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In view of the tumor-inhibiting effect of α-santalol in various cancers and the role of E2F transcription factor 1 (E2F1) as an important target for anticancer research, this study investigates the relation between α-santalol and E2F1, as well as the effect of α-santalol on liver cancer progression and the corresponding mechanism. Concretely, liver cancer cells were treated with different concentrations of α-santalol. The IC50 value of α-santalol was determined using Probit regression analysis. Then, transcription factors that are targeted by α-santalol and differentially expressed in liver cancer were screened out. The clinicopathological impact of E2F1 and its targets were evaluated and predicted. The expressions of E2F1 and high-mobility group box 2 (HMGB2) and their correlation in the liver cancer tissues were analyzed by bioinformatics. The effects of E2F1 and HMGB2 on the biological characteristics of liver cancer cells were examined through loss/gain-of-function and molecular assays. With the extension of treatment time, the inhibitory effects of 10 µmol/L and 20 µmol/L α-santalol on cancer cell survival rate were enhanced (P < 0.001). E2F1 and HMGB2 were highly expressed and positively correlated in liver cancer tissues (P < 0.05). High E2F1 expression was correlated with large tumors and high TNM stages (P < 0.05). E2F1 knockdown promoted the effects of α-santalol on dose-dependently inhibiting viability, colony formation, invasion and migration (P < 0.05). Moreover, E2F1 knockdown reduced the IC50 value and HMGB2 level, while HMGB2 overexpression produced opposite effects. HMGB2 overexpression and E2F1 knockdown mutually counteracted their effects on the IC50 value and on the viability and apoptosis of α-santalol-treated liver cancer cells (P < 0.01). Collectively, blocking the E2F1/HMGB2 pathway enhances the intervention effects of α-santalol on the proliferation, migration and invasion of liver cancer cells.
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Proteína HMGB2 , Neoplasias Hepáticas , Sesquiterpenos Policíclicos , Humanos , Línea Celular Tumoral , Proteína HMGB2/genética , Proliferación Celular , Neoplasias Hepáticas/tratamiento farmacológico , Factores de Transcripción/metabolismo , Factores de Transcripción E2F/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Objective Local recurrence, distant metastasis, and perineural invasion (PNI) viciously occur in salivary adenoid cystic carcinoma (SACC), resulting in a poor prognosis. This study aimed to explore the mechanism by which circular RNA RNF111 (circ-RNF111) regulates PNI in SACC by targeting the miR-361-5p/high mobility group box 2 (HMGB2) axis. Method Circ-RNF111 and HMGB2 were highly expressed in SACC specimens, while miR-361-5p was underexpressed. Functional experiments showed that ablating circ-RNF111 or promoting miR-361-5p hindered the biological functions and PNI of SACC-LM cells. Results HMGB2 overexpression induced the reversal of SACC-LM cell biological functions and PNI caused by circ-RNF111 knockout. Furthermore, reduction of circ-RNF111 suppressed PNI in a SACC xenograft model. Circ-RNF111 regulated HMGB2 expression through targeted modulation of miR-361-5p. Conclusion Taken together, circ-RNF111 stimulates PNI in SACC by miR-361-5p/HMGB2 axis and may serve as a potential therapeutic target for SACC (AU)
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Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Proteína HMGB2/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Carcinoma Adenoide Quístico/patología , Línea Celular Tumoral , Movimiento Celular/genética , Invasividad Neoplásica/genética , Proteínas Nucleares/metabolismo , /genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Background: High mobility group box 2 (HMGB2) is abnormally expressed in human cancers and participated in multiple biological behaviors, such as proliferation, invasion and prognosis. However, its role in hepatocellular carcinoma (HCC) is largely unknown. Methods: In clinical sample analysis, 62 HCC patients were enrolled in this study. The expression of HMGB2 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical method, clinical prognosis data were analyzed by Kaplan-Meier analysis. In cellular and molecular biology experiments, HMGB2 expression was analyzed in HCC cells. HMGB2 knockdown model was constructed by small interfering RNA (siRNA). Cell counting kit-8 (CCK-8) and cell migration & invasion assay were used to evaluate cell proliferative potential and motility. Recombinant human vimentin protein was used to partially restore the expression and function of vimentin. Western blot and immunochemical staining were performed to detect HMGB2 protein, zinc finger E-box binding homeobox 1 (ZEB1) and vimentin. Flow cytometry analyses were performed to determine the alteration of cell cycle in different groups. Results: HMGB2 was abnormally overexpressed in HCC. HMGB2 knockdown reduced malignant behaviors especially the proliferative potential and motility of HCC cells. The inhibition of HCC cells proliferation and mobility could be partially restored via treatment with recombinant vimentin protein. Our findings confirmed abnormal activation of HMGB2-ZEB1 vimentin axis facilitates HCC malignant proliferation and motility. The elevated HMGB2 expression in clinical samples was related to postoperative survival time of HCC patients. It indicated HMGB2 promotes the proliferation and motility potential of HCC via HMGB2-ZEB1-vimentin axis activation. Conclusions: HMGB2 is up-regulated in HCC and affects the malignant transformation by modulating HMGB2-ZEB1-vimentin signaling pathway, which may provide a research basis for evaluating the disease progression and developing clinical treatment strategies of HCC.
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Objective Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT.Methods We summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures.Results The median age of the studied SCCOPT cases (n=37) was 56.00 (range, 22-80) years. Almost 80% of them had a stage â ¢ or â £ tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. Conclusions SCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT.
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Carcinoma de Células Pequeñas , Neoplasias Ováricas , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Células Pequeñas/diagnóstico , Carcinoma de Células Pequeñas/terapia , Carcinoma de Células Pequeñas/patología , Carcinoma Epitelial de Ovario , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , PronósticoRESUMEN
OBJECTIVE: Local recurrence, distant metastasis, and perineural invasion (PNI) viciously occur in salivary adenoid cystic carcinoma (SACC), resulting in a poor prognosis. This study aimed to explore the mechanism by which circular RNA RNF111 (circ-RNF111) regulates PNI in SACC by targeting the miR-361-5p/high mobility group box 2 (HMGB2) axis. METHOD: Circ-RNF111 and HMGB2 were highly expressed in SACC specimens, while miR-361-5p was underexpressed. Functional experiments showed that ablating circ-RNF111 or promoting miR-361-5p hindered the biological functions and PNI of SACC-LM cells. RESULTS: HMGB2 overexpression induced the reversal of SACC-LM cell biological functions and PNI caused by circ-RNF111 knockout. Furthermore, reduction of circ-RNF111 suppressed PNI in a SACC xenograft model. Circ-RNF111 regulated HMGB2 expression through targeted modulation of miR-361-5p. CONCLUSION: Taken together, circ-RNF111 stimulates PNI in SACC by miR-361-5p/HMGB2 axis and may serve as a potential therapeutic target for SACC.
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Carcinoma Adenoide Quístico , MicroARNs , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , ARN Circular/genética , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Factores de Transcripción/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Invasividad Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proliferación Celular , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVE To study the mechanism of interfering with long non-coding RNA nicotinamide nucleotide transhydrogenase-antisense RNA1 （LncRNA NNT-AS1） expressing to reduce paclitaxel （TAX） resistance in non-small cell lung cancer （NSCLC） cells. METHODS NSCLC TAX-resistant cell line （A549/TAX） was constructed， and the expressions of LncRNA NNT-AS1 in normal， parental， and drug-resistant cells were observed. The targeting relationship of microRNA-582-5p （miR-582- 5p） with LncRNA NNT-AS1 and high mobility group box2 （HMGB2） was verified. A549/TAX cells were cultured in vitro to observe the effects of interfering with LncRNA NNT-AS1 alone or interfering with LncRNA NNT-AS1 and miR-582-5p on the expressions of LncRNA NNT-AS1 and miR-582-5p， the mRNA and protein expressions of HMGB2， cell viability， clone formation and apoptosis. The effects of interfering with LncRNA NNT-AS1 on tumor growth and the expression of miR-582-5p and the mRNA and protein expressions of HMGB2 in tumor tissue were observed in nude mice. RESULTS Compared with normal cells， LncRNA NNT-AS1 was highly expressed in parental and drug-resistant cells （P＜0.05）， showing an increasing trend. It was validated that miR-582-5p had a targeting relationship with LncRNA NNT-AS1 and HMGB2. After interfering with the expression of LncRNA NNT-AS1， the expression of LncRNA NNT-AS1 and the mRNA and protein expressions of HMGB2， cell viability and the number of cloned cells in A549/TAX cell， decreased significantly， while the expression of miR-582-5p and the apoptotic rate increased significantly （P＜0.05）； simultaneously interfering with the expression of miR-582-5p could reverse above changes （P＜ 0.05）. Interfering with the expression of LncRNA NNT-AS1 in tumor cell could significantly reduce tumor volume and tumor weight of nude mice bearing tumors； at the same time， the expression of miR-582-5p was up-regulated significantly and the mRNA and protein expressions of HMGB2 were down-regulated significantly （P＜0.05）. CONCLUSIONS Interfering with the expression of LncRNA NNT-AS1 may alleviate TAX chemotherapy resistance in NSCLC through targeted up-regulation of miR-582-5p and down-regulation of HMGB2.
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Objective Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT.Methods We summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures.Results The median age of the studied SCCOPT cases (n=37) was 56.00 (range, 22-80) years. Almost 80% of them had a stage Ⅲ or Ⅳ tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. Conclusions SCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT.
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Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Células Pequeñas/patología , Carcinoma Epitelial de Ovario , Neoplasias Ováricas/terapia , PronósticoRESUMEN
Spinal cord injury (SCI), characterized by sensory disturbance and motor deficits, is associated with excessive inflammatory cytokine production of microglial cells. Previous studies have demonstrated High mobility group box 2 (HMGB2) as a microglial pro-inflammatory factor in stroke. This present study aims to evaluate the function of HMGB2 in a SCI rat model induced by striking the spinal cord at T9 to T12 using a rod. Our results showed that the levels of HMGB2 were significantly increased in the spinal cord tissues of SCI rats. Besides, HMGB2 downregulation was achieved by receiving an injection of lentivirus encoding HMGB2 shRNA in the spinal cord. Knockdown of HMGB2 suppressed SCI-induced microglial activation and neuroinflammation, as well as alleviated neuronal loss. In addition, we confirmed that HMGB2 silencing lessened lipopolysaccharide (LPS)-induced neuroinflammation in BV-2 cells. Furthermore, our findings demonstrated that HMGB2 knockdown suppressed the canonical nuclear factor of kB (NF-κB) signaling pathway both in vivo and in vitro. Collectively, this study manifested strong anti-inflammatory roles of HMGB2 knockdown on microglia-mediated neuroinflammation and suggested that HMGB2 might serve as a potential target for SCI therapy.
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Microglía , Traumatismos de la Médula Espinal , Ratas , Animales , Regulación hacia Abajo , Enfermedades Neuroinflamatorias , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Inflamación/complicaciones , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/terapia , Médula Espinal/metabolismoRESUMEN
Background: Hypertension-mediated organ damage (HMOD) is an emerging problem among young adults. The potential role of chronic immune-mediated inflammation in the pathogenesis of HMOD is increasingly being recognized. High-mobility group box 2 (HMGB2) is known for its role in the modulation of innate immunity and exerts signaling functions that affect various inflammatory diseases. However, the association between HMGB2 and HMOD in young adults remains unclear. Objectives: The aim of this study was to explore the association between HMGB2 and subclinical HMOD in young adults. Design: This is a cross-sectional study. Methods: Body composition, carotid ultrasound, carotid-femoral PWV (cf-PWV) measures, echocardiography, serum HMGB2 levels, and serum classic cardiometabolic risk factors were measured in 988 untreated young adults. We estimated the risk related to serum HMGB2 using multivariable-adjusted linear and logistic regression models. Then, we conducted a pathway overrepresentation analysis to examine which key biological pathways may be linked to serum HMGB2 in young adults with HMOD. Results: Among the 988 untreated young adults, we identified four distinct hypertension phenotypes: normotension (40.0%), white-coat hypertension (16.0%), masked hypertension (20.9%), and sustained hypertension (23.1%). High levels of serum HMGB2 were related to increased carotid intima-media thickness (cIMT) and left ventricular mass index (LVMI), higher cf-PWV and blood pressure, and a lower estimated glomerular filtration rate (eGFR). Linear regression analysis showed that serum HMGB2 was positively associated with cf-PWV and negatively associated with eGFR in all patients. Multivariate analysis showed that high levels of serum HMGB2 were associated with high odds of subclinical HMOD (damage in at least one organ). Biological pathway analysis indicated that patients with high serum HMGB2 levels had increased activity of pathways, related to endothelial dysfunction, inflammatory processes, and atherosclerosis. Conclusion: High serum concentrations of HMGB2 are associated with an increased risk of subclinical HMOD in untreated young adults.
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High mobility group box 2 (HMGB2) is a non-histone chromosomal protein involved in various biological processes, including cellular senescence. However, its role in cellular senescence has not been evaluated extensively. To determine the regulatory role and mechanism of HMGB2 in cellular senescence, we performed gene expression analysis, senescence staining, and tube formation assays using young and senescent microvascular endothelial cells (MVECs) after small RNA treatment or HMGB2 overexpression. HMGB2 expression decreased with age and was regulated at the transcriptional level. siRNA-mediated downregulation inhibited cell proliferation and accelerated cellular senescence. In contrast, ectopic overexpression delayed senescence and maintained relatively higher tube-forming activity. To determine the HMGB2 downregulation mechanism, we screened miRNAs that were significantly upregulated in senescent MVECs and selected HMGB2-targeting miRNAs. Six miRNAs, miR-23a-3p, 23b-3p, -181a-5p, -181b-5p, -221-3p, and -222-3p, were overexpressed in senescent MVECs. Ectopic introduction of miR-23a-3p, -23b-3p, -181a-5p, -181b-5p, and -221-3p, with the exception of miR-222-3p, led to the downregulation of HMGB2, upregulation of senescence-associated markers, and decreased tube formation activity. Inhibition of miR-23a-3p, -181a-5p, -181b-5p, and -221-3p delayed cellular senescence. Restoration of HMGB2 expression using miRNA inhibitors represents a potential strategy to overcome the detrimental effects of cellular senescence in endothelial cells.
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MicroARNs , Senescencia Celular/genética , Regulación hacia Abajo/genética , Células Endoteliales/metabolismo , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , MicroARNs/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: High-mobility group box 2 (HMGB2) is considered as oncogene in non-small cell lung cancer (NSCLC), while its clinical implication is still unknown. This study aimed to explore the correlation of HMGB2 with clinicopathological characteristics and prognosis in NSCLC patients. METHODS: A total of 133 NSCLC patients who received radical excision were enrolled. HMGB2 expression in the tumor specimens and paired adjacent tissue specimens was determined by immunohistochemical assay (for protein expression) and reverse transcription quantitative polymerase chain reaction assay (for gene expression), respectively. RESULTS: HMGB2 protein expression was higher in tumor tissue compared with adjacent tissue, and it could distinguish tumor tissue from adjacent tissue (area under the curve (AUC): 0.775, 95%confidence interval (95%CI): 0.720-0.830). Meanwhile, tumor HMGB2 protein high expression correlated with lymph node (LYN) metastasis and advanced TNM stage. Additionally, tumor HMGB2 protein high expression associated with worse disease-free survival (DFS), while HMGB2 protein expression did not correlate with overall survival (OS). Besides, HMGB2 mRNA expression was raised in tumor tissue compared with adjacent tissue, and it had a good value in differentiating tumor tissue from adjacent tissue (AUC: 0.875, 95% CI: 0.834-0.915). Furthermore, tumor HMGB2 mRNA high expression correlated with higher Eastern Cooperative Oncology Group performance status score, LYN metastasis, and advanced TNM stage. Meanwhile, tumor HMGB2 mRNA high expression associated with shorter DFS and OS. CONCLUSION: HMGB2 could be a biomarker that reflects disease features and prognosis of NSCLC, which is beneficial to improve clinical efficacy in NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Proteína HMGB2/genética , Neoplasias Pulmonares , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Supervivencia sin Enfermedad , Humanos , Neoplasias Pulmonares/genética , PronósticoRESUMEN
Cells in articular cartilage are zonal arranged. Cells in superficial zone cartilage are generally small and proliferative. Appropriate negative pressure stimulation is beneficial to cell survival and tissue repair. Whether negative pressure has promotive impact on the proliferation activity of the superficial zone chondrocytes is of interest. In this study, we isolated superficial chondrocytes from the mandibular condylar cartilage of rats. After negative pressure treatment, the cells were collected for RNA-sequencing, quantitative real-time PCR and western blotting assays, aiming to detect the proliferative responses of chondrocytes to negative pressure and explore the potential molecular mechanisms. Data from RNA-sequencing analysis indicated that the superficial chondrocytes responded to the 4 h -10 kPa treatment by a significant increase in proliferation. In addition, the expression of high-mobility group box 2 (HMGB2) and the phosphorylation of AKT were obviously promoted. Knockdown of HMGB2 decreased AKT phosphorylation and diminished the negative pressure-induced proliferation of chondrocytes, as shown by decreased expression of Ki67 and cyclin-dependent kinase 6 (CDK6). In contrast, overexpression of HMGB2 enhanced AKT phosphorylation and further promoted proliferative activity. Moreover, LY294002, an AKT inhibitor, suppressed the proliferative activity of chondrocytes under negative pressure, while SC79, an activator of AKT phosphorylation, enhanced the proliferation of chondrocytes. Our data demonstrated that HMGB2 exhibits a promotion impact on chondrocyte proliferation under negative pressure via the phosphorylation of AKT. These results provide a new perspective for superficial zone chondrocytes proliferation under negative pressure, which should be benefit for cartilage regeneration.
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Condrocitos/metabolismo , Proteína HMGB2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Proliferación Celular , Condrocitos/citología , Femenino , Ratones , Ratones Endogámicos C57BL , FosforilaciónRESUMEN
Understanding of the mechanism of adipogenesis is essential for the control of obesity, which predisposes toward numerous health problems. High-mobility group box protein 2 (HMGB2) is a non-histone chromosomal protein that facilitates DNA replication, transcription, recombination, and repair. Here, we studied the role of HMGB2 in adipogenic differentiation. The expression of HMGB2 was measured at the mRNA and protein levels in cultured 3T3-L1 pre-adipocyte cells and during the process of adipogenic differentiation induced bya cocktail of insulin, 3-isobutyl-1-methylxanthine, and dexamethasone. This increased in the early phase and decreased in the late phase of differentiation. However, 3T3-L1 pre-adipocyte cells did not differentiate into adipocytes after the knockdown of HMGB2 expression by small interfering RNA (siRNA). Similarly, mesenchymal stem cells (MSCs) isolated from Hmgb2-/- mice did not express peroxisome proliferator-activated receptor gamma (PPARγ) in response to the adipocyte differentiation cocktail and did not differentiate. Wnt/ß-catenin signaling is a negative regulator of adipogenic differentiation. We found that ß-catenin expression was downregulated during 3T3-L1 adipogenic differentiation, as expected, but not when endogenous HMBG2 expression was knocked down using siRNA. These results indicate that HMGB2 plays an essential role in the early phase of the differentiation of pre-adipocytes and MSCs, and probably interacts with other regulators, such as PPARγ and Wnt/ß-catenin signaling.
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Adipocitos/citología , Adipogénesis/fisiología , Proteína HMGB2/metabolismo , Células Madre Mesenquimatosas/citología , Vía de Señalización Wnt , Adipocitos/metabolismo , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
High-mobility group box 2 (HMGB2) belongs to the HMG-box family that participates in a variety of biologic processes. Recent studies have suggested that HMGB2 plays an important role in the innate immunity of fish. Cherry Valley duck is the main duck bred for meat consumption in China, but there is limited research available on the impact of duck HMGB2 (duHMGB2) in antiviral innate immunity. Here, duHMGB2 genes were first cloned and analyzed from the spleen of Cherry Valley ducks. We show that duHMGB2 is widely distributed in most tissues of healthy ducks, and duHMGB2 was differentially expressed in three organs (the spleen, brain, and lung) of ducks during different viral infections. duHMGB2 is mainly expressed in the nucleus of duck embryo fibroblast (DEF) cells. However, duHMGB2 is released into the cytoplasm after viral infection. DuHMGB2 induced expression of several genes that regulate the immune response. Moreover, duHMGB2 activated and upregulatede transcription factor NF-κB promoter activity. We also used single gene manipulations (knockout or overexpression) to confirm that duHMGB2 can inhibit the replication of duck plague virus, duck Tembusu virus, and the novel duck reovirus in DEF cells. These data show that duHMGB2 can activate the antiviral innate immunity of the host. Thus, duHMGB2 may be considered an immune adjuvant against infectious diseases in duck.
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Patos/inmunología , Fibroblastos/fisiología , Proteína HMGB2/metabolismo , Virosis/inmunología , Virus/inmunología , Animales , Línea Celular , Clonación Molecular , Resistencia a la Enfermedad , Técnicas de Silenciamiento del Gen , Proteína HMGB2/genética , Proteína HMGB2/inmunología , Inmunidad Innata , FN-kappa B/genética , Regiones Promotoras Genéticas , Transducción de Señal , TranscriptomaRESUMEN
BACKGROUND: Increased expression of high mobility group box 2 (HMGB2) has been reported to promote the progression of several malignancies and be related to poor outcome. However, few studies have explored the relationship between HMGB2 and osteosarcoma. In this study, we aimed to obtain a better understanding of HMGB2 and its function in osteosarcoma. METHODS: Utilizing osteosarcoma paraffin sections and osteosarcoma cell lines, we observed the clinico-pathological relationship of osteosarcoma with HMGB2 expression and investigated the functions of HMGB2 in vitro. The possible pathways and regulation networks in which HMGB2 is involved were further explored through analysis of miRNA, mRNA and lncRNA micro array data sets. RESULTS: Strong expression of HMGB2 was found to be related with Enneking staging (P=0.002), tumor size (P=0.006), metastasis (P<0.001), and survival (P=0.011) in osteosarcoma. Multivariate analysis revealed that HMGB2 might have independent prognostic value in osteosarcoma (P=0.022). Kaplan-Meier curves and the log-rank test showed that survival time was significantly reduced in OS patients with strong HMGB2 expression (P=0.0056). In vitro experiments showed that HMGB2 overexpression promoted cell proliferation and enhanced the migration and invasion ability of osteosarcoma cells. Gene Ontology (GO) term analysis of osteosarcoma cell lines revealed HMGB2 to have various functions and to be mainly enriched in regulation of cell proliferation, cell death, and DNA binding. A competing endogenous RNA (ceRNA) network of miR-139-5p and six candidate lncRNAs was also suggested as targeting HMGB2 in osteosarcoma. CONCLUSIONS: Our findings suggest that HMGB2 might have various functions in promoting the progression of osteosarcoma and may serve as a new target for osteosarcoma research.
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HELICOBACTER PYLORI: (H. pylori), a common pathogenic bacterium in the stomach, has been demonstrated to be a major cause of gastric cancer (GC). The typical pathological evolution of H. pylori infection-induced GC involves development from gastric atrophy, via intestinal metaplasia (IM) and dysplasia, to intestinal-type GC. During this process, IM is considered to be an "irreversible point" that significantly increases the risk for GC. Therefore, the elucidation of the mechanism underlying IM is of great significance for the prevention and treatment of gastric mucosal carcinogenesis associated with H. pylori infection. Caudal type homeoboxes (CDXs) are transcription factors involved in intestinal differentiation establishment and the maintenance of normal intestinal mucosa and IM. H. pylori infection increases the expression of CDXs through epigenetic regulation, the nuclear factor-kappaB signaling pathway and its downstream proinflammatory factors, and the transforming growth factor-beta signaling pathway, leading to the progression from normal gastric mucosa to IM. However, the precise mechanisms of gastric intestinal metaplasia have not yet been fully elucidated. In this review, we focus on research progress revealing the functions of CDXs in H. pylori infection-induced IM, as well as the regulators modulating this process.
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Factor de Transcripción CDX2/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , Helicobacter pylori , Proteínas de Homeodominio/metabolismo , Neoplasias Gástricas/etiología , Animales , Factor de Transcripción CDX2/genética , Epigénesis Genética , Genes Homeobox , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Proteínas de Homeodominio/genética , Humanos , Metaplasia , FN-kappa B/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Laryngeal cancer (LCA) is a common head and neck cancer. Lysine demethylase 5B (KDM5B) knockdown is expected as a new target for cancer prevention. We investigated the molecular mechanism of KDM5B in LCA. MATERIALS AND METHODS: The levels of KDM5B, microRNA (miR)-139-3p and high-mobility-group box 2 (SOX2) in LCA tissues and cells, normal tissues and cells were detected. The effect of KDM5B on LCA was evaluated. The upstream miR of KDM5B and the downstream gene and pathway of KDM5B were predicted and their effects on LCA were analyzed. The Wnt/ß-catenin pathway-specific activator agonist was delivered into LCA cells expressing miR-139-3p mimic to evaluate the role of the Wnt/ß-catenin pathway. RESULTS: KDM5B was highly expressed in LCA, and inhibition of KDM5B suppressed LCA progression. miR-139-3p, downregulated in LCA tissues, was a regulatory miR of KDM5B. Overexpression of miR-139-3p significantly inhibited the malignant biological behaviors of LCA cells. KDM5B promoted SOX2 expression via histone demethylation. SOX2 was highly expressed in LCA, and overexpression of SOX2 promoted LCA progression by inducing the Wnt/ß-catenin pathway. Activated Wnt/ß-catenin pathway attenuated the inhibitory effect of miR-139-3p mimic on the malignant biological behaviors of LCA cells. CONCLUSION: miR-139-3p overexpression inhibited LCA development via regulating the KDM5B/SOX2 axis and inhibiting the Wnt/ß-catenin pathway.
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Melanoma is responsible for the majority of deaths caused by skin cancer. Antitumor activity of microRNA-329 (miR-329) has been seen in several human cancers. In this study, we identify whether miR-329 serves as a candidate regulator in melanoma. Melanoma-related differentially expressed genes were screened with its potential molecular mechanism predicted. Melanoma tissues and pigmented nevus tissues were collected, where the levels of miR-329 and high-mobility group box 2 (HMGB2) were determined. To characterize the regulatory role of miR-329 on HMGB2 and the ß-catenin pathway in melanoma cell activities, miR-329 mimics, miR-329 inhibitors, and siRNA-HMGB2 were transfected into melanoma cells. Cell viability, migration, invasion, cell cycle, and apoptosis were assessed. miR-329 was predicted to influence melanoma by targeting HMGB2 via the ß-catenin pathway. High level of HMGB2 and low miR-329 expression were observed in melanoma tissues. HMGB2 was targeted and negatively regulated by miR-329. In melanoma cells transfected with miR-329 mimics or siRNA-HMGB2, cell proliferation, migration, and invasion were impeded, yet cell cycle arrest and apoptosis were promoted, corresponding to decreased levels of ß-catenin, cyclin D1, and vimentin and increased levels of GSK3ß and E-cadherin. Collectively, our results show that miR-329 can suppress the melanoma progression by downregulating HMGB2 via the ß-catenin pathway.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína HMGB2/metabolismo , Melanoma/metabolismo , MicroARNs/metabolismo , Neoplasias Cutáneas/metabolismo , beta Catenina/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptosis , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/genética , Proteína HMGB2/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patología , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Vimentina/genética , Vimentina/metabolismo , beta Catenina/genéticaRESUMEN
Cervical cancer is one of the leading killers for female worldwide. Nevertheless, the less knowledge of molecular mechanism for cervical cancer limited the improvement of treatment effects. High-mobility group box 2 (HMGB2) belongs to the HMGB family, which could play diverse roles in cell proliferation. This work mainly aimed to study the functions of HMGB2 on cervical cancer cells proliferation. HMGB2 was highly expressed in cervical cancer tissue. The results of real-time polymerase chain reaction and Western blot analysis showed that HMGB2 was expressed in all the five cervical cancer cells (HeLa, CaSki, SiHa, C-33A, and C4-1 cells). In addition, HMGB2 overexpression obviously improved cell viability and promoted cell cycle progression, which suggested that HMGB2 could promote proliferation of cervical cancer cells. Moreover, HMGB2 overexpression increased the level of p-AKT and reduced the levels of p21 and p27. However, HMGB2 downregulation had contrary influences on cell proliferation, cell cycle distribution and the levels of p-AKT, p21, and p27. Notably, LY294002, as an inhibitor of AKT signaling pathway, could significantly weaken the effects of HMGB2 overexpression, which indicated that HMGB2 might promote cell proliferation by activating AKT signaling pathway. Therefore, HMGB2 was hopeful to be a candidate as a new biomarker and therapy target for cervical cancer.