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The transforming growth factor-ß (TGF-ß) signaling pathway is pivotal in inducing epithelial-mesenchymal transition (EMT) and promoting cancer metastasis. Long non-coding RNAs (lncRNAs) have emerged as significant players in these processes, yet their precise mechanisms remain elusive. Here, we demonstrate that TGF-ß-upregulated lncRNA 1 (TBUR1) is significantly activated by TGF-ß via Smad3/4 signaling in lung adenocarcinoma (LUAD) cells. Functionally, TBUR1 triggers EMT, enhances LUAD cell migration and invasion in vitro, and promotes metastasis in nude mice. Mechanistically, TBUR1 interacts with heterogeneous nuclear ribonucleoproteins C (hnRNPC) to stabilize GRB2 mRNA in an m6A-dependent manner. Clinically, TBUR1 is upregulated in LUAD tissues and correlates with poor prognosis, highlighting its potential as a prognostic biomarker and therapeutic target for LUAD. Taken together, our findings underscore the crucial role of TBUR1 in mediating TGF-ß-induced EMT and metastasis in LUAD, providing insights for future therapeutic interventions.
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Acute kidney injury (AKI) stands as a prevalent and economically burdensome condition worldwide, yet its complex molecular mechanisms remain incompletely understood. To address this gap, our study employs a multifaceted approach, combining mass spectrometry and RNA sequencing technologies, to elucidate the intricate molecular landscape underlying nephrotoxin-induced AKI in mice by cisplatin- and LPS-induced. By examining the protein and RNA expression profiles, we aimed to uncover novel insights into the pathogenesis of AKI and identify potential diagnostic and therapeutic targets. Our results demonstrate significant down-regulation of Slc34a1 and Slc34a3, shedding light on their crucial roles in AKI pathology and highlighting their promise as actionable targets for diagnosis and treatment. This comprehensive analysis not only enhances our understanding of AKI pathophysiology but also offers valuable avenues for the development of targeted interventions to mitigate its clinical impact. SIGNIFICANCE: Nephrotoxicity acute kidney injury (AKI) is a common clinical condition whose pathogenesis is the process by which some drugs, chemicals or other factors cause damage to the kidneys, resulting in impaired kidney function. Although it has been proved that different nephrotoxic substances can affect the kidney through different pathways, whether they have a commonality has not been registered. Here, we combined transcriptomics and proteomics to study the molecular mechanism of LPS and cisplatin-induced nephrotoxic acute kidney injury finding that the down-regulation of Slc34a1 and Slc34a3 may be a critical link in nephrotoxic acute kidney injury, which can be used as a marker for its early diagnosis.
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Lesión Renal Aguda , Cisplatino , Regulación hacia Abajo , Proteómica , Transcriptoma , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Animales , Ratones , Proteómica/métodos , Cisplatino/efectos adversos , Cisplatino/toxicidad , Lipopolisacáridos/toxicidad , Masculino , Perfilación de la Expresión GénicaRESUMEN
OBJECTIVE: The purpose of this study was to investigate the learning curve of percutaneous endoscopic transforaminal discectomy (PETD) and interlaminar unilateral biportal endoscopic discectomy (UBED) in the treatment of lumbar disc herniation (LDH). METHODS: Between 2018 and 2023, 120 consecutive patients with lumbar disc herniation (LDH) treated by endoscopic lumbar discectomy were retrospectively included. The PETD group comprised 87 cases, and the UBED group comprised 33 cases. Cumulative sum analysis was used to evaluate the learning curve, with the occurrence of complications or unresolved symptoms defined as surgical failure, and variables of different phases of the learning curve being compared. RESULTS: The learning curve analysis identified the cutoff point at 40 cases in the PETD group and 15 cases in the UBED group. In the mastery phase, both PETD and UBED demonstrated a significant reduction in operation times (approximately 38 min for PTED and 49 min for UBED). In both PETD and UBED groups, the surgical failure rates during the learning and mastery phases showed no statistically significant differences. The visual analogue scale at the last follow-up was significantly lower than before surgery in both the PETD and UBED groups. CONCLUSION: PETD and UBED surgery are effective in the treatment of LDH with a low incidence of complications. However, achieving mastery in PETD necessitates a learning curve of 40 cases, while UBED requires a minimum of 15 cases to reach proficiency.
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Discectomía Percutánea , Endoscopía , Desplazamiento del Disco Intervertebral , Curva de Aprendizaje , Vértebras Lumbares , Humanos , Desplazamiento del Disco Intervertebral/cirugía , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Discectomía Percutánea/métodos , Discectomía Percutánea/educación , Masculino , Femenino , Persona de Mediana Edad , Vértebras Lumbares/cirugía , Vértebras Lumbares/diagnóstico por imagen , Adulto , Endoscopía/métodos , Endoscopía/educación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: This study aimed to evaluate the relationship between LINC00665 expression levels and the risk of hepatocellular carcinoma (HCC) in Chinese Han nationality patients and to explore the influence of LINC00665 dysregulation on the proliferation and migration potential of HCC cells. PATIENTS AND METHODS: We investigated the expression of LINC00665 in The Cancer Genome Atlas (TCGA) database. Then, we confirmed the expression of LINC00665 in 54 pairs of surgical tissues from HCC patients and in liver cancer cell lines by quantitative real-time polymerase chain reaction. Furthermore, we manipulated the expression level of LINC00665 and examined the cell proliferation and migration abilities of HCC cells. RESULTS: In the TCGA cohort, a high level of LINC00665 in patients with HCC was significantly associated with tumor stage, tumor differentiation grade, and overall survival. In our HCC patient cohort, overexpression of LINC00665 in patients showed positive correlations with alpha-fetoprotein level, Barcelona Clinic Liver Cancer stage, and tumor differentiation grade. In addition, LINC00665 was upregulated in HCC cells, especially in cells with rapid growth rates and high migration abilities. A new LINC00665 isoform with a length of 1,371 nucleotides was identified in MHCC-97H cells. Interfering with LINC00665 expression weakened the proliferation and migration abilities of HCC cells. In contrast, LINC00665 overexpression enhanced proliferation and migration abilities. CONCLUSION: LINC00665 was upregulated in HCC tissues and cells and might be used to predict a poor prognosis of HCC patients. In addition, LINC00665 may promote the malignant progression of HCC by enhancing proliferation and migration capacities.
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BACKGROUND: The purpose of the present study was to evaluate changes in pulmonary function, caused by preoperative halo-pelvic traction (HPT) for the treatment of extremely severe and rigid kyphoscoliosis, with use of 3-dimensional computed tomography (3D-CT) reconstruction and pulmonary function tests (PFTs). METHODS: Twenty-eight patients with severe and rigid scoliosis (Cobb angle, >100°) underwent preoperative HPT and staged posterior spinal fusion. CT, radiographic assessment, and PFT were performed during pre-traction and post-traction visits. The changes in total lung volume were evaluated with use of 3D-CT reconstruction, and the changes in pulmonary function were evaluated with PFTs at each time point. Differences were analyzed with use of 2-tailed paired Student t tests, and correlations were analyzed with use of Spearman rank tests. RESULTS: None of the patients had pulmonary complications during traction, and all radiographic spinal measurements improved significantly after HPT. The main Cobb angle was corrected from 143.30° ± 20.85° to 62.97° ± 10.83° between the pre-traction and post-traction evaluations. Additionally, the C7-S1 distance was lengthened from 280.48 ± 39.99 to 421.26 ± 32.08 mm between the pre-traction and post-traction evaluations. Furthermore, 3D lung reconstruction demonstrated a notable increase in total lung volume (TLV) (from 1.30 ± 0.25 to 1.83 ± 0.37 L) and maximum lung height (from 176.96 ± 27.44 to 202.31 ± 32.45 mm) between the pre-traction and post-traction evaluations. Moreover, PFTs showed that total lung capacity (TLC) improved between the pre-traction and post-traction evaluations (from 2.06 ± 0.32 to 2.98 ± 0.82 L) and that the changes in T1-T12 distance and maximum lung height were correlated with changes in TLV (p = 0.0288 and p = 0.0007, respectively). CONCLUSIONS: The application of HPT is a safe and effective method for improving pulmonary function in patients with extremely severe and rigid scoliosis before fusion surgery. The TLV as measured with CT-based reconstruction was greatly increased after HPT, mainly because of the changes in thoracic height. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.
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Cifosis , Escoliosis , Fusión Vertebral , Humanos , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Tracción/métodos , Imagenología Tridimensional , Estudios Retrospectivos , Resultado del Tratamiento , Cifosis/diagnóstico por imagen , Cifosis/cirugía , Cifosis/complicaciones , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X/efectos adversos , Fusión Vertebral/métodosRESUMEN
BACKGROUND: The incidence of mechanical complications is high in patients undergoing posterior spinal fusion (PSF) for adult spinal deformity (ASD), especially for cases with severe sagittal malalignment or a prior spinal fusion requiring three-column osteotomy (3-CO) or spinopelvic fixation (SPF). The purpose of this systematic review and meta-analysis was to compare the complications, revisions, radiographic spinopelvic parameters, health-related quality of life (HRQoL), and surgical data of PSF using multiple-rod constructs to those of two-rod constructs for the treatment of ASD. METHODS: A comprehensive literature search was performed for relevant studies in PubMed, EMBASE, Web of Science, and the Cochrane Library. Complications, revisions, spinopelvic parameters, HRQoL, and surgical date were compared between patients with ASD who underwent PSF using multiple-rod constructs (multi-rod group) and two-rod constructs (two-rod group). RESULTS: Ten studies, comprising 797 patients with ASD (399 in the multi-rod group and 398 in the two-rod group), were included. All these studies were retrospective cohort studies. There were no significant differences in the surgical, wound-related, and systemic complications between the groups. In the multi-rod group, we noted a significantly lower incidence of rod fracture (RR, 0.43; 95% CI 0.33 to 0.57, P < 0.01), pseudoarthrosis (RR, 0.38; 95% CI 0.28 to 0.53, P < 0.01), and revisions (RR, 0.44; 95% CI 0.33 to 0.58, P < 0.01); a superior restoration of PI-LL (WMD, 3.96; 95% CI 1.03 to 6.88, P < 0.01) and SVA (WMD, 31.53; 95% CI 21.16 to 41.90, P < 0.01); a better improvement of ODI score (WMD, 6.82; 95% CI 2.33 to 11.31, P < 0.01), SRS-22 total score (WMD, 0.44; 95% CI 0.06 to 0.83, P = 0.02), and VAS-BP score (WMD, 1.02; 95% CI 0.31 to 1.73, P < 0.01). CONCLUSION: Compared with the two-rod constructs, PSF using multiple-rod constructs was associated with a lower incidence of mechanical complications, a lower revision rate, a superior restoration of sagittal alignment, and a better improvement of HRQoL, without increasing surgical invasiveness. Multiple-rod constructs should be routinely considered to for ASD patients, especially for cases with severe sagittal malalignment or a prior spinal fusion requiring 3-CO or SPF.
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Fusión Vertebral , Procedimientos Quirúrgicos Torácicos , Humanos , Adulto , Estudios Retrospectivos , Fusión Vertebral/efectos adversos , Calidad de Vida , Columna VertebralRESUMEN
Background: This study aimed to confirm the role of paraspinal muscle degeneration and low vertebral bone mineral density (vBMD) of the lumbosacral region in the development of distal instrumentation-related problems (DIPs) in degenerative lumbar scoliosis (DLS) patients undergoing long-instrumented spinal fusion. Methods: From 2013 to 2019, 125 DLS patients with 24-month follow-up after long-instrumented spinal fusion in Beijing Chao-Yang Hospital were retrospectively recruited and divided into DIP and non-DIP groups. Demographic characteristics, surgical data, and radiographic parameters were statistically compared between the groups. Degeneration of the paraspinal muscle was evaluated using the relative gross cross-sectional area (rGCSA), relative functional cross-sectional area (rFCSA), ratio of the rFCSA to rGCSA, gross muscle-fat index, and functional muscle-fat index of the multifidus (MF), erector spinae (ES), paraspinal extensor muscle (PSE), and psoas major determined by preoperative magnetic resonance imaging (MRI). The vBMD of the lumbosacral region and lower instrumented vertebra (LIV) was assessed using Hounsfield unit (HU) values determined by computed tomography (CT) scans. The DeLong test was performed to select MRI and CT scan variables. Multivariable logistic regression analysis was applied to determine the independent predictive factors of DIPs. Results: The incidence of DIPs was 16.0% (20/105). There were no significant differences in demographic characteristics or surgical data between the groups. The rFCSAs of the MF (65.74±21.51 vs. 92.37±21.68; P<0.001), ES (82.67±21.44 vs. 111.48±24.21; P<0.001) and PSE (144.31±36.12 vs. 208.48±41.57; P<0.001) and the HU values of the lumbosacral region (103.80±22.64 vs.. 132.19±19.17; P<0.001) and LIV (111.70±23.23 vs. 128.69±20.70; P=0.005) were significantly lower in the DIP group. Significantly less preoperative pelvic tilt and greater postoperative lumbosacral lordosis and sagittal vertical axis (SVA) values were observed in the DIP group. The rFCSA of the PSE, the HU value of the lumbosacral region, and the postoperative SVA value were detected as independent predictive factors of DIPs. Conclusions: Lower muscularity of the PSE, a lower vBMD of the lumbosacral region, and postoperative sagittal malalignment were independent predictive factors of DIPs. Surgeons should emphasize the preoperative evaluation of paraspinal muscle and bone mass in DLS patients.
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Lipid droplets (LDs) are multifunctional organelles consisting of a central compartment of non-polar lipids shielded from the cytoplasm by a phospholipid monolayer. The excessive accumulation of LDs in cells is closely related to the development and progression of many diseases in humans and animals, such as liver-related and cardiovascular diseases. Thus, regulating the LDs size and abundance is necessary to maintain metabolic homeostasis. This study found that lipopolysaccharide (LPS) stimulation reduced the LDs content in the mouse liver. We tried to explain the possible molecular mechanisms at the broad protein and mRNA levels, finding that inhibition of the peroxisome proliferator-activated receptors (PPAR) signalling pathway by LPS may be a critical factor in reducing LDs content.
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Lipopolisacáridos , Receptores Activados del Proliferador del Peroxisoma , Humanos , Animales , Ratones , Lipopolisacáridos/farmacología , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Gotas Lipídicas/metabolismo , Transcriptoma , Proteómica , Hígado/metabolismo , Metabolismo de los Lípidos/fisiologíaRESUMEN
BACKGROUND: Long non-coding RNA colon cancer-associated transcript 1 (CCAT1) is involved in transforming multiple cancers into malignant cancer types. Previous studies underlining the mechanisms of the functions of CCAT1 primarily focused on its decoy for miRNAs (micro RNAs). However, the regulatory mechanism of CCAT1-protein interaction associated with tumor metastasis is still largely unknown. The present study aimed to identify proteome-wide CCAT1 partners and explored the CCAT1-protein interaction mediated tumor metastasis. METHODS: CCAT1-proteins complexes were purified and identified using RNA antisense purification coupled with the mass spectrometry (RAP-MS) method. The database for annotation, visualization, and integrated discovery and database for eukaryotic RNA binding proteins (EuRBPDB) websites were used to bioinformatic analyzing CCAT1 binding proteins. RNA pull-down and RNA immunoprecipitation were used to validate CCAT1-Vimentin interaction. Transwell assay was used to evaluate the migration and invasion abilities of HeLa cells. RESULTS: RAP-MS method worked well by culturing cells with nucleoside analog 4-thiouridine, and cross-linking was performed using 365 nm wavelength ultraviolet. There were 631 proteins identified, out of which about 60% were RNA binding proteins recorded by the EuRBPDB database. Vimentin was one of the CCAT1 binding proteins and participated in the tumor metastasis pathway. Knocked down vimetin ( VIM ) and rescued the downregulation by overexpressing CCAT1 demonstrated that CCAT1 could enhance tumor migration and invasion abilities by stabilizing Vimentin protein. CONCLUSION: CCAT1 may bind with and stabilize Vimentin protein, thus enhancing cancer cell migration and invasion abilities.
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Neoplasias del Colon , MicroARNs , ARN Largo no Codificante , Humanos , Células HeLa , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Vimentina/genética , Vimentina/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Colon/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Movimiento Celular/genéticaRESUMEN
Intervertebral disc degeneration (IDD) is a major contributor to back, neck, and radicular pain. It is related to changes in tissue structure and function, including the breakdown of the extracellular matrix (ECM), aging, apoptosis of the nucleus pulposus, and biomechanical tissue impairment. Recently, an increasing number of studies have demonstrated that inflammatory mediators play a crucial role in IDD, and they are being explored as potential treatment targets for IDD and associated disorders. For example, interleukins (IL), tumour necrosis factor-α (TNF-α), chemokines, and inflammasomes have all been linked to the pathophysiology of IDD. These inflammatory mediators are found in high concentrations in intervertebral disc (IVD) tissues and cells and are associated with the severity of LBP and IDD. It is feasible to reduce the production of these proinflammatory mediators and develop a novel therapy for IDD, which will be a hotspot of future research. In this review, the effects of inflammatory mediators in IDD were described.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Degeneración del Disco Intervertebral/metabolismo , Mediadores de Inflamación/metabolismo , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Núcleo Pulposo/metabolismoRESUMEN
BACKGROUND: CDK4/6 inhibitors combined with endocrine therapy has become the preferred treatment approach for patients with estrogen receptor-positive metastatic breast cancer. However, the predictive biomarkers and mechanisms of innate resistance to CDK4/6 inhibitors remain largely unknown. We sought to elucidate the molecular hallmarks and therapeutically actionable features of patients with resistance to CDK4/6 inhibitors. METHODS: A total of 36 patients received palbociclib and endocrine therapy were included in this study as the discovery cohort. Next-generation sequencing of circulating tumour DNA in these patients was performed to evaluate somatic alterations associated with innate resistance to palbociclib. Then the candidate biomarker was validated in another independent cohort of 104 patients and publicly available datasets. The resistance was verified in parental MCF-7 and T47D cells, as well as their derivatives with small interfering RNA transfection and lentivirus infection. The relevant mechanism was examined by RNA sequencing, chromatin immunoprecipitation and luciferase assay. Patient-derived organoid and patient-derived xenografts studies were utilized to evaluated the antitumor activity of rational combinations. RESULTS: In the discovery cohort, S6K1 amplification (3/35, 9%) was identified as an important reason for innate resistance to CDK4/6 inhibitors. In the independent cohort, S6K1 was overexpressed in 15/104 (14%) patients. In those who had received palbociclib treatment, patients with high-expressed S6K1 had significantly worse progression free survival than those with low S6K1 expression (hazard ratio = 3.0, P = 0.0072). Meta-analysis of public data revealed that patients with S6K1 amplification accounted for 12% of breast cancers. Breast cancer patients with high S6K1 expression had significantly worse relapse-free survival (hazard ratio = 1.31, P < 0.0001). In breast cancer cells, S6K1 overexpression, caused by gene amplification, was sufficient to promote resistance to palbociclib. Mechanistically, S6K1 overexpression increased the expression levels of G1/S transition-related proteins and the phosphorylation of Rb, mainly through the activation of c-Myc pathway. Notably, this resistance could be abrogated by the addition of mTOR inhibitor, which blocked the upstream of S6K1, in vitro and in vivo. CONCLUSIONS: S6K1 amplification is an important mechanism of innate resistance to palbociclib in breast cancers. Breast cancers with S6K1 amplification could be considered for combinations of CDK4/6 and S6K1 antagonists.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas , Proteínas Quinasas S6 Ribosómicas 70-kDa , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , ADN Tumoral Circulante , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc , Receptores de Estrógenos/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/genéticaRESUMEN
Purpose: Colorectal cancer (CRC) is among the most common cancers worldwide and an important cause of cancer-related death. Inherited genetic variation plays a vital role in the occurrence and development of CRC. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in MMP2 with CRC risk. Patients and Methods: Three candidates, MMP2 SNPs, rs1053605, rs243849, and rs14070, were selected and genotyped using the Agena MassARRAY RS1000 system, and their association with risk of CRC was evaluated in 663 CRC cases and 663 healthy controls by calculating odds ratio (OR) with 95% confidence interval (95% CI) values. Results: The minor allele of rs243849 (T) was significantly less frequent in cases than controls (p = 0.021), and this SNP was associated with a decreased risk of CRC under co-dominant (p = 0.033), dominant (p = 0.021), and log-additive (p = 0.017) models, after adjusting for confounding factors. After stratification, rs243849 was found to be protective against CRC in patients who were non-smoking, consumed alcohol, and were ≥60 years old (p < 0.05). Conversely, rs1053605 was associated with disease occurrence in patients with CRC who consumed alcohol and were <60 years old (p < 0.05). Furthermore, rs1053605 genotype was associated with an increased risk of colon cancer (p < 0.05), while that of rs243849 was associated with a decreased risk of rectal cancer (p < 0.05). The rs1053605-rs243849 CT haplotype exhibited a protective role in CRC risk, following adjustment for confounders (p = 0.014). The rs14070 SNP was not associated with CRC risk. Finally, the false discovery rate (FDR) method was used to validate the study results. Conclusion: Overall, the MMP2 gene polymorphisms, rs243849 and rs1053605, may be useful for predicting CRC progression.
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As a pathogenic microorganism, Listeria monocytogenes is widely used in the research of bacterial pathogenesis and host defense. The phagosomal escape of L. monocytogenes is essential for its replication in the cytoplasm of the host. Here, we reported that the protein abundance of the Six-transmembrane epithelial antigen of the prostate 3 (Steap3) was decreased upon L. monocytogenes infection compared to uninfected cells in macrophages. However, the decreased Steap3 abundance was not regulated by the host but was caused by LLO secreted by L. monocytogenes. Functional experiments showed that deletion of Steap3 facilitated entry of L. monocytogenes from the phagosome into the cytoplasm. Then, the comprehensive proteomic analysis revealed that the deletion of Steap3 could affect the proteins abundance of the lysosomal signaling pathway in macrophages. Among these proteins affected by Steap3, we discovered that only the Ganglioside GM2 activator (Gm2a) inhibited the phagosomal escape of L. monocytogenes as Steap3. In summary, we found that the Steap3-Gm2a axis could restrict the phagosomal escape of L. monocytogenes and serve the potential molecular drug targets for antibacterial treatment.
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Toxinas Bacterianas , Listeria monocytogenes , Listeriosis , Masculino , Humanos , Listeriosis/microbiología , Gangliósido G(M2)/metabolismo , Proteínas Hemolisinas/metabolismo , Gangliósidos/metabolismo , Proteómica , Toxinas Bacterianas/metabolismo , Proteínas de Choque Térmico/metabolismo , Fagosomas/microbiologíaRESUMEN
NIMA-related kinase 7 (NEK7) is a serine/threonine kinase involved in cell cycle progression via mitotic spindle formation and cytokinesis. It has been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer, and colorectal cancer. Moreover, NEK7 regulated the NLRP3 inflammasome to activate Caspase-1, resulting in cell pyroptosis. In the present study, we investigated whether NEK7 is involved in cell pyroptosis of hepatocellular carcinoma (HCC). Interestingly, we found that NEK7 was significantly related to expression of pyroptosis marker GSDMD in HCC. We found that NEK7 expression was significantly correlated with GSDMD expression in bioinformatics analysis, and NEK7 expression was significantly co-expressed with GSDMD in our HCC specimens. Cell viability, migration, and invasion capacity of HCC cell lines were inhibited, and the tumor growth in the xenograft mouse model was also suppressed following knockdown of NEK7 expression. Mechanistic studies revealed that knockdown of NEK7 in HCC cells significantly upregulated the expression of pyroptosis markers such as NLRP3, Caspase-1, and GSDMD. Coculture of HCC cells stimulated hepatic stellate cell activation by increasing p-ERK1/2 and α-SMA. Knockdown of NEK7 impaired the stimulation of HCC cells. Therefore, downregulation of NEK7 inhibited cancer-stromal interaction by triggering cancer cell pyroptosis. Taken together, this study highlights the functional role of NEK7-regulated pyroptosis in tumor progression and cancer-stromal interaction of HCC, suggesting NEK7 as a potential target for a new therapeutic strategy of HCC treatment.
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Transforming growth factor-ß (TGF-ß) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-ß signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-ß and AKT signaling pathways during breast cancer progression.
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Neoplasias de la Mama/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Núcleo Celular/metabolismo , Femenino , Humanos , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Fosforilación , Pronóstico , Estabilidad Proteica , Transducción de Señal , Ubiquitina-Proteína Ligasas/genética , Pez CebraRESUMEN
The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is still dismal. Elucidation of associated genomic alteration may provide effective therapeutic strategies for PDAC treatment. NIMA-related protein kinase 7 is widely expressed in various tumors, including breast cancer, colorectal cancer and lung cancer, and promotes the proliferation of liver cancer cells in vitro and in vivo. We investigated the protein expression level of NEK7 in tumor tissues and adjacent normal tissues using immunohistochemistry of 90 patients with PADC. Meanwhile, the RNA expression level of NEK7 was examined using database-based bioinformatic analysis. Correlation and significance of NEK7 expression with patient clinicopathological features and prognosis were examined. Cell proliferation, cell adhesion, migration and invasion capabilities were measured following downregulation of NEK7 expression. 3D tumor organoids of pancreatic cancer were established and splenic xenografted into nude mice, then liver metastatic ability of NEK7 was evaluated in following 4 weeks. We observed NEK7 expression was upregulated in tumor tissues compared to normal tissues at both RNA and protein levels using bioinformatic analysis and immunohistochemistry analysis in PDAC. NEK7 expression was undetectable in normal pancreatic ducts; NEK7 was overexpressed in primary tumor of PDAC; NEK7 expression was highly correlated with advanced T stage, poorly differentiated histological grade invasive ductal carcinoma, and lymphatic invasion. Meanwhile, patients with higher NEK7 expression accompanied by worse survival outcome. Moreover, NEK7 promoted migration, invasion, adhesion, proliferation and liver metastatic ability of pancreatic cancer cells. Taken together, our data indicate that NEK7 promotes pancreatic cancer progression and it may be a potential marker for PDAC prognosis.
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Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.
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Autophagy is the main degradation pathway to eliminate long-lived and aggregated proteins, aged or malfunctioning organelles, which is essential for the intracellular homeostasis and prevention of malignant transformation. Although the processes of autophagosome biogenesis have been well illuminated, the mechanism of autophagosome transport remains largely unclear. In this study, we demonstrated that the ninein-like protein (Nlp), a well-characterized centrosomal associated protein, was able to modulate autophagosome transport and facilitate autophagy. During autophagy, Nlp colocalized with autophagosomes and physically interacted with autophagosome marker LC3, autophagosome sorting protein Rab7 and its downstream effector FYCO1. Interestingly, Nlp enhanced the interaction between Rab7 and FYCO1, thus accelerated autophagic flux and the formation of autophagolysosomes. Furthermore, compared to the wild-type mice, NLP deficient mice treated with chemical agent DMBA were prone to increased incidence of hepatomegaly and liver cancer, which were tight associated with the hepatic autophagic defect. Taken together, our findings provide a new insight for the first time that the well-known centrosomal protein Nlp is also a new regulator of autophagy, which promotes the interaction of Rab7 and FYCO1 and facilitates the formation of autophagolysosome.
Asunto(s)
Autofagia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Nucleares/genética , Proteínas de Unión a GTP rab7/genética , Animales , Antracenos/farmacología , Autofagosomas/genética , Centrosoma/metabolismo , Hepatomegalia/genética , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Ratones , Piperidinas/farmacologíaRESUMEN
Macrophages are sentinels in the organism which can resist and destroy various bacteria through direct phagocytosis. Here, we reported that expression level of mitochondrial ribosomal protein S35 (Mrps35) continued to decrease over infection time after Listeria monocytogenes (L. monocytogenes) infected macrophages. Our results indicated that knockdown Mrps35 increased the load of L. monocytogenes in macrophages. This result supported that Mrps35 played the crucial roles in L. monocytogenes infection. Moreover, we performed the comprehensive proteomics to analyze the differentially expressed protein of wild type and Mrps35 Knockdown Raw264.7 cells by L. monocytogenes infection over 6 h. Based on the results of mass spectrometry, we presented a wide variety of hypotheses about the mechanism of Mrps35 controlling the L. monocytogenes intracellular proliferation. Among them, experiments confirmed that Mrps35 and 60S ribosomal protein L22-like 1 (Rpl22l1) were a functional correlation or potentially a compensatory mechanism during L. monocytogenes infection. This study provided new insights into understanding that L. monocytogenes infection changed the basic synthesis or metabolism-related proteins of host cells.