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Cellular Oncology (Dordrecht) Jul 2024Esophageal squamous cell carcinoma (ESCC) is a prevalent tumor in the gastrointestinal tract, but our understanding of the molecular mechanisms underlying ESCC remains...
PURPOSE
Esophageal squamous cell carcinoma (ESCC) is a prevalent tumor in the gastrointestinal tract, but our understanding of the molecular mechanisms underlying ESCC remains incomplete. Existing studies indicate that SUMO specific peptidase 1 (SENP1) plays a crucial role in the development and progression of various malignant tumors through diverse molecular mechanisms. However, the functional mechanism and clinical implications of SENP1 in the progression of ESCC remain unclear.
METHODS
Bulk RNA-Sequencing (RNA-seq) was used to compare potential genes in the esophageal tissues of mice with ESCC to the control group. The up-regulated SENP1 was selected. The protein level of SENP1 in ESCC patient samples was analyzed by immunohistochemistry and western blot. The potential prognostic value of SENP1 on overall survival of ESCC patients was examined using tissue microarray analysis and the Kaplan-Meier method. The biological function was confirmed through in vitro and in vivo knockdown approaches of SENP1. The role of SENP1 in cell cycle progression and apoptosis of ESCC cells was analyzed by flow cytometry and western blot. The downstream signaling pathways regulated by SENP1 were investigated via using RNA-Seq. SENP1-associated proteins were identified through immunoprecipitation. Overexpression of Sirtuin 6 (SIRT6) wildtype and mutant was performed to investigate the regulatory role of SENP1 in ESCC progression in vitro.
RESULTS
Our study discovered that SENP1 was upregulated in ESCC tissues and served as a novel prognostic factor. Moreover, SENP1 enhanced cell proliferation and migration of ESCC cell lines in vitro, as well as promoted tumor growth in vivo. Thymidine kinase 1 (TK1), Geminin (GMNN), cyclin dependent kinase 1(CDK1), and cyclin A2 (CCNA2) were identified as downstream genes of SENP1. Mechanistically, SENP1 deSUMOylated SIRT6 and subsequently inhibited SIRT6-mediated histone 3 lysine 56 (H3K56) deacetylation on those downstream genes. SIRT6 SUMOylation mutant (4KR) rescued the growth inhibition upon SENP1 depletion.
CONCLUSIONS
SENP1 promotes the malignant progression of ESCC by inhibiting the deacetylase activity of SIRT6 pathway through deSUMOylation. Our findings suggest that SENP1 may serve as a valuable biomarker for prognosis and a target for therapeutic intervention in ESCC.
PubMed: 38954215
DOI: 10.1007/s13402-024-00956-4 -
Methods in Molecular Biology (Clifton,... 2024Identifying the mechanisms of action of existing and novel drugs is essential for the development of new compounds for therapeutic and commercial use. Here we provide a...
Identifying the mechanisms of action of existing and novel drugs is essential for the development of new compounds for therapeutic and commercial use. Here we provide a technique to identify these mechanisms through isolating mutant cell lines that show resistance to drug-induced phenotypes using Dictyostelium discoideum REMI libraries. This approach provides a robust and rapid chemical-genetic screening technique that enables an unbiased approach to identify proteins and molecular pathways that control drug sensitivity. Mutations that result in drug resistance often occur in target proteins thus identifying the specific protein targets for drugs and bioactive natural products. Following the identification of a list of putative molecular targets user selected compound targets can be analyzed to confirm and validate direct inhibitory effects.
Topics: Dictyostelium; Mutation; DNA Restriction Enzymes; Gene Library; Drug Resistance; Small Molecule Libraries
PubMed: 38954208
DOI: 10.1007/978-1-0716-3894-1_15 -
Clinical Advances in Hematology &... 2024
Topics: Humans; Thyroid Neoplasms; Lung Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA; Neoplasm Metastasis
PubMed: 38953729
DOI: No ID Found -
Clinical Advances in Hematology &... 2024
Topics: Humans; Thyroid Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA; Disease Management; Protein Kinase Inhibitors
PubMed: 38953728
DOI: No ID Found -
Clinical Advances in Hematology &... 2024
Topics: Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA; Protein Kinase Inhibitors; Disease Management
PubMed: 38953727
DOI: No ID Found -
Clinical Advances in Hematology &... 2024
Topics: Humans; Thyroid Neoplasms; Lung Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA
PubMed: 38953726
DOI: No ID Found -
Clinical Advances in Hematology &... 2024Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is... (Review)
Review
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is 0.1 to 0.3% in non-small cell lung cancer (NSCLC) and as high as 26% in pediatric papillary thyroid carcinoma. Detection methods include immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing. Management of NTRK fusion-positive lung cancer primarily involves targeted therapies, notably the tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib. Both agents demonstrate high response rates and durable disease control, particularly in metastatic adenocarcinoma of the lung. They are preferred as first-line treatments because of their efficacy over immunotherapy. Possible adverse events include dizziness, weight gain, neuropathy-like pain, and liver enzyme elevation. Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion-positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Topics: Humans; Protein Kinase Inhibitors; Thyroid Neoplasms; Lung Neoplasms; Indazoles; Pyrazoles; Oncogene Proteins, Fusion; Pyrimidines; Receptor, trkA; Benzamides; Treatment Outcome
PubMed: 38953725
DOI: No ID Found -
Applied and Environmental Microbiology Jul 2024To cope with a high-salinity environment, haloarchaea generally employ the twin-arginine translocation (Tat) pathway to transport secretory proteins across the cytoplasm...
UNLABELLED
To cope with a high-salinity environment, haloarchaea generally employ the twin-arginine translocation (Tat) pathway to transport secretory proteins across the cytoplasm membrane in a folded state, including Tat-dependent extracellular subtilases (halolysins) capable of autocatalytic activation. Some halolysins, such as SptA of J7-2, are produced at late-log phase to prevent premature enzyme activation and proteolytic damage of cellular proteins in haloarchaea; however, the regulation mechanism for growth phase-dependent expression of halolysins remains largely unknown. In this study, a DNA-protein pull-down assay was performed to identify the proteins binding to the 5'-flanking sequence of encoding halolysin SptA in strain J7-2, revealing a TrmBL2-like transcription factor (NgTrmBL2). The Δ mutant of strain J7-2 showed a sharp decrease in the production of SptA, suggesting that NgTrmBL2 positively regulates expression. The purified recombinant NgTrmBL2 mainly existed as a dimer although monomeric and higher-order oligomeric forms were detected by native-PAGE analysis. The results of electrophoretic mobility shift assays (EMSAs) showed that NgTrmBL2 binds to the 5'-flanking sequence of in a non-specific and concentration-dependent manner and exhibits an increased DNA-binding affinity with the increase in KCl concentration. Moreover, we found that a distal -regulatory element embedded in the neighboring upstream gene negatively regulates expression and thus participates in the growth phase-dependent biosynthesis of halolysin SptA.
IMPORTANCE
Extracellular proteases play important roles in nutrient metabolism, processing of functional proteins, and antagonism of haloarchaea, but no transcription factor involved in regulating the expression of haloaechaeal extracellular protease has been reported yet. Here we report that a TrmBL2-like transcription factor (NgTrmBL2) mediates the growth phase-dependent expression of an extracellular protease, halolysin SptA, of haloarchaeon J7-2. In contrast to its hyperthermophilic archaeal homologs, which are generally considered to be global transcription repressors, NgTrmBL2 functions as a positive regulator for sptA expression. This study provides new clues about the transcriptional regulation mechanism of extracellular protease in haloarchaea and the functional diversity of archaeal TrmBL2.
PubMed: 38953660
DOI: 10.1128/aem.00741-24 -
Journal of Bacteriology Jul 2024causes a serious diarrheal disease and is a common healthcare-associated bacterial pathogen. Although it has a major impact on human health, the mechanistic details of...
causes a serious diarrheal disease and is a common healthcare-associated bacterial pathogen. Although it has a major impact on human health, the mechanistic details of intestinal colonization remain undefined. is highly sensitive to oxygen and requires anaerobic conditions for growth. However, the mammalian gut is not devoid of oxygen, and tolerates moderate oxidative stress . The genome encodes several antioxidant proteins, including a predicted superoxide reductase (SOR) that is upregulated upon exposure to antimicrobial peptides. The goal of this study was to establish SOR enzymatic activity and assess its role in protecting against oxygen exposure. Insertional inactivation of rendered more sensitive to superoxide, indicating that SOR contributes to antioxidant defense. Heterologous expression in conferred protection against superoxide-dependent growth inhibition, and the corresponding cell lysates showed superoxide scavenging activity. Finally, a SOR mutant exhibited global proteome changes under oxygen stress when compared to the parent strain. Collectively, our data establish the enzymatic activity of SOR, confirm its role in protection against oxidative stress, and demonstrate SOR's broader impacts on the vegetative cell proteome.IMPORTANCE is an important pathogen strongly associated with healthcare settings and capable of causing severe diarrheal disease. While considered a strict anaerobe , has been shown to tolerate low levels of oxygen in the mammalian host. Among other well-characterized antioxidant proteins, the genome encodes a predicted superoxide reductase (SOR), an understudied component of antioxidant defense in pathogens. The significance of the research reported herein is the characterization of SOR's enzymatic activity, including confirmation of its role in protecting against oxidative stress. This furthers our understanding of pathogenesis and presents a potential new avenue for targeted therapies.
PubMed: 38953644
DOI: 10.1128/jb.00175-24 -
Oncoimmunology 2024The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from -mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.
Topics: Humans; Oxaliplatin; Female; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Immune Checkpoint Inhibitors; Aged; Antineoplastic Combined Chemotherapy Protocols; Mutation; Microsatellite Instability; Treatment Outcome; Aged, 80 and over
PubMed: 38952672
DOI: 10.1080/2162402X.2024.2372886