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RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.
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Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Humanos , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Proteínas/genética , Neoplasias Colorretais/patologia , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Proliferação de Células , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismoRESUMO
BACKGROUND: Determining the origin of bone metastatic cancer (OBMC) is of great significance to clinical therapeutics. It is challenging for pathologists to determine the OBMC with limited clinical information and bone biopsy. METHODS: We designed a regional multiple-instance learning algorithm to predict the OBMC based on hematoxylin-eosin (H&E) staining slides alone. We collected 1041 cases from eight different hospitals and labeled 26,431 regions of interest to train the model. The performance of the model was assessed by ten-fold cross validation and external validation. Under the guidance of top3 predictions, we conducted an IHC test on 175 cases of unknown origins to compare the consistency of the results predicted by the model and indicated by the IHC markers. We also applied the model to identify whether there was tumor or not in a region, as well as distinguishing squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumor. FINDINGS: In the within-cohort, our model achieved a top1-accuracy of 91.35% and a top3-accuracy of 97.75%. In the external cohort, our model displayed a good generalizability with a top3-accuracy of 97.44%. The top1 consistency between the results of the model and the immunohistochemistry markers was 83.90% and the top3 consistency was 94.33%. The model obtained an accuracy of 98.98% to identify whether there was tumor or not and an accuracy of 93.85% to differentiate three types of cancers. INTERPRETATION: Our model demonstrated good performance to predict the OBMC from routine histology and had great potential for assisting pathologists with determining the OBMC accurately. FUNDING: National Science Foundation of China (61875102 and 61975089), Natural Science Foundation of Guangdong province (2021A15-15012379 and 2022A1515 012550), Science and Technology Research Program of Shenzhen City (JCYJ20200109110606054 and WDZC20200821141349001), and Tsinghua University Spring Breeze Fund (2020Z99CFZ023).
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Adenocarcinoma , Neoplasias Ósseas , Carcinoma de Células Escamosas , Aprendizado Profundo , Humanos , Algoritmos , Neoplasias Ósseas/diagnósticoRESUMO
Background: Camptocormia is a postural deformity that is characterized by a markedly flexed lumbar spine, with symptoms that worsen with walking and standing. Here, we report a case of camptocormia associated with Parkinson's disease. Case description: A 70-year-old man with a 7-year history of Parkinson's disease presented with a fall injury that caused lower back pain for 3 months and was aggravated for 2 months. He had been diagnosed with a compression fracture after the fall and had undergone percutaneous kyphoplasty at a local hospital. MRI showed non-union of the L1 vertebra and compression fracture of L2. The patient underwent posterior osteotomy, canal decompression, and internal fixation of the T10-L3 intervertebral plate with bone graft fusion. Postoperative examination showed that the lumbar lordosis was corrected and sensation was restored in both lower extremities. However, after 1 month, the fixation was loosened and a correction surgery was performed at our hospital. At the most recent follow-up at 1.5 years, the patient was found to be in good general health and did not complain of lower back discomfort. He was also actively exercising according to the rehabilitation regimen and had resumed social life. Conclusion: This is a rare case of camptocormia in a Parkinson's patient that highlights the need for careful evaluation of whether internal spinal fixation surgery is beneficial in such patients.
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AIMS: Vascular tumors are composed of benign, intermediate, and malignant lesions. The diagnosis is challenging because some entities demonstrate overlapping morphologies and harbor the same genetic alterations. We describe herein a cohort of vascular tumors with clinicopathologic, immunohistochemical, and molecular features. METHODS AND RESULTS: 118 vascular tumors including 56 angiosarcomas, 18 epithelioid haemangioendotheliomas (EHE), 25 epithelioid haemangiomas (EH), 8 pseudomyogenic haemangioendotheliomas (PHE), 1 papillary intralymphatic angioendothelioma (PILA), 2 kaposiform haemangioendotheliomas (KHE), 3 Kaposi sarcomas, 2 retiform haemangioendotheliomas (RHE), and 3 anastomosing haemangiomas were assessed. FOSB, c-Fos, CAMTA1, and TFE3 expression and gene rearrangements were analyzed by immunohistochemical staining and FISH, respectively. Our results showed that FOSB expression was diffusely positive in all 8 PHEs, focally or sparsely in 12 EHs, and in 2 angiosarcomas. C-FOS expression was sparsely to diffusely positive in 15 EHs, focally or sparsely in 17 angiosarcomas, 1 EHE, 1 Kaposi sarcoma, and 1 PHE. CAMTA1 expression was positive in only 12 EHEs. TFE3 expression was focally or sparsely positive in all 8 PHEs, 22 angiosarcomas, 6 EHEs, 3 EHs, 2 Kaposi sarcomas, and 2 AHs. FOSB rearrangement was found in 5 PHEs, FOS rearrangement only in 1 EH, CAMTA1 rearrangement in 4 EHEs. CONCLUSIONS: FOSB and CAMTA1 are useful diagnostic markers for PHE and EHE, respectively. FOSB and FOS fusion represent a subset of epithelioid haemangioma. TFE3 is not a diagnostically meaningful marker in a majority of vascular tumors. The combined utility of these markers will facilitate the differential diagnosis in vascular tumors with morphologic overlap.
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(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6−p47phox oxidative−stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber−DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6−p47phox oxidative−stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6−p47phox downregulated.
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Dislipidemias , Interleucina-6 , Hepatopatias Alcoólicas , NADPH Oxidases , Estresse Oxidativo , Condicionamento Físico Animal , Animais , Peso Corporal , Interleucina-6/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismoRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.
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Lúpus Eritematoso Sistêmico/metabolismo , Receptor de TWEAK/metabolismo , Animais , Apoptose , Autoimunidade , Fibrose , Humanos , Camundongos , Fatores de Necrose Tumoral/metabolismoRESUMO
Parkin (Park2), a RING-between-RING-type E3 ubiquitin ligase, has been implicated in regulating NF-κB. Mutations in Parkin are associated with Parkinson's disease. Here we investigated the interaction of Parkin with Receptor-interacting protein kinase 1 (RIPK1) kinase, a key mediator of multiple signaling pathways activated by TNFR1 including NF-κB pathway. We report that Parkin interacts with RIPK1 and mediates K63 ubiquitination of RIPK1 on K376 in TNFR1-signaling pathway. The expression of Parkin promotes the recruitment of transforming growth factor ß (TGF-ß)-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB) essential molecule (NEMO), Sharpin and A20 in complex I associated with TNFR1 upon TNFα stimulation. Ubiquitination of RIPK1 by Parkin increases the activation of NF-κB and mitogen-activated protein kinases (MAPKs) by promoting the phosphorylation of inhibitor of kappa B kinase (IKK)α/ß and IκBα and nuclear translocation of p65. Thus, we conclude that Parkin modulates the K63 ubiquitination status of RIPK1 to promote the activation of NF-κB and MAPKs.
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NF-kappa B/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Lisina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Biológicos , Domínios Proteicos , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression. CNF1 also promoted pulmonary metastasis in a xenograft mouse model through these mechanisms. PAK1 phosphorylation correlated with advanced grades of PCa in human clinical PCa tissues. These results suggest that CNF1 derived from UPEC plays an important role in PCa progression through activating a Cdc42-PAK1 signal axis and up-regulating the expression of MMP-9. Therefore, surveillance for and treatment of cnf1-carrying UPEC strains may diminish PCa progression and thus have an important clinical therapeutic impact. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Proteínas de Escherichia coli/fisiologia , Neoplasias da Próstata/etiologia , Animais , Toxinas Bacterianas , Movimento Celular , Progressão da Doença , Xenoenxertos , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Transplante de Neoplasias , Fosforilação/fisiologia , Neoplasias da Próstata/patologia , Regulação para Cima , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Targeting CD47 efficiently enhances macrophage phagocytosis in both physiological and pathological conditions. Anti-CD47 antibodies have been shown to inhibit the progression of several types of cancer. However, the mechanism of anti-CD47 monoclonal antibody (mAb) treatment remains controversial. In this study, we confirmed that CD47 protein is highly expressed in ovarian cancer, and is correlated with poor clinical characteristics and prognosis. CD47 knockdown in the ovarian cancer cell line, SK-OV-3, promoted phagocytosis by macrophages in vitro and inhibited tumor growth in vivo. These data combined suggest that CD47 inhibition is a potential strategy for cancer treatment. Using an anti-CD47 mAb, we found that CD47 inhibition in both SK-OV-3 cells and primary cancer cells was able to recapitulate our knockdown results and led to an increase in the number of infiltrating macrophages. In addition, the CD133+ tumor initiating cells expressed a high level of CD47, and anti-CD47 mAb treatment was able to trigger the phagocytosis of this cell population. In conclusion, our results indicate that CD47 inhibits macrophage phagocytosis of ovarian cancer cells, and down-regulation of CD47 or inhibiting CD47 by mAb was able to reverse the negative effect. Thus, CD47 antibody therapy may be a promising strategy to treat ovarian cancer.
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Antígeno CD47/metabolismo , Macrófagos/metabolismo , Neoplasias Ovarianas/patologia , Evasão Tumoral/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Protein poly ADP-ribosylation (PARylation) is a widespread post-translational modification at DNA lesions, which is catalyzed by poly(ADP-ribose) polymerases (PARPs). This modification regulates a number of biological processes including chromatin reorganization, DNA damage response (DDR), transcriptional regulation, apoptosis, and mitosis. PARP1, functioning as a DNA damage sensor, can be activated by DNA lesions, forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity. Here, we highlight molecular insights into PARylation recognition, the expanding role of PARylation in DDR pathways, and the functional interaction between PARylation and ubiquitination, which will offer us a better understanding of the biological roles of this unique post-translational modification.
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Dano ao DNA , Reparo do DNA , DNA/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Recombinação Homóloga , Humanos , Processamento de Proteína Pós-TraducionalRESUMO
Urinary tract infections (UTIs) are one of the most common bacterial infections in humans, causing cystitis, pyelonephritis, and renal failure. Uropathogenic Escherichia coli (UPEC) is the leading cause of UTIs. Accurate and rapid discrimination of UPEC lineages is useful for epidemiological surveillance. Fimbriae are necessary for the adherence of UPEC strains to host uroepithelia, and seem to be abundant and diverse in UPEC strains. By analyzing all the possible fimbrial operons in UPEC strains, we found that closely related strains had similar types of chaperone-usher fimbriae, and the diversity of fimbrial genes was higher than that of multilocus sequence typing (MLST) genes. A typing assay based on the polymorphism of four gene sequences (three fimbrial genes and one housekeeping gene) and the diversity of fimbriae present was developed. By comparison with the MLST, whole-genome sequence (WGS) and fumC/fimH typing methods, this was shown to be accurate and have high resolution, and it was also relatively inexpensive and easy to perform. The assay can supply more discriminatory information for UPEC lineages, and have the potential to be applied in epidemiological surveillance of UPEC isolates.
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Tyroserleutide (YSL) is an active, low-molecular-weight polypeptide with in vitro and in vivo anticancer effects on human hepatocellular carcinoma BEL-7402 cells. In this study, we studied the effects of YSL on PI3K/AKT in the BEL-7402 cells to explore its anti-tumor mechanism. Results showed that YSL could up-regulate the mRNA and protein expression of tumor suppressor PTEN and increase their activities, meanwhile inhibited the mRNA and protein expression of oncogene AKT and decreased the kinase activities of AKT and PDK1. The resuming balance effect of YSL between PTEN and AKT could prevent the transmission of tumor cell proliferation signals in the PI3K/AKT pathway. Inhibition of AKT would change the status of downstream effectors in the PI3K/AKT pathway: (1) inhibition of AKT up-regulated expression of cell cycle regulatory factors of downstream - P21 and P27 which repressed cell cycle and inhibited proliferation of tumor cells. (2) Inhibition of AKT decreased the phosphorylation level of MDM2, and then increased the protein level of P53 which would accelerate death proceeding of tumor cells. (3) Inactivation of AKT removed its inhibition effect on phosphorylation of Bad, which might decrease protein level of apoptosis inhibitor Bcl-2 and Bcl-XL, damaging mitochondria of tumor cells and inducing apoptosis.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Oligopeptídeos/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , RNA Mensageiro/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Synthetic hexaploid wheat (Triticum turgidumxAegilops tauschii) was created to explore for novel genes from T. turgidum and Ae. tauschii that can be used for common wheat improvement. In the present paper, research advances on the utilization of synthetic hexaploid wheat for wheat genetic improvement in China are reviewed. Over 200 synthetic hexaploid wheat (SHW) accessions from the International Maize and Wheat Improvement Centre (CIMMYT) were introduced into China since 1995. Four cultivars derived from these, Chuanmai 38, Chuanmai 42, Chuanmai 43 and Chuanmai 47, have been released in China. Of these, Chuanmai 42, with large kernels and resistance to stripe rust, had the highest average yield (>6 t/ha) among all cultivars over two years in Sichuan provincial yield trials, outyielding the commercial check cultivar Chuanmai 107 by 22.7%. Meanwhile, by either artificial chromosome doubling via colchicine treatment or spontaneous chromosome doubling via a union of unreduced gametes (2n) from T. turgidum-Ae. tauschii hybrids, new SHW lines were produced in China. Mitotic-like meiosis might be the cytological mechanism of spontaneous chromosome doubling. SHW lines with genes for spontaneous chromosome doubling may be useful for producing new SHW-alien amphidiploids and double haploid in wheat genetic improvement.