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المؤلفون: Qi Zeng, Shengfeng Xu, Natalie Y.L. Ngoi, Yin Shi, Zu Ye
المصدر: Free Radical Biology and Medicine. 177:72-87
مصطلحات موضوعية: MAPK/ERK pathway, Tumor microenvironment, Tumor hypoxia, Cell Survival, Hydrogen Peroxide, mTORC1, Biology, medicine.disease_cause, p38 Mitogen-Activated Protein Kinases, Biochemistry, Cell Hypoxia, Neoplasm Proteins, Mice, Physiology (medical), Tumor Microenvironment, medicine, Cancer research, Animals, Humans, Phosphorylation, Protein Tyrosine Phosphatases, Signal transduction, Carcinogenesis, Protein kinase B, PI3K/AKT/mTOR pathway
الوصف: Hypoxia within the tumor microenvironment, which leads to excessive ROS and genomic instability, is one of the hallmarks of cancer, contributing to self-renewal capability, metastasis, and radio-chemotherapy resistance. PRL-3 is an oncoprotein involved in various pro-survival signaling pathways, such as Ras/Erk, PI3K/Akt, Src/STAT, mTORC1 and JAK/STAT. However, there is little evidence connecting PRL-3-mediated apoptosis resistance to tumor microenvironmental stress. In this study, by profiling the PRL-3 expression of multiple tumor types retrieved from public databases (TCGA and NCBI GEO), we confirmed the oncogenic function of PRL-3 and found an intriguing connection between PRL-3 expression and tumor hypoxia signature genes. Moreover, by using CoCl2, a hypoxia mimetic and ROS inducer, we discovered that cells stably expressing PRL-3, but not catalytically-inactive mutant PRL-3 C104S, showed significant resistance to CoCl2 -induced apoptosis. This resistance to apoptosis was found to depend on p38 MAPK signaling and was further confirmed in other conditions of microenvironmental stress, including UV, H2O2 and hypoxia. Mechanistically, we proved that PRL-3 is a direct phosphatase of p38 MAPK under stressed conditions. Additionally, in mouse models of tumor metastasis, higher lung metastatic burden and lower p38 MAPK phosphorylation were found in mice seeded with GFP-PRL-3 expressing cells compared with those seeded with GFP-Ctrl cells. Taken together, our study identified a critical role of RPL-3 in tumorigenesis by negatively regulating p38 MAPK activity in order to facilitate tumor cell adaptation to a hypoxic stressed tumor microenvironment and suggests that PRL-3 could serve as a promising novel therapeutic target for cancer patients.
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المؤلفون: Tao Li, Xiafukati Fulati, Tuerhongjiang Tuxun, Jing Wu, Shadike Apaer, Hao Wen, Hai-zhang Ma, Jin-Ming Zhao, Nuerzatijiang Anweier, Qi Zeng
المصدر: BioMed Research International
BioMed Research International, Vol 2021 (2021)مصطلحات موضوعية: 0301 basic medicine, Eotaxin, Echinococcosis, Hepatic, Chemokine, Article Subject, medicine.medical_treatment, Albendazole, Echinococcus multilocularis, Interleukin-23, T-Lymphocytes, Regulatory, General Biochemistry, Genetics and Molecular Biology, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Echinococcosis, medicine, Animals, Humans, Mice, Inbred BALB C, General Immunology and Microbiology, biology, business.industry, Immunity, General Medicine, Th1 Cells, medicine.disease, biology.organism_classification, Disease Models, Animal, 030104 developmental biology, Cytokine, 030220 oncology & carcinogenesis, Immunology, biology.protein, Medicine, Cytokines, Th17 Cells, Female, Chemokines, business, Research Article, medicine.drug
الوصف: Objective. Alveolar echinococcosis (AE) is a zoonosis caused by the larval stage of the metacestode Echinococcosis multilocularis with a tumor-like behavior in the targeted organ, especially in the liver. Surgery with albendazole is first-line modality for AE. Drug discontinuation is usually based upon the parasitic viability shown by the positron emission tomography (PET) scan. However, as a demanding and expensive method, it is not widely practiced in majority of the endemic regions. Further understanding on the cytokine and chemokine response profiles in AE patients may provide an interesting insight for potential markers in viability assessment. Methods. Mice were inoculated with Echinococcus multilocularis intrahepatically to develop the hepatic AE murine model. Oral albendazole administration was then applied for three months after the first inoculation, and peripheral and regional immune cells including type 1 T helper cells (Th), Th2, Th17, regulatory T (Treg) cells, related cytokines, and chemokines were examined. Results. The hepatic AE lesion was confirmed by ultrasound examination resulting in a successful rate of 70%. Among the 17 cytokines and chemokines detected, plasma levels of IL-23 were significantly higher in E. multilocularis-infected mice when compared to the control group; furthermore, more obvious increasing levels were found after albendazole treatment ( p < 0.05 ). All chemokine levels other than eotaxin and MCP-3 were slightly higher in E. multilocularis-infected mice compared to the control group ( p > 0.05 ). Eotaxin levels were significantly decreased in mice with E. multilocularis infection followed by albendazole treatment ( p < 0.05 ). Both IL-17A and IL-23 expressions in hepatic AE lesions were significantly higher and related with disease activity. Conclusion. Albendazole administration influenced the balance of immune response and promotes the secretion of proinflammatory factors which is beneficial to parasite clearance. IL-23 seems to be associated with the successful albendazole treatment in mice with E. multilocularis infection; such a change could be translated into clinical application in the near future.
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المؤلفون: Qi Zeng, Cheng William Hong, Min Thura, Jie Li, Jimmy Hong, Abhishek Gupta, Joel Sng, Koon Hwee Ang
المصدر: Bioscience Reports
مصطلحات موضوعية: Immunogen, COVID-19 Vaccines, viruses, Biophysics, Biology, medicine.disease_cause, Antibodies, Viral, Biochemistry, Virus, Epitope, Antibodies, Monoclonal, Murine-Derived, Epitopes, Mice, Immune system, Immunogenicity, Vaccine, Immunity, Virology, medicine, Animals, Coronavirus Nucleocapsid Proteins, Humans, Molecular Biology, Pandemics, Research Articles, Coronavirus, Immune Evasion, Nucleocapsid protein, Sequence Homology, Amino Acid, SARS-CoV-2, Pharmacology & Toxicology, COVID-19, Cell Biology, Th1 Cells, Vaccination, Severe acute respiratory syndrome-related coronavirus, Models, Animal, Spike Glycoprotein, Coronavirus, Vaccines, Subunit, biology.protein, Antibody, Vaccine
الوصف: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding ‘viral immune escape’ since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The ‘Intra-viral’ Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.
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المؤلفون: Minquan Xia, Xin Zhou, Qi Zeng, Zhaoxia Cai, Dong U. Ahn, Xiaomeng Li
المصدر: Journal of agricultural and food chemistry. 69(31)
مصطلحات موضوعية: MAPK/ERK pathway, Lipopolysaccharides, Integrins, Lipopolysaccharide, Immunoglobulins, Nitric Oxide Synthase Type II, Integrin alpha5, Nitric Oxide, Nitric oxide, chemistry.chemical_compound, Immunoglobulin Fab Fragments, Mice, Animals, Protein kinase A, biology, Macrophages, NF-kappa B, General Chemistry, Molecular biology, Nitric oxide synthase, Toll-Like Receptor 4, RAW 264.7 Cells, chemistry, Cyclooxygenase 2, TLR4, biology.protein, Immunoglobulin Y, Tumor necrosis factor alpha, Mitogen-Activated Protein Kinases, General Agricultural and Biological Sciences
الوصف: High-purity Fab fragment and immunoglobulin Y (IgY) were prepared to evaluate their anti-inflammatory activity in the lipopolysaccharide (LPS)-induced Raw 264.7 macrophage system. Compared with IgY, the Fab fragment possessed a greater potency in inhibiting the inflammation by nitric oxide (NO)/inducible nitric oxide synthase (iNOS) and prostaglandin-E2 (PGE2)/cyclooxygenase-2 (COX-2) pathways. The Fab fragment attenuated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) to 38.07 ± 1.86-48.39 ± 11.33 pg/mL (63.1-71.0% inhibition), 31.59 ± 3.91-38.08 ± 4.44 pg/mL (72.4-77.1% inhibition), and 20.62 ± 0.46-21.91 ± 0.65 pg/mL (50-53% inhibition), respectively. Additionally, the Fab fragment significantly inhibited the translocation of nuclear transcription factor-κB (NF-κB) p65 and the phosphorylation of mitogen-activated protein kinase (MAPK) proteins, including ERK1/2 (41.5/33.2%), JNK1/2 (44.2/39.6%), and p38 (42.2%). The Fab fragment could be internalized into cells, and the pretreatment of RAW 264.7 macrophages with the Fab fragment reduced the mRNA expression of the Toll-like receptor (TLR4, 32.7-44.4% inhibition) and αVβ3 integrin (76.1% inhibition). In conclusion, Fab fragments regulated the TLR4 and αVβ3 integrin-mediated inflammatory processes by blocking the NF-κB and MAPKs pathways in the LPS-induced RAW 264.7 macrophage system.
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المؤلفون: Jayantha Gunaratne, Tuan Zea Tan, Jianbiao Zhou, Qi Zeng, Phyllis S.Y. Chong, Wee Joo Chng, Sabrina Hui Min Toh, Jing Yuan Chooi, Zit-Liang Chan, Sheena Wee
المصدر: Oncogene. 38:1508-1519
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Myeloid, Phosphatase, Biology, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, Transactivation, 0302 clinical medicine, Cyclin D1, Genetics, medicine, Animals, Humans, Wnt Signaling Pathway, Molecular Biology, beta Catenin, Wnt signaling pathway, Myeloid leukemia, Xenograft Model Antitumor Assays, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Wnt Proteins, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Catenin, Cancer research, Protein Tyrosine Phosphatases, Signal transduction, Protein Binding, Transcription Factors
الوصف: Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.
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المؤلفون: Qi Zeng, Zu Ye, Abhishek Gupta, Qiancheng Xiong, Min Thura, Ke Guo, Abdul Qader Omer Al-aidaroos, Jie Li, Koon Hwee Ang, Jun Yi Ong
المصدر: Communications Biology
Communications Biology, Vol 4, Iss 1, Pp 1-10 (2021)مصطلحات موضوعية: 0301 basic medicine, DNA damage, QH301-705.5, medicine.medical_treatment, Medicine (miscellaneous), Antineoplastic Agents, Cancer immunotherapy, Biology, Humanized antibody, Giant Cells, Article, General Biochemistry, Genetics and Molecular Biology, Metastasis, Immediate-Early Proteins, Polyploidy, 03 medical and health sciences, Mice, 0302 clinical medicine, SOX2, Neoplasms, medicine, Secondary Prevention, Animals, Biology (General), Author Correction, Cancer stem cells, Cell migration, Immunotherapy, Oncogenes, medicine.disease, Embryonic stem cell, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Protein Tyrosine Phosphatases, General Agricultural and Biological Sciences
الوصف: PRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in ‘tumor removal’ animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an ‘Adjuvant Immunotherapy’ after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.
Thura and colleagues report that PRL3 promotes PGCCs, which are found to be enriched in relapsed tumours. The authors demonstrated that this relapse can be prevented using PRL3-zumab for use in adjuvant immunotherapy to target PRL3-expressing PGCCs, thus preventing metastasis and relapse. -
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المؤلفون: Xiaorui Shi, Liqian Zhou, Tongyu Li, Wei Liu, Hangxiang Wang, Tian Xie, Jianqin Wan, Xu Liu, Yiting Qiao, Guo Chen, Yaru Shi, Fu Wang, Qi Zeng, Hui Xie, Jianxiang Chen, Youwei Sun
المصدر: Nucleic Acids Research
مصطلحات موضوعية: 0301 basic medicine, Genome instability, Lung Neoplasms, DNA damage, Kruppel-Like Transcription Factors, Regulator, Mice, Nude, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, Genome Integrity, Repair and Replication, Biology, Genomic Instability, Mice, 03 medical and health sciences, chemistry.chemical_compound, Stomach Neoplasms, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Hydroxyurea, DNA Breaks, Double-Stranded, Phosphorylation, Zinc finger, Binding Sites, Endodeoxyribonucleases, Osteoblasts, Nuclear Proteins, Recombinational DNA Repair, Cancer, Epithelial Cells, DNA, Neoplasm, medicine.disease, Survival Analysis, Xenograft Model Antitumor Assays, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Cancer cell, Cancer research, Camptothecin, Female, Carrier Proteins, Homologous recombination, DNA, Protein Binding
الوصف: Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3′ or 5′ overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8f282f33bdff15d61abf794519f2764
https://doi.org/10.1093/nar/gkx1258 -
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المؤلفون: Motomi Osato, Qi Zeng, Yafeng Zhou, Phyllis S.Y. Chong, Shaw-Cheng Liu, Jianbiao Zhou, Ying Qing Ching, Siok Bian Ng, Chin Hin Ng, Shi Wang, Wee Joo Chng, Chonglei Bi, Tuan Zea Tan, Jing Yuan Chooi, Lip-Lee Cheong, Xiao Lu, Zit-Liang Chan
المصدر: Molecular Cancer Research. 15:294-303
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Myeloid, Carcinogenesis, HL-60 Cells, Biology, Transfection, Immediate-Early Proteins, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Animals, Humans, Molecular Biology, Stem Cells, RNA-Binding Proteins, Myeloid leukemia, medicine.disease, Neoplasm Proteins, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Protein Tyrosine Phosphatases, Signal transduction, Stem cell, Reprogramming, Signal Transduction
الوصف: PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo. Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell–like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell–like properties to leukemia cells that is important for leukemogenesis. Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294–303. ©2016 AACR.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::915a5b9f160379705804167a22ecb6a9
https://doi.org/10.1158/1541-7786.mcr-16-0275-t -
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المؤلفون: Meng Zhou, Hui Shen, Yu-qi Zeng, Xiaochun Chen, Xiaodong Pan, Jing Zhang, Lumeng Yang, Yuan-Gui Zhu, Xiaoman Dai, Bing Ye
المصدر: Chinese Medical Journal, Vol 129, Iss 23, Pp 2845-2852 (2016)
Chinese Medical Journalمصطلحات موضوعية: 0301 basic medicine, Pathology, medicine.medical_specialty, Ubiquitin-Protein Ligases, Transgene, Blotting, Western, lcsh:Medicine, Apoptosis, Mice, Transgenic, Alzheimer's Disease, Unfolded Protein Response Pathway, Mice, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Heat shock protein, medicine, Animals, Endoplasmic Reticulum Chaperone BiP, Caspase 12, Heat-Shock Proteins, Neurons, Amyloid β, Endoplasmic Reticulum Stress, Amyloid beta-Peptides, biology, business.industry, Endoplasmic reticulum, lcsh:R, General Medicine, medicine.disease, Immunohistochemistry, Frontal Lobe, Blot, 030104 developmental biology, Unfolded Protein Response, Cancer research, biology.protein, Unfolded protein response, Original Article, Alzheimer's disease, business, Transcription Factor CHOP, 030217 neurology & neurosurgery
الوصف: Background: Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods: The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway. Results: Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions: These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.
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المؤلفون: Jing Yuan Chooi, Wee Joo Chng, Qi Zeng, Julia S.L. Lim, Daniel D Waller, Michael Sebag, Jianbiao Zhou, Tae-Hoon Chung, Yan Ting Hee, Phyllis S.Y. Chong, Zea Tuan Tan
المصدر: Cancer research. 79(18)
مصطلحات موضوعية: 0301 basic medicine, STAT3 Transcription Factor, endocrine system, Cancer Research, Antineoplastic Agents, Apoptosis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Mice, SCID, Biology, Bortezomib, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, immune system diseases, Mice, Inbred NOD, hemic and lymphatic diseases, medicine, Tumor Cells, Cultured, Gene silencing, Animals, Humans, Phosphorylation, Protein kinase B, Multiple myeloma, Cell Proliferation, Regulation of gene expression, Interleukin-6, medicine.disease, Prognosis, Xenograft Model Antitumor Assays, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Survival Rate, 030104 developmental biology, Oncology, Proteasome, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Female, Signal transduction, Protein Tyrosine Phosphatases, Multiple Myeloma, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Signal Transduction
الوصف: Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed “deactivation” of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. Significance: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5010d6dede174f4938beceb2a9130849
https://pubmed.ncbi.nlm.nih.gov/31337650
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