RESUMEN
Transmembrane serine proteases are a group of enzymes that are implicated in diverse biological processes. Transmembrane serine protease 11E (TMPRSS11E) is expressed in epithelial cells. Previous studies on TMPRSS11E mainly focused on its function in tumor progression. In this study, we investigated the association of TMPRSS11E with the inflammatory response. We found that TMPRSS11E levels were upregulated in the BAL fluid of patients with acute respiratory distress syndrome and LPS-stimulated cultured epithelial cells. In an LPS-induced acute lung injury mouse model and a cercal ligation and puncture-induced sepsis model, increased expression levels of TMPRSS11E were also observed in the lung tissues. Knockdown of TMPRSS11E suppressed the proinflammatory cytokine release and alleviated lung injury. In addition, increased TMPRSS11E expression was detected in lung tissues of poly(I:C)-challenged mice, and overexpression of TMPRSS11E aggregated the lung injury. Unexpectedly, ectopic TMPRSS11E expression in macrophages was observed. Protease-activated receptor-1 was proteolytically activated by TMPRSS11E and enhanced the levels of proinflammatory cytokines. Taken together, our results indicate that TMPRSS11E can be induced during inflammatory response triggered by infection. Therefore, interventions with TMPRSS11E can aid in the treatment of pulmonary inflammation.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Animales , Ratones , Lesión Pulmonar Aguda/patología , Citocinas/metabolismo , Inflamación/patología , Lipopolisacáridos/farmacología , Pulmón/patología , Poli I-C/farmacologíaRESUMEN
PAX5, a member of the paired box gene family of transcription factors, is a B-cell-specific activator protein that plays important roles during B lymphopoiesis. Two putative PAX5 binding sites in the human GINS1 promoter region were identified. EMSA, ChIP and luciferase assay showed that PAX5 functions as a positive transcription factor for GINS1 expression. Furthermore, coordinated expression of PAX5 and GINS1 was observed in mice B cells under physiological conditions and LPS stimulation situations. A similar pattern was also observed in human DLBCL cell lines under differentiation-inducing conditions. In addition, both PAX5 and GINS1 were highly expressed and significantly correlated in DLBCL specimens and cell lines. These findings suggested that dysregulation of PAX5 played an extremely important role in controlling the universal phenomenon of tumor progression through increased expression of GINS1 in DLBCL. In addition, circ1857 that was generated using back splicing of PAX5 pre-mRNA could further stabilize GINS1 mRNA, modulate GINS1 expression and promote lymphoma progression. To the best of our knowledge, this report is the first to demonstrate the role of GINS1 in DLBCL progression, and the mechanism of GINS1 upregulation using both circ1857 and PAX5 in DLBCL was revealed. Our results suggested that GINS1 may be a possible therapeutic target for DLBCL.
Asunto(s)
Factor de Transcripción PAX5 , Factores de Transcripción , Ratones , Animales , Humanos , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Factores de Transcripción/genética , Regulación de la Expresión Génica , Línea Celular , Proliferación Celular/genética , Proteínas de Unión al ADN/genéticaRESUMEN
TMPRSS11E was found to be upregulated in human nonsmall cell lung cancer samples (NSCLC) and cell lines, and high expression was associated with poor survival of NSCLC patients. The results of in vitro and in vivo experiments showed that overexpressing TMPRSS11E resulted in A549 cell proliferation and migration promotion, while the TMPRSS11E S372A mutant with the mutated catalytic domain lost the promoting function. In addition, in mouse xenograft models, silencing TMPRSS11E expression inhibited the growth of 95D cell-derived tumors. To explore the mechanism of marked upregulation of TMPRSS11E in NSCLC cells, promoter analysis, EMSA, and ChIP assays were performed. STAT3 was identified as the transcription factor responsible for TMPRSS11E transcription. Moreover, the purified recombinant TMPRSS11E catalytic domain exhibited enzymatic activity for the proteolytic cleavage of PAR2. Recombinant TMPRSS11E catalytic domain incubation further activated the PAR2-EGFR-STAT3 pathway. These findings established a mechanism of TMPRSS11E-PAR2-EGFR-STAT3 positive feedback, and the oncogenic role of TMPRSS11E as a PAR2 modulator in NSCLC was revealed.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Serina Proteasas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción STAT3/metabolismoRESUMEN
GINS1 is overexpressed in several types of cancers including leukemia and linked to poor outcomes. However, GINS1 remains poorly investigated in DLBCL (diffuse large B-cell lymphoma). This project aimed to explore the expression, functions and regulation of GINS1 in DLBCL. In this study, through analysis of clinical specimens from DLBCL patients, we uncovered that GINS1 was upregulated in DLBCL. By EMSA, ChIP and luciferase reporter assays, it was found that FOXP1 transcriptionally activated GINS1 expression by directly binding to the promoter region of the GINS1 gene. Western blotting and RT-PCR also revealed that GINS1 expression positively correlated with FOXP1 in human DLBCL specimens and cell lines. In an in vivo xenograft lymphoma mouse model, the FOXP1/GINS1 regulatory axis was also validated. Moreover, with CCK8 cell proliferation assays and colony formation assay, elevated GINS1 expression was found to be associated with doxorubicin resistance in lymphoma cells. Our findings showed that the FOXP1-GINS1 axis played a critical role in DLBCL development and doxorubicin resistance, and targeting the FOXP1-GINS1 axis could be a potential therapeutic approach for DLBCL treatment.
RESUMEN
Cardamine hupingshanensis (K. M. Liu, L. B. Chen, H. F. Bai and L. H. Liu) is a perennial herbal species endemic to China with narrow distribution. It is known as an important plant for investigating the metabolism of selenium in plants because of its ability to accumulate selenium. However, the phylogenetic position of this particular species in Cardamine remains unclear. In this study, we reported the chloroplast genome (cp genome) for the species C. hupingshanensis and analyzed its position within Cardamine. The cp genome of C. hupingshanensis is 155,226 bp in length and exhibits a typical quadripartite structure: one large single copy region (LSC, 84,287 bp), one small single copy region (17,943 bp) and a pair of inverted repeat regions (IRs, 26,498 bp). Guanine-Cytosine (GC) content makes up 36.3% of the total content. The cp genome contains 111 unique genes, including 78 protein-coding genes, 29 tRNA genes and 4 rRNA genes. A total of 115 simple sequences repeats (SSRs) and 49 long repeats were identified in the genome. Comparative analyses among 17 Cardamine species identified the five most variable regions (trnH-GUG-psbA, ndhK-ndhC, trnW-CCA-trnP-UGG, rps11-rpl36 and rpl32-trnL-UAG), which could be used as molecular markers for the classification and phylogenetic analyses of various Cardamine species. Phylogenetic analyses based on 79 protein coding genes revealed that the species C. hupingshanensis is more closely related to the species C. circaeoides. This relationship is supported by their shared morphological characteristics.