and a TIBL concentration ≥ 57.7 µmol/L had significantly longer lymph node dissection times (both P < 0.05). CONCLUSION: The "five steps four quadrants" modularized en bloc dissection technique for accessing the hepatic hilum lymph node is safe and feasible for LPD. This technique is expected to improve the efficiency of hepatic hilum lymph node dissection and shorten the learning curve; thus, it is worthy of further clinical promotion and application.

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.

BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

BACKGROUND: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype. METHODS: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis. RESULTS: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favourably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintains temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts. CONCLUSION: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.

CDC123 promotes Hepatocellular Carcinoma malignant progression by regulating CDKAL1.

The cell proliferation protein 123 (CDC123) is involved in the synthesis of the eukaryotic initiation factor 2 (eIF2), which regulates eukaryotic translation. Although CDC123 is considered a candidate oncogene in breast cancer, its expression and role in Hepatocellular Carcinoma (HCC) remain unknown. Herein, we obtained the CDC123 RNA-seq and clinical prognostic data from the TCGA database. The mRNA level revealed that CDC123 was highly expressed in HCC patients, and Kaplan-Meier analysis implied better prognoses in HCC patients with low CDC123 expression (P < 0.001). The multivariate Cox analysis revealed that the CDC123 level was an independent prognostic factor (P < 0.001). We further confirmed a high CDC123 expression in HCC cell lines. Additionally, we found that CDC123 knockdown in HCC cell lines significantly inhibited cellular proliferation, invasion, and migration. Moreover, CDC123 was co-expressed with the CDK5 Regulatory Subunit-Associated Protein 1 Like 1 (CDKAL1), whose mRNA level was decreased after silencing CDC123. Therefore, we hypothesized that CDC123 promotes HCC progression by regulating CDKAL1.

[Research progress of caput femoris posterior tilt and its impact on prognosis in nondisplaced femoral neck fractures].

There are still many unresolved problems in the treatment and prognosis of nondisplaced femoral neck fractures, such as nonunion and avascular necrosis of the caput femoris .In order to reduce the risk of various complications after non-displaced femoral neck fractures, the caput femoris posterior tilt of femoral neck fractures and its impact on prognosis have attracted more and more attention. A large number of scholars' studies have found that when the posterior tilt exceeds 20°, the risk of internal fixation failure increases significantly. Based on this concept, we can choose to use primary artificial joint replacement instead of three-screw internal fixation according to the different posterior tilt angles of patients to reduce the incidence of postoperative complications. At the same time, our analysis found that comminution of the posterior segment of the femoral neck would lead to an increase in the posterior inclination angles. The purpose of this review was to investigate the relationship between caput femoris posterior tilt of femoral neck fractures and surgical outcome, and to introduce a new method for measuring caput femoris posterior tilt of the femoral neck.

FOXA1/MND1/TKT axis regulates gastric cancer progression and oxaliplatin sensitivity via PI3K/AKT signaling pathway.

BACKGROUND: Drug resistance is a main factor affecting the chemotherapy efficacy of gastric cancer (GC), in which meiosis plays an important role. Therefore, it is urgent to explore the effect of meiosis related genes on chemotherapy resistance. METHODS: The expression of meiotic nuclear divisions 1 (MND1) in GC was detected by using TCGA and clinical specimens. In vitro and in vivo assays were used to investigate the effects of MND1. The molecular mechanism was determined using luciferase reporter assay, CO-IP and mass spectrometry (MS). RESULTS: Through bioinformatics, we found that MND1 was highly expressed in platinum-resistant samples. In vitro experiments showed that interference of MND1 significantly inhibited the progression of GC and increased the sensitivity to oxaliplatin. MND1 was significantly higher in 159 GC tissues in comparison with the matched adjacent normal tissues. In addition, overexpression of MND1 was associated with worse survival, advanced TNM stage, and lower pathological grade in patients with GC. Further investigation revealed that forkhead box protein A1 (FOXA1) directly binds to the promoter of MND1 to inhibit its transcription. CO-IP and MS assays showed that MND1 was coexpressed with transketolase (TKT). In addition,TKT activated the PI3K/AKT signaling axis and enhanced the glucose uptake and lactate production in GC cells. CONCLUSIONS: Our results confirm that FOXA1 inhibits the expression of MND1, which can directly bind to TKT to promote GC progression and reduce oxaliplatin sensitivity through the PI3K/AKT signaling pathway.

Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood-Brain Barrier and Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown. Here, the authors investigate these using a complex in vitro model for GBM and its surrounding BBB. The model recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability and morphology that is altered in the presence of a tumor spheroid. It is demonstrated that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis with next-generation low volume sample workflows of these cultured microtissues revealed potential clinically relevant proteins involved in tumor aggressiveness and TMZ resistance, demonstrating the utility of complex in vitro models for interrogating the tumor microenvironment and therapy validation.

Multiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors.

Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform to achieve direct and multiplexed profiling of circulating RNAs in extracellular vesicles for blood-based GBM characterization. The technology, termed 'enzyme ZIF-8 complexes for regenerative and catalytic digital detection of RNA' (EZ-READ), leverages an RNA-responsive transducer to regeneratively convert and catalytically enhance signals from rare RNA targets. Each transducer comprises hybrid complexes - protein enzymes encapsulated within metal organic frameworks - to configure strong catalytic activity and robust protection. Upon target RNA hybridization, the transducer activates directly to liberate catalytic complexes, in a target-recyclable manner; when partitioned within a microfluidic device, these complexes can individually catalyze strong chemifluorescence reactions for digital RNA quantification. The EZ-READ platform thus enables programmable and reliable RNA detection, across different-sized RNA subtypes (miRNA and mRNA), directly in sample lysates. When clinically evaluated, the EZ-READ platform established composite signatures for accurate blood-based GBM diagnosis and subtyping.

4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition.

OBJECTIVES: Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. METHODS: WT or Nrf2 knockout (Nrf2-/-) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. RESULTS: 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-ß1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. CONCLUSION: 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.

Facet modulation of nickel-ruthenium nanocrystals for efficient electrocatalytic hydrogen evolution.

Constructing highly active electrocatalysts towards hydrogen evolution reaction (HER) in both alkaline and acidic media is essential for achieving a sustainable energy economy. Here, a facile ethylene glycol reduction strategy was employed to design the nickel-ruthenium nanocrystals (Ni-Ru NC) with an exposed highly active Ru (101) facet as an efficient electrocatalyst for HER. Testings show Ni-Ru NC outperforms the benchmark catalyst Pt/C by delivering extraordinarily low overpotentials of 21.1 and 70.9 mV to drive 10 mA cm-2 in acidic and alkaline solutions, respectively. The results of experimental and theoretical studies suggest that Ni can modulate the electronic structure of the Ru NC and optimize the hydrogen adsorption free energy on Ru's surface, which accelerates the charge transfer kinetics and enhances the HER performance. The study support the potential application of facet-modulated Ru-based HER eleccatalyst in an alkaline environment.

Serum hsa_circ_0000615 is a prognostic biomarker of sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Circular RNAs (circRNAs) can shape tumor progression and chemoresistance. How specific circRNAs shape hepatocellular carcinoma (HCC) chemoresistance, however, remains to be fully elucidated. METHODS: In total, serum samples were collected from 202 HCC patients that had completed four sorafenib chemotherapy cycles. Serum hsa_circ_0000615 levels in these patients were quantified via quantitative real-time polymerase chain reaction (qRT-PCR), with demographic details and survival outcomes being recorded for subsequent analyses. RESULTS: We found hsa_circ_0000615 to be significantly upregulated in chemoresistant HCC patients relative to chemosensitive patients, with such upregulation being positively correlated with disease stage. Moreover, the area under the curve (AUC) value for hsa_circ_0000615 was moderately good, and high levels of hsa_circ_0000615 expression were associated with shorter overall survival among chemoresistant HCC patients. CONCLUSION: Our results highlight hsa_circ_0000615 as a promising driver of sorafenib resistance in HCC patients, highlighting it as a promising target for the treatment of this deadly cancer type.

HS1BP3, transcriptionally regulated by ESR1, promotes hepatocellular carcinoma progression.

PURPOSE: To explore the role of HS1-binding protein 3 (HS1BP3) in hepatocellular carcinoma (HCC) and the potential mechanism. METHODS: The effect of HS1BP3 in the prognosis of HCC was analyzed. The influence of HS1BP3 silence on proliferation, migration, cell cycle, and apoptosis of HCC cells (Huh-7 and Sun-449) were evaluated. The upstream transcription factors of HS1BP3 were further explored. RESULTS: The high expression of HS1BP3 in HCC was significantly associated with poor prognosis. The silencing of HS1BP3 inhibited proliferation, invasion, migration, and promoted G1 phase cell cycle arrest and apoptosis of HCC cells. Estrogen receptors 1 (ESR1) inhibited proliferation and improved the prognosis of HCC via fusion with HS1BP3 promoter. CONCLUSION: HS1BP3 may serve as a novel tumor-promoting factor transcriptionally regulated by ESR1.

Integrative multi-omics approach to targeted therapy for glioblastoma.

This review describes recent technological advances applied to glioblastoma (GBM), a brain tumor with dismal prognosis. International consortial efforts suggest the presence of molecular subtypes within histologically identical GBM tumors. This emphasizes that future treatment decisions should no longer be made based solely on morphological analyses, but must now take into consideration such molecular and cellular heterogeneity. The use of single-cell technologies has advanced our understanding and assignation of functional subtypes revealing therapeutic vulnerabilities. Our team has developed stratification approaches in the past few years, and we have been able to identify patient cohorts enriched for various signaling pathways. Importantly, our Glioportal brain tumor resource has been established under the National Neuroscience Institute Tissue Bank in 2021. This resource offers preclinical capability to validate working hypotheses established from patient clinical datasets. This review highlights recent developments with the ultimate goal of assigning functional meaning to molecular subtypes, revealing therapeutic vulnerabilities.

3D genome organization in the epithelial-mesenchymal transition spectrum.

BACKGROUND: The plasticity along the epithelial-mesenchymal transition (EMT) spectrum has been shown to be regulated by various epigenetic repertoires. Emerging evidence of local chromatin conformation changes suggests that regulation of EMT may occur at a higher order of three-dimensional genome level. RESULTS: We perform Hi-C analysis and combine ChIP-seq data across cancer cell lines representing different EMT states. We demonstrate that the epithelial and mesenchymal genes are regulated distinctively. We find that EMT genes are regulated within their topologically associated domains (TADs), with only a subset of mesenchymal genes being influenced by A/B compartment switches, indicating topological remodeling is required in the transcriptional regulation of these genes. At the TAD level, epithelial and mesenchymal genes are associated with different regulatory trajectories. The epithelial gene-residing TADs are enriched with H3K27me3 marks in the mesenchymal-like states. The mesenchymal gene-residing TADs, which do not show enrichment of H3K27me3 in epithelial-like states, exhibit increased interaction frequencies with regulatory elements in the mesenchymal-like states. CONCLUSIONS: We propose a novel workflow coupling immunofluorescence and dielectrophoresis to unravel EMT heterogeneity at single-cell resolution. The predicted three-dimensional structures of chromosome 10, harboring Vimentin, identify cell clusters of different states. Our results pioneer a novel avenue to decipher the complexities underlying the regulation of EMT and may infer the barriers of plasticity in the 3D genome context.

Chinese herbal injections for radiation pneumonitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Radiation pneumonitis is a common dose-limiting factor in radiotherapy for thoracic malignancies, and its treatment encounters a bottleneck. As an essential adjuvant treatment method, Chinese herbal injections (CHIs) have been used to treat radiation pneumonitis (RP), and clinical studies have appeared potentially beneficial and nontoxic. However, the efficacy and safety of CHIs for RP have not been evaluated comprehensively. METHODS: The systematic review and meta-analysis will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) statement guidelines. The Cochrane Library, PubMed, EMBASE, SinoMed, CNKI, VIP, and Wan Fang Databases were systematically searched from inception until January 20, 2022. The selection of studies, data extraction, and assessment of the risk of bias will be performed by 2 reviewers independently. The total effective rate was used as a primary outcome measure; the secondary outcomes are quality of life, clinical symptoms and signs, inflammatory cytokines, and adverse effects. Cochrane Review Manager (RevMan5.3) software will be used for data synthesis and analysis. RESULTS AND CONCLUSION: This systematic review will evaluate the efficacy and safety of CHIs in treating radiation pneumonitis to provide more comprehensive evidence for the treatment of clinical RP. INPLASY REGISTRATION NUMBER: INPLASY202210106.

Prognostic role of preoperative albumin-bilirubin score in posthepatectomy liver failure and mortality: a systematic review and meta-analysis.

Posthepatectomy liver failure (PHLF) is a life-threatening complication after liver resection, resulting in an increased morbidity and mortality. Epidemiological evidence of the association between preoperative albumin-bilirubin (ALBI) score, a newly established model for assessing liver functional reserve, and the risk of PHLF and mortality remains controversial. A systematical search for relevant literature was performed in PubMed, Embase, and Web of Science databases from December 2014 to September 2020. Odds ratio (OR) value and 95% confidence interval (CI) were extracted or calculated to synthetically estimate the association of preoperative ALBI score with PHLF and mortality. Meta-analyses were performed using a random-effects model. Twelve studies with a total of 21,348 patients were included in this meta-analysis. It was indicated that, compared to patients with a lower preoperative ALBI grade, patients with a higher grade had a significantly elevated risk of PHLF (6 studies, 18,291 patients; OR = 2.48, 95%CI: 2.00-3.07) and mortality (4 studies15, 139 patients; OR = 2.35, 95% CI: 1.38-4.00). In addition, when it was expressed as a continuous variable, ALBI was also a significant predictor of PHLF (6 studies, 3,833 patients; OR = 3.16, 95% CI: 2.07-4.81, per 1-point increase in ALBI score). No significant publication biases were detected as suggested by funnel plots inspection and Begg's tests. The current meta-analysis demonstrates that preoperative elevated ALBI is associated with higher risk of PHLF and mortality after hepatectomy.

LncRNA SNHG1 modulates adipogenic differentiation of BMSCs by promoting DNMT1 mediated Opg hypermethylation via interacting with PTBP1.

Recent evidence indicates that the abnormal differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) plays a pivotal role in the pathogenesis of osteoporosis. LncRNA SNHG1 has been found to be associated with the differentiation ability of BMSCs. In this study, we aimed to elucidate the role of lncRNA SNHG1 and its associated pathway on the differentiation of BMSCs in osteoporosis. Mice that underwent bilateral ovariectomy (OVX) were used as models of osteoporosis. Induced osteogenic or adipogenic differentiation was performed in mouse BMSCs. Compared to sham animals, lncRNA SNHG1 expression was upregulated in OVX mice. Also, the in vitro expression of SNHG1 was increased in adipogenic BMSCs but decreased in osteogenic BMSCs. Moreover, overexpression of SNHG1 enhanced the adipogenic capacity of BMSCs but inhibited their osteogenic capacity as determined by oil red O, alizarin red, and alkaline phosphatase staining, while silencing of SNHG1 led to the opposite results. LncRNA SNHG1 interacting with the RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) promoted osteoprotegerin (Opg) methylation and suppressed Opg expression via mediating DNA methyltransferase (DNMT) 1. Furthermore, Opg was showed to regulate BMSC differentiation. Knockdown of SNHG1 decreased the expressions of adipogenic related genes but increased that of osteogenic related genes. However, the knockdown of Opg partially reversed those effects. In summary, lncRNA SNHG1 upregulated the expression of DNMT1 via interacting with PTBP1, resulting in Opg hypermethylation and decreased Opg expression, which in turn enhanced BMSC adipogenic differentiation and contributed to osteoporosis.

YY1 activates EMI2 and promotes the progression of cholangiocarcinoma through the PI3K/Akt signaling axis.

BACKGROUND: Cholangiocarcinoma (CCA) is one of the deadliest cancers of the digestive tract. The prognosis of CCA is poor and the 5-year survival rate is low. Bioinformatic analysis showed that early mitotic inhibitor 2 (EMI2) was overexpressed in CCA but the underlying mechanism is not known. METHODS: The data on bile duct carcinoma from TCGA and GEO databases were used to detect the expression of EMI2. The transcription factors of EMI2 were predicted using JASPAR and PROMO databases. Among the predicted transcription factors, YY1 has been rarely reported in cholangiocarcinoma, and was verified using the luciferase reporter gene assay. RT-PCR was performed to predict the downstream pathway of EMI2, and PI3K/Akt was suspected to be associated with it. Subsequently, in vivo and in vitro experiments were conducted to verify the effects of silencing and overexpressing EMI2 and YY1 on the proliferation, invasion, and metastasis of the bile duct cancer cells. RESULTS: EMI2 was highly expressed in CCA. Silencing EMI2 inhibited the proliferation, invasion, and migration of CCA cells, arrested cell cycle in the G1 phase, and promoted of apoptosis. The luciferase reporter gene assay showed that YY1 bound to the promoter region of EMI2, and after silencing YY1, the expression of EMI2 decreased and the progression of CCA was inhibited. Moreover, key proteins in the PI3K/Akt signaling pathway decreased after silencing EMI2. CONCLUSION: EMI2 may be one of the direct targets of YY1 and promotes the progression of CCA through the PI3K/Akt signaling pathway.

lncRNA SNHG1 induced by SP1 regulates bone remodeling and angiogenesis via sponging miR-181c-5p and modulating SFRP1/Wnt signaling pathway.

BACKGROUND: We aimed to investigate the functions and underlying mechanism of lncRNA SNHG1 in bone differentiation and angiogenesis in the development of osteoporosis. METHODS: The differential gene or proteins expressions were measured by qPCR or western blot assays, respectively. The targeted relationships among molecular were confirmed through luciferase reporter, RIP and ChIP assays, respectively. Alkaline phosphatase (ALP), alizarin red S (ARS) and TRAP staining were performed to measure the osteoblast/osteoclast differentiation of BMSCs. The viability, migration and angiogenesis in BM-EPCs were validated by CCK-8, clone formation, transwell and tube formation assays, respectively. Western blot and immunofluorescence detected the cytosolic/nuclear localization of ß-catenin. Ovariectomized (OVX) mice were established to confirm the findings in vitro. RESULTS: SNHG1 was enhanced and miR-181c-5p was decreased in serum and femoral tissue from OVX mice. SNHG1 directly inhibited miR-181c-5p to activate Wnt3a/ß-catenin signaling by upregulating SFRP1. In addition, knockdown of SNHG1 promoted the osteogenic differentiation of BMSCs by increasing miR-181c-5p. In contrast, SNHG1 overexpression advanced the osteoclast differentiation of BMSCs and inhibited the angiogenesis of BM-EPCs, whereas these effects were all reversed by miR-181c-5p overexpression. In vivo experiments indicated that SNHG1 silencing alleviated osteoporosis through stimulating osteoblastogenesis and inhibiting osteoclastogenesis by modulating miR-181c-5p. Importantly, SNHG1 could be induced by SP1 in BMSCs. CONCLUSIONS: Collectively, SP1-induced SNHG1 modulated SFRP1/Wnt/ß-catenin signaling pathway via sponging miR-181c-5p, thereby inhibiting osteoblast differentiation and angiogenesis while promoting osteoclast formation. Further, SNHG1 silence might provide a potential treatment for osteoporosis.