Publications by authors named "Chunze Zhang"

32 Publications

Allopurinol Protects Against Cholestatic Liver Injury in Mice Not Through Depletion of Uric Acid.

Toxicol Sci 2021 05;181(2):295-305

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.

Cholestasis is one of the most severe manifestations of liver injury and has limited therapeutic options. Allopurinol (AP), an inhibitor of uric acid (UA) synthesis, was reported to prevent liver damage in several liver diseases. However, whether AP protects against intrahepatic cholestatic liver injury and what is the role of UA in the pathogenesis of cholestasis remain unknown. In this study, we reported that AP attenuated liver injury in a mouse model of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). AP showed no significant effect on glutathione depletion, inflammation, or bile acid metabolism in livers of ANIT-treated mice. Instead, AP significantly improved fatty acid β-oxidation in livers of ANIT-treated mice, which was associated with activation of PPARα. The protective effect of AP on cholestatic liver injury was not attributable to the depletion of UA, because both exogenous and endogenous UA prevented liver injury in ANIT-treated mice via inhibition of NF-kB-mediated inflammation. In conclusion, the present study provides a new perspective for the therapeutic use of AP and the role of UA in cholestatic liver injury.
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http://dx.doi.org/10.1093/toxsci/kfab034DOI Listing
May 2021

LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin.

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.

Background: A dysfunctional gut epithelial barrier allows the augmented permeation of endotoxins, luminal antigens, and bacteria into the bloodstream, causing disease. The maintenance of gut epithelial barrier integrity may be regulated by multiple factors. Herein we analyze the role of leucine-rich repeat-containing protein 19 (LRRC19) in regulating the permeability of the gut epithelial barrier.

Methods: We utilized Lrrc19 knockout (KO) mice and clinical samples through transmission electron, intestinal permeability assay, Western blot, and immunofluorescence staining to characterize the role of LRRC19 in the permeability of the gut epithelial barrier.

Results: We found that LRRC19, which is expressed in gut epithelial cells, impairs gut barrier function. Transmission electron micrographs revealed a tighter junction and narrower gaps in the colon epithelium cells in LRRC19 KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage in LRRC19 KO mice than in wild-type mice. We found that LRRC19 could reduce the expression of zonula occludens (ZO)-1, ZO-3, and occludin in the colonic epithelial cells. The decreased expression of ZO-1, ZO-3, and occludin was dependent on degrading protein kinase C (PKC) ζ and PKCι/λ through K48 ubiquitination by LRRC19. The expression of LRRC19 was also negatively correlated with ZO-1, ZO-3, occludin, PKCζ, and PKCι/λ in human colorectal cancers.

Conclusions: The protein LRRC19 can promote the permeability of the gut epithelial barrier through degrading PKC ζ and PKCι/λ to reduce the expression of ZO-1, ZO-3, and occludin.
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http://dx.doi.org/10.1093/ibd/izaa354DOI Listing
January 2021

IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.

Theranostics 2021 1;11(6):2564-2580. Epub 2021 Jan 1.

School of Medicine, Nankai University, 94 Weijin Road, Tianjin, PR China.

Tumor microenvironment interacts with tumor cells to regulate their stemness properties through various cytokines and cytokine receptors. Previous studies revealed the possible role of interleukin 20 receptor subunit alpha (IL20RA) signaling in the progression of several types of tumors. However, its regulatory effects on the stemness and the microenvironment of breast cancer need to be studied. Immunohistochemical staining and western blot analysis were used to evaluate the association between IL20RA and SOX2 in breast tumors and noncancerous tissues. Enzyme-linked immunosorbent assay and TCGA dataset analysis were performed to determine the function of IL20RA signaling in breast cancer progression. Gain- and loss-of-function methods were performed to examine the effects of IL20RA on the stemness of breast cancer cells. The stemness features were analyzed by detecting the expression of core stemness genes, side population (SP), sphere formation ability, and aldehyde dehydrogenase (ALDH) activity. Flow cytometric analysis was applied to detect the changes of tumor-infiltration lymphocytes in tumor tissues in mice. Based on the relevant molecular mechanisms elucidated in this study, a novel IL20RA-targeted liposomal nanoparticle encapsulating the signal transducer and activator of transcription 3 (STAT3) inhibitor stattic (NP-Stattic-IL20RA) was synthesized. These NPs were combined with anti-programmed death ligand 1 (PD-L1) antibody and chemotherapy to inhibit the development of breast tumors in mice. IL20RA is highly expressed in human breast cancers and is positively associated with the SOX2 expression. IL20RA increases the SP and ALDH proportions of breast cancer cells, enhances the sphere formation ability, and promotes the expression of core stemness genes, such as and , as well as increases chemoresistance of breast cancer cells. IL20RA promotes the tumor-initiating ability and lung metastasis of breast cancer cells . In addition, IL20RA activates the Janus kinase 1 (JAK1)-STAT3-SOX2 signaling pathway, leading to increased expression of PD-L1 and reduced recruitment of anti-cancer lymphocytes, including CD8 T cells and natural killer cells. Meanwhile, IL20RA signaling enhances the proportion of myeloid-derived suppressor cells. Combined with anti-PD-L1 antibody and NPs-Stattic-IL20RA, the chemotherapeutic efficacy was increased in breast cancer mouse models . Collectively, our results reveal that the IL20RA pathway is a novel signaling pathway involved in promoting the stemness features of breast cancer along with the formation of a tumor-favorable immune microenvironment. Targeting the IL20RA population with STAT3 signaling inhibition combined with anti-PD-L1 antibody can increase the therapeutic efficacy of chemotherapeutic agents for breast cancer. This study thus introduces a promising novel strategy for breast cancer therapy.
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http://dx.doi.org/10.7150/thno.45280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806486PMC
January 2021

Eubacterium rectale contributes to colorectal cancer initiation via promoting colitis.

Gut Pathog 2021 Jan 12;13(1). Epub 2021 Jan 12.

Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii At Manoa, 2538 McCarthy Mall, Snyder Hall, Honolulu, HI, 96822, USA.

Background: Inflammatory bowel disease caused by microbial dysbiosis is an important factor contributing to colorectal cancer (CRC) initiation. The 'driver-passenger' model in human gut microbial dysbiosis suggests that 'driver' bacteria may colonize with low relative abundance on tumor site but persistently induce chronic change in normal intestinal epithelium and initiate CRC. They are gradually replaced by 'passenger' bacteria later on, due to their low adaptability to the on-tumor site niche.

Results: To reveal site-specific bacterial taxon markers in CRC patients, we analyzed the gut mucosal microbiome of 75 paired samples of on-tumor and tumor-adjacent sites, 75 off-tumor sites, and 26 healthy controls. Linear discriminant analysis of relative abundance profiles revealed unique bacterial taxon distribution correlated with specific tumor sites, with Eubacterium having the distribution characteristic of potential driver bacteria. We further show that Eubacterium rectale endotoxin activates the transcription factor NF-κΒ, which regulates multiple aspects of innate and adaptive immune responses in normal colon epithelial cells. Unlike the 'passenger' bacterium Fusobacterium nucleatum, E. rectale promotes dextran sodium sulfate-induced colitis in Balb/c mice.

Conclusions: Our findings reveal that E. rectale functions as a 'driver' bacterium and contributes to cancer initiation via promoting inflammation.
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http://dx.doi.org/10.1186/s13099-020-00396-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805161PMC
January 2021

Analyses of Potential Driver and Passenger Bacteria in Human Colorectal Cancer.

Cancer Manag Res 2020 12;12:11553-11561. Epub 2020 Nov 12.

TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, People's Republic of China.

Introduction: Besides genetic and epigenetic alterations that lead to carcinogenesis and development of colorectal cancer (CRC), intestinal microbiomes are recently recognized to play a critical role in CRC progression. The abundant species associated with human CRC have been proposed for their roles in promoting tumorigenesis. However, a recent "driver-passenger" model suggests that these CRC-associated species with high relative abundances may be passenger bacteria that take advantage of the tumor environment instead of initiating CRC, whereas the driver species that initiate CRC have been replaced by passenger bacteria due to the alteration of the intestinal niche.

Methods: Here, to reveal potential driver and passenger bacteria during CRC progression, we compare the gut mucosal microbiomes of 75 triplet-paired CRC samples collected from on-tumor site, adjacent-tumor site, and off-tumor site, and 26 healthy controls.

Results: Our analyses revealed potential driver bacteria in four genera and two families, and potential passenger bacteria in 14 genera or families. and were predicted to be potential driver bacteria. Moreover, 14 potential passenger bacteria were identified and divided into five groups. Group I passenger bacteria contain , and . Group II passenger bacteria contain . Group III passenger bacteria contain . Group IV passenger bacteria contain , and . Group V passenger bacteria contain . Co-occurrence network analysis reveals a low correlation relationship between driver and passenger bacteria in CRC patients compared with healthy controls.

Discussion: These driver and passenger species may serve as bio-marker species for screening cohorts with high risk to initiate CRC or patients with CRC, respectively. Further functional studies will help understand the roles of driver and passenger bacteria in CRC initiation and development.
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http://dx.doi.org/10.2147/CMAR.S275316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669530PMC
November 2020

A novel NGS-based microsatellite instability (MSI) status classifier with 9 loci for colorectal cancer patients.

J Transl Med 2020 05 28;18(1):215. Epub 2020 May 28.

Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.

Background: With the recent emergence of immune checkpoint inhibitors, microsatellite instability (MSI) status has become an important biomarker for immune checkpoint blockade therapy. There are growing technical demands for the integration of different genomic alterations profiling including MSI analysis in a single assay for full use of the limited tissues.

Methods: Tumor and paired control samples from 64 patients with primary colorectal cancer were enrolled in this study, including 14 MSI-high (MSI-H) cases and 50 microsatellite stable (MSS) cases determined by MSI-PCR. All the samples were sequenced by a customized NGS panel covering 2.2 MB. A training dataset of 28 samples was used for selection of microsatellite loci and a novel NGS-based MSI status classifier, USCI-msi, was developed. NGS-based MSI status, single nucleotide variant (SNV) and tumor mutation burden (TMB) were detected for all patients. Most of the patients were also independently detected by immunohistochemistry (IHC) staining.

Results: A 9-loci model for detecting microsatellite instability was able to correctly predict MSI status with 100% sensitivity and specificity compared with MSI-PCR, and 84.3% overall concordance with IHC staining. Mutations in cancer driver genes (APC, TP53, and KRAS) were dispersed in MSI-H and MSS cases, while BRAF p.V600E and frameshifts in TCF7L2 gene occurred only in MSI-H cases. Mismatch repair (MMR)-related genes are highly mutated in MSI-H samples.

Conclusion: We established a new NGS-based MSI classifier, USCI-msi, with as few as 9 microsatellite loci for detecting MSI status in CRC cases. This approach possesses 100% sensitivity and specificity, and performed robustly in samples with low tumor purity.
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http://dx.doi.org/10.1186/s12967-020-02373-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257555PMC
May 2020

Inhibition of UDP-glucuronosyltransferases by different furoquinoline alkaloids.

Xenobiotica 2020 Oct 5;50(10):1170-1179. Epub 2020 May 5.

Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China.

Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb-drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs).The recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition type and parameters were determined, and docking was employed to elucidate the inhibition difference of furoquinoline alkaloids towards UGTs.Dictamine, haplopine, γ-fagarine and skimmianine strongly inhibited UGT1A3, UGT1A7, UGT1A9 and UGT2B4, respectively. Among them, dictamnine inhibited more than 70% of the four UGTs. Inhibition kinetics determination showed that they all exerted competitive inhibition, and the inhibition kinetic constant () was determined to be 8.3, 7.2, 3.7 and 33.9 μM, respectively. extrapolation (IVIVE) was employed to demonstrate the inhibition possibility for four alkaloids. Skimmianine was proved to be more suitable for clinical application. docking study indicated that the hydrophobic interactions played a key role in the inhibition of furoquinoline alkaloids towards three of the four UGTs. In conclusion, monitoring the interactions between furoquinoline alkaloids and drugs mainly undergoing UGTs-catalyzed metabolism is necessary.
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http://dx.doi.org/10.1080/00498254.2020.1760400DOI Listing
October 2020

Induction of Inflammatory Macrophages in the Gut and Extra-Gut Tissues by Colitis-Mediated Escherichia coli.

iScience 2019 Nov 26;21:474-489. Epub 2019 Oct 26.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China. Electronic address:

Inflammatory macrophages play a critical role in gut and extra-gut inflammatory disorders, which may be promoted through the dysbiosis of gut microbiota. However, it is poorly understood how gut microbiota affect inflammatory macrophages. Here, we found that increased Escherichia coli (E. coli) in inflamed colon may induce inflammatory macrophages in gut and extra-gut tissues. These E. coli are different from other commensal and pathogenic E. coli in genomic components and also in ability to induce inflammatory responses. Dominant E. coli from colitic tissues induce gut inflammatory macrophages through a regulating network consisted of IL-18, IFN-γ, IL-12, and IL-22 in gut tissues. These E. coli also directly activate macrophages. Cytosolic inflammasome components PCKδ, NLRC4, caspase8, and caspase1/11 are involved in E. coli-mediated activation in both gut epithelial cells and macrophages. These disclose a novel mechanism for how dysbiosis of gut microbiota in colitis cause inflammatory macrophages related to multiple diseases.
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http://dx.doi.org/10.1016/j.isci.2019.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849333PMC
November 2019

Dimethylaminomicheliolide (DMAMCL) Suppresses the Proliferation of Glioblastoma Cells via Targeting Pyruvate Kinase 2 (PKM2) and Rewiring Aerobic Glycolysis.

Front Oncol 2019 2;9:993. Epub 2019 Oct 2.

State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.

Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis, which consequently suppresses the proliferation of GBM cells. Hence, DMAMCL represents a potential PKM2-targeted therapeutic agent against GBM.
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http://dx.doi.org/10.3389/fonc.2019.00993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783512PMC
October 2019

Suggestions for “14-3-3zeta Positive Cells Show More Tumorigenic Characters in Human Glioblastomaâ€.

Turk Neurosurg 2020 ;30(3):469-470

Tianjin University, College of Precision Instruments and Q9 Optoelectronics Engineering, Neural Engineering & Rehabilitation Lab, Department of Biomedical Engineering, Tianjin, China.

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http://dx.doi.org/10.5137/1019-5149.JTN.25760-19.2DOI Listing
January 2020

Elevated nuclear YBX1 expression and the clinicopathological characteristics of patients with solid tumors: a meta-analysis.

Cancer Manag Res 2019 14;11:4391-4402. Epub 2019 May 14.

School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China.

Y-box binding protein 1 (YBX1) is a multifunctional protein linked to tumor progression and its elevated expression is an indicator of poor prognosis in various cancers. This meta-analysis aimed to investigate the prognostic value and clinical significance of YBX1 in malignant cancer. Relevant articles published through September 12, 2018 were identified from a comprehensive electronic and manual search in PubMed, Web of Science and Embase databases. The combined odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to estimate the relationship among clinicopathological characteristics, overall survival and disease-free-survival of patients with solid tumor and YBX1 expression. The study included 27 studies and 5,996 patients. Our analysis revealed significant association between increased YBX1 expression and tumor differentiation status, tumor size and lymph node metastasis; moreover, the pooled HR values demonstrated that high nuclear YBX1 expression was significantly associated with worse overall survival (HR=2.14; 95% CI: 1.72-2.67, <0.001). The evidence supports YBX1 as a tumor biomarker to guide clinical management and indicate prognosis.
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http://dx.doi.org/10.2147/CMAR.S195243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526190PMC
May 2019

Linear double-stranded DNAs as innovative biological parts to implement genetic circuits in mammalian cells.

FEBS J 2019 06 11;286(12):2341-2354. Epub 2019 Apr 11.

Department of Colorectal Surgery, Tianjin Union Medical Center, China.

Synthetic biology employs engineering principles to redesign biological systems for biomedical or industrial purposes. Innovation and application of original biological parts for genetic circuit construction will significantly facilitate and expedite the development of synthetic biology. Here, we built two- or three-input linear double-stranded DNA (ldsDNA)-based Boolean AND gate genetic circuits in mammalian cells. Bioluminescence imaging revealed the feasibility of ldsDNA-based Boolean AND gate circuits in vivo. Inhibition of DNA-PKcs, a pivotal enzyme in nonhomologous end joining, significantly attenuated the output signals from ldsDNA-based Boolean AND gate circuits. We further showed that ldsDNA with additional terminal random nucleotide(s) could undergo end nucleotide deletion and generate in-frame proteins via the Boolean AND gate response. Additionally, ldsDNAs or plasmids with identical overlapping sequences could also serve as input signals for Boolean AND gate genetic circuits. Our work establishes ldsDNAs as innovative biological parts for building low noise-signal ratio Boolean AND gate circuits with application potential in biomedical engineering fields.
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http://dx.doi.org/10.1111/febs.14816DOI Listing
June 2019

S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes.

Leukemia 2019 08 8;33(8):2034-2046. Epub 2019 Feb 8.

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Myelodysplastic syndromes (MDS) are characterized by dysplastic and ineffective hematopoiesis that can result from aberrant expansion and activation of myeloid-derived suppressor cells (MDSCs) within the bone marrow (BM) niche. MDSCs produce S100A9, which mediates premature death of hematopoietic stem and progenitor cells (HSPCs). The PD-1/PD-L1 immune checkpoint impairs immune responses by inducing T-cell exhaustion and apoptosis, but its role in MDS is uncharacterized. Here we report an increased expression of PD-1 on HSPCs and PD-L1 on MDSCs in MDS versus healthy donors, and that this checkpoint is also activated in S100A9 transgenic (S100A9Tg) mice, and by treatment of BM mononuclear cells (BM-MNC) with S100A9. Further, MDS BM-MNC treated with recombinant PD-L1 underwent cell death, suggesting that the PD-1/PD-L1 interaction contributes to HSPC death in MDS. In accordance with this notion, PD-1/PD-L1 blockade restores effective hematopoiesis and improves colony-forming capacity in BM-MNC from MDS patients. Similar findings were observed in aged S100A9Tg mice. Finally, we demonstrate that c-Myc is required for S100A9-induced upregulation of PD-1/PD-L1, and that treatment of MDS HSPCs with anti-PD-1 antibody suppresses the expression of Myc target genes and increases the expression of hematopoietic pathway genes. We conclude anti-PD-1/anti-PD-L1 blocking strategies offer therapeutic promise in MDS in restoring effective hematopoiesis.
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http://dx.doi.org/10.1038/s41375-019-0397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687540PMC
August 2019

An Improved NGS Library Construction Approach Using DNA Isolated from Human Cancer Formalin-Fixed Paraffin-Embedded Samples.

Anat Rec (Hoboken) 2019 06 25;302(6):941-946. Epub 2018 Nov 25.

Key Laboratory of Molecular and Cellular Systems Biology, Tianjin Normal University, Tianjin, 300387, China.

Identification of genomic alterations from formalin-fixed paraffin-embedded (FFPE) samples using next-generation sequencing (NGS) is very important for cancer-targeted therapy today. To achieve a higher efficiency and shorter turn-around time for NGS library preparation, here, we compared NGS library preparation processes and outcomes with three commercial library construction methods and two hybridization capture methods thus, developed an improved NGS library construction approach. This improved approach took advantage of both methods and resulted in a higher output from the same input DNA, including higher library construction success rate, higher probe capture rate, and shorter turn-around time. Using this approach, targeted region libraries could be constructed within only 1 day for FFPE samples; therefore, this approach has potential applications of NGS in routine clinical tests. Anat Rec, 302:941-946, 2019. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ar.24002DOI Listing
June 2019

Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3.

Front Pharmacol 2018 8;9:881. Epub 2018 Aug 8.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) . Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.
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http://dx.doi.org/10.3389/fphar.2018.00881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092588PMC
August 2018

Author Correction: Kanglaite sensitizes colorectal cancer cells to Taxol via NF-κΒ inhibition and connexin 43 upregulation.

Sci Rep 2018 Apr 12;8(1):6141. Epub 2018 Apr 12.

Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii at Manoa 2538 McCarthy Mall, Snyder Hall, Honolulu, HI, 96822, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-24089-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895681PMC
April 2018

The prognostic value of NRF2 in solid tumor patients: a meta-analysis.

Oncotarget 2018 Jan 3;9(1):1257-1265. Epub 2017 Aug 3.

School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is known as a potential therapeutic target of solid tumor for that it is a master regulator of the injury and inflammation response, including controlling antioxidant cell progress. Recent studies showed that NRF2 played significant roles in tumorigenesis and tumor progression, however no association and relationship between NRF2 expression and different clinical manifestation of solid tumor had been accurately evaluated. The present meta-analysis picked up 17 suitable articles from EMBASE, PubMed, and ISI Web of Science databases, including 2238 patients. Combined with results of hazard ratios (HRs) and 95% confidence intervals (CIs), we concluded that a higher expression of NRF2 would have worse impact on overall survival (HR = 2.29, 95% CI 1.80-2.91, < 0.05) and disease-free survival (HR = 2.34, 95% CI 1.36-4.00, < 0.05) by a random-effect model. Moreover, further results were positively correlated to the clinical diagnosis, curative effect observation and prognosis, including tumor differentiation, lymph node metastasis, distant metastasis and clinical stage. Consequently, our data shown that NRF2 is a potential poor prognostic factor in a variety of solid tumors.
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http://dx.doi.org/10.18632/oncotarget.19838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787436PMC
January 2018

The prognostic value of over-expressed TrkB in solid tumors: a systematic review and meta-analysis.

Oncotarget 2017 Nov 25;8(59):99394-99401. Epub 2017 Jul 25.

Department of Immunology, Tianjin Medical University, Tianjin, China.

It is reported recently Tropomyosin-related receptor Kinase B (TrkB) plays key roles in the anoikis resistance during the processes of tumorigenesis and metastasis. However, its prognostic significance for clinical patients remains inconclusive. In order to establish a correct and practicable link between increased TrkB and prognostication of human solid tumors, a meta-analysis was performed in this article. A systematic literature research in the electronic databases PubMed, Embase and Web of Science was performed to identify eligible studies. A fixed-effects meta-analytical model was employed to correlate TrkB expression with OS, DFS and clinicopathological features. A total of 11 studies covering 1516 patients with various solid tumors were recruited in this meta-analysis. TrkB over-expression was associated with poorer OS and poorer DFS in multivariate analysis. Additionally, the pooled odds ratios (ORs) indicated that TrkB over-expression was associated with large tumor size, lymph node metastasis, distant metastasis and a higher clinical stage. Overall, these results indicated that TrkB over-expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognosis factor.
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http://dx.doi.org/10.18632/oncotarget.19561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725101PMC
November 2017

Resveratrol ameliorates ionizing irradiation-induced long-term immunosuppression in mice.

Int J Radiat Biol 2018 01 12;94(1):28-36. Epub 2017 Dec 12.

a Department of Oncology , Institute of Integrative Oncology, Tianjin Union Medical Center , Tianjin , China.

Purpose: Ionizing radiation has been associated with adverse effects on the immune system. Currently, there are no effective treatment options to ameliorate these effects. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced long-term immunosuppression in mice.

Materials And Methods: Mice were exposed to total body irradiation and treated with resveratrol or vehicle. Several immune parameters were measured, including thymus and spleen weights, T-lymphocyte and B-lymphocyte count in peripheral blood, concanavalin A and lipopolysaccharide induced lymphocyte proliferation. To explore the mechanism, we investigated intracellular ROS level of lymphocytes and mice plasma cytokine levels.

Results: Treatment with resveratrol ameliorated TBI-induced atrophy of the thymus and spleen, reduction of lymphocyte count and decline of lymphocyte proliferation. TBI exhibited significantly reduced level of IL-2, IL-4, IL-7 and IFN-γ compared with the control mice and treatment with resveratrol attenuated the reduction.

Conclusion: The results of the present study suggest that treatment with resveratrol could ameliorate irradiation induced long-term immune malfunction at least partly via modulation of plasma cytokine.
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http://dx.doi.org/10.1080/09553002.2018.1408976DOI Listing
January 2018

Identification of genes involved in the four stages of colorectal cancer: Gene expression profiling.

Mol Cell Probes 2018 02 24;37:39-47. Epub 2017 Nov 24.

Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, PR China. Electronic address:

Background: Colorectal cancer (CRC) is a common cancer with high morbidity and mortality. However, its molecular mechanism is not clear, nor the genes related to CRC stages.

Methods: Gene expression data in CRC and healthy colorectal tissues were obtained from gene expression omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between control and CRC (stage I, II, III, and IV), obtaining 4 DEG sets. VennPlex was utilized to find all DEGs and intersection DEGs. Functional interactions between all DEGs and protein-protein interactions (PPIs) between intersection DEGs were analyzed using ReactomeFIViz and STRING, respectively, and networks were visualized. Known CRC-related genes were down-loaded from Comparative Toxicogenomics Database and mapped to PPI network.

Results: Totally, 851, 760, 729, and 878 DEGs were found between control and CRC stage I, II, III, and IV, respectively. Taken together, 1235 DEGs were found, as well as 128 up-regulated intersection DEGs, 365 down-regulated intersection DEGs, and 0 contra-regulated DEG. A functional interaction network of all DEGs and a PPI network of intersection DEGs were constructed, in which CDC20, PTTG1, and MAD2L1 interacted with BUB1B; UGT2B17 interacted with ADH1B; MCM7 interacted with MCM2. BUB1B, ADH1B, and MCM2 were known CRC-related genes. Gradually upregulated expressions of CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 in stage I, II, III, and IV CRC were confirmed by using quantitative PCR. Besides, up-regulated intersection DEGs enriched in pathways about Cell cycle, DNA replication, and p53 signaling.

Conclusion: CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 might be CRC stage-related genes.
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http://dx.doi.org/10.1016/j.mcp.2017.11.004DOI Listing
February 2018

Common genetic variant rs3802842 in 11q23 contributes to colorectal cancer risk in Chinese population.

Oncotarget 2017 Sep 31;8(42):72227-72234. Epub 2017 Jul 31.

Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China.

A genome-wide association study identified a common genetic variant rs3802842 at 11q23 to be associated with CRC risk with OR=1.1 and = 5.80E-10 in European population. In Chinese population, several genetic association studies have investigated the association between rs3802842 variant and CRC risk. However these studies reported both positive and negative association results. It is still necessary to evaluate a specific variant in a specific population, which would be informative to reveal the disease mechanism. Until recently, there is no a systemic study to evaluate the potential association between rs3802842 and CRC risk in Chinese population by a meta-analysis method. Here, we aim to evaluate this association in Chinese population by a meta-analysis method using 12077 samples including 5816 CRC cases and 6261 controls. We identified the T allele of rs3802842 to be significantly related with an increase CRC risk (=2.22E-05, OR=1.14, 95% CI 1.07-1.21) in Chinese population.
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http://dx.doi.org/10.18632/oncotarget.19702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641125PMC
September 2017

Connexin 43 enhances paclitaxel cytotoxicity in colorectal cancer cell lines.

Exp Ther Med 2017 Aug 13;14(2):1212-1218. Epub 2017 Jun 13.

Laboratory of Biomedicine and Nanophotonics, Tianjin Union Medical Center, Tianjin 300121, P.R. China.

Colorectal cancer has a relatively low sensitivity to paclitaxel. The purpose of this study was to investigate the role of connexin 43 (Cx43), which is a structural component of gap junctional communication (GJC), in paclitaxel cytotoxicity in colorectal cancer cells. Three colorectal cancer cell lines (HCT106, HCT116 and LoVo) were transfected with Cx43 and used to examine paclitaxel cytotoxicity. A western blot assay was used to confirm Cx43 expression in transfected cell lines as well as the expression of several proteins that are associated with paclitaxel cytotoxicity. A parachute dye-coupling assay was used to measure GJC function. An MTT assay was used to analyze the viability of paclitaxel-treated cells. Cx43 expression level and GJC function were significantly upregulated by the transfection (P<0.05). The viability of transfected cells was significantly inhibited compared with that of untransfected cells when treated with paclitaxel (20 or 80 nM) at high culture density but not at low culture density (P<0.05). Cx43 transfection significantly increased the mitotic arrest, tubulin polymerization and apoptosis effects of paclitaxel (P<0.05). It was also found that paclitaxel had an inhibitory effect on GJC function after 12 h of treatment in LoVo cells (P<0.05). These results indicate that Cx43 may serve as a target of paclitaxel chemotherapy for colorectal cancer.
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http://dx.doi.org/10.3892/etm.2017.4589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526126PMC
August 2017

SMAD7 rs4939827 variant contributes to colorectal cancer risk in Chinese population.

Oncotarget 2017 Jun;8(25):41125-41131

Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China.

A genome-wide association study identified a common genetic variant rs4939827 at 18q21 in SMAD7 to be related with colorectal cancer (CRC) risk with OR=1.2 and P =7.80E-28. Until recently, several meta-analysis studies have been conducted, and reported significant association between rs4939827 and CRC risk. However none of these studies evaluated the potential association between rs4939827 and CRC risk in Chinese population. In this study, we evaluated this association by a meta-analysis using 12077 samples including 5816 CRC cases and 6261 controls. In the end, we identified the T allele of rs4939827 to be significantly related with an increase CRC risk (P=2.22E-05, OR=1.14, 95% CI 1.07-1.21) in Chinese population.
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http://dx.doi.org/10.18632/oncotarget.17065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522279PMC
June 2017

Kanglaite sensitizes colorectal cancer cells to Taxol via NF-κΒ inhibition and connexin 43 upregulation.

Sci Rep 2017 04 28;7(1):1280. Epub 2017 Apr 28.

Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii at Manoa 2538 McCarthy Mall, Snyder Hall, Honolulu, HI, 96822, USA.

Taxol, a first-line anti-tumour drug, has low effectiveness against colorectal cancer. Combination with other agents is an effective strategy to enhance Taxol cytotoxicity. Kanglaite injection is an extract from Coix lacryma-jobi seed and is usually combined with other agents to treat cancer. The aim of this study was to investigate the treatment effect of Taxol combined with Kanglaite on colorectal cancer cell lines. Kanglaite pretreatment followed by Taxol treatment was found to show the best synergism among all combination strategies. This combination also resulted in the smallest tumour volume in a Balb/c mice model. Kanglaite inhibited the expression of nuclear factor (NF)-κΒ and upregulated that of connexin 43, both of which sensitized cancer cells to Taxol. Moreover, Kanglaite increased many cellular variations caused by Taxol, including tubulin polymerization, caspase-3 cleavage, and upregulated expression of survivin and cyclin B1. These results suggest that Kanglaite pretreatment may increase the effect of Taxol on colorectal cancer.
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http://dx.doi.org/10.1038/s41598-017-01480-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430786PMC
April 2017

Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms.

Molecules 2016 Nov 29;21(12). Epub 2016 Nov 29.

Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin 300070, China.

As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 μM for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC of 0.84 μM and 11.28 μM for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver-Burk plot versus the concentrations of CAG, the inhibition constant () was calculated to be 0.034 μM and 20.98 μM for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/ standard ([I]/ < 0.1, low possibility; 1 > [I]/ > 0.1, medium possibility; [I]/ > 1, high possibility), it was successfully predicted here that an in vivo herb-drug interaction between AST/CAG and drugs mainly undergoing UGT1A8- or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 μM and 20.98 μM, respectively.
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http://dx.doi.org/10.3390/molecules21121616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274106PMC
November 2016

Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury.

Arch Toxicol 2017 May 16;91(5):2235-2244. Epub 2016 Nov 16.

Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.
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http://dx.doi.org/10.1007/s00204-016-1877-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331015PMC
May 2017

Investigation of an SPR biosensor for determining the influence of connexin 43 expression on the cytotoxicity of cisplatin.

Analyst 2016 May;141(11):3411-20

Institute of Micro & Nano Optics, Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China.

The real-time and label free detection abilities of surface plasmon resonance (SPR) biosensors provide a way of evaluating the influence of some genes' expression on anti-tumor drug cytotoxicity. However, studies in this field are lacking. Connexin 43 is a tumor suppressor gene and the mechanism of its effect in cisplatin cytotoxicity is still unclear. A phase SPR biosensor was used to determine the influence of connexin 43 expression on cisplatin cytotoxicity in three cancer cell lines. The results showed that the SPR signal curves have two stages. In the first hour, the SPR signal shows dramatic changes which are related to connexin 43 expression. In the subsequent stage, the SPR signal slowly declines and is related to apoptosis. Comparison of SPR measurements from several conventional biological assays showed that connexin 43 expression can affect cellular response to cisplatin in the period of oxidative stress, and results in the cells being more sensitive to cisplatin. The conclusion is further confirmed by long-term SPR measurement results and cellular morphological changes.
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http://dx.doi.org/10.1039/c6an00264aDOI Listing
May 2016

A Meta-analysis on the Effect of Ulinastatin on Serum Levels of C-Reactive Protein, Interleukin 6, and Tumor Necrosis Factor Alpha in Asian Patients with Acute Pancreatitis.

Genet Test Mol Biomarkers 2016 Mar 18;20(3):118-24. Epub 2016 Jan 18.

1 Department of Colorectal Surgery, Tianjin Union Medicine Centre , Tianjin, P.R. China .

Objectives: We aimed to investigate the influence of ulinastatin (UTI) on the serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in Asian patients with acute pancreatitis (AP) by performance of a meta-analysis.

Methods: Two investigators independently searched 11 databases, including PUBMED, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Cochrane Library, Wanfang database, China National Knowledge Infrastructure (CNKI), Chinese Journal Full-text Database, and China Biomedicine Database. The full-text articles were screened and the data were extracted using a standardized data extraction form. All statistical analyses were conducted with Stata software, version 12.0 (Stata Corporation, College Station, TX).

Results: A total of 94 studies were initially retrieved, and 10 studies containing 424 Asian patients with AP were ultimately enrolled in this meta-analysis. The results revealed that the serum levels of CRP, IL-6, and TNF-α in Asian AP patients significantly decreased after UTI therapy (CRP: standardized mean difference [SMD] = 3.26, 95% confidence interval [CI] = 1.69-4.83, p < 0.001; IL-6: SMD = 5.92, 95% CI = 2.09-9.75, p = 0.002; TNF-α: SMD = 4.07, 95% CI = 0.79-7.35, p = 0.015).

Conclusion: The results of this meta-analysis suggest that UTI can effectively depress the serum levels of CRP, IL-6, and TNF-α in Asian patients with AP, and thereby inhibit inflammation.
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http://dx.doi.org/10.1089/gtmb.2015.0192DOI Listing
March 2016

Micheliolide overcomes KLF4-mediated cisplatin resistance in breast cancer cells by downregulating glutathione.

Onco Targets Ther 2015 28;8:2319-27. Epub 2015 Aug 28.

Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.

Micheliolide (MCL) is a promising novel compound with broad-spectrum anticancer activity. However, little is known regarding its action and mechanism in breast cancer. To explore the potential therapeutic application of MCL as a chemosensitivity modulator, this study investigated the effects of MCL on cisplatin sensitivity in breast cancer and the underlying mechanisms. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay and a xenograft tumor model, MCL enhanced the cisplatin sensitivity of the breast cancer cell line MCF-7 both in vitro and in vivo. Treatment of MCF-7 cells with low-dose cisplatin (10 µM) was sufficient to enrich the proportion of ALDH(+) cells and upregulate Krüppel-like factor 4 (KLF4) expression. The results obtained from knockdown and overexpression experiments demonstrate that KLF4 is both necessary and sufficient to induce a cisplatin resistance phenotype in breast cancer cells. Furthermore, the glutathione (GSH) content was elevated in MCF-7 cells after overexpression of KLF4. KLF4-mediated resistance to cisplatin was found to be abrogated by treatment with buthionine sulfoximine, an inhibitor of GSH synthesis. MCL induced GSH depletion and severe cell death in KLF4-overexpressing MCF-7 cells following exposure to cisplatin. Therefore, these results suggest that MCL-mediated direct depletion of GSH represents a major mechanism in reversing KLF4-induced cisplatin resistance in MCF-7 cells.
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http://dx.doi.org/10.2147/OTT.S88661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559251PMC
September 2015

One case of inflammatory myofibroblastic tumor--a case report.

J Cancer Res Ther 2015 Aug;11 Suppl 1:C131-3

Tianjin State Key Laboratory of Modern Chinese Medicine, Institute of Traditional Chinese Medicine Research, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.

Inflammatory myofibroblastic tumor is a rare mesenchymal tumor, it can also be found on the trunk, head and neck, internal organs, and soft tissue. It has been named as inflammatory pseudotumor, plasma cell granuloma, solitary mast cell tumor, pseudotumor pneumonia and tissue cells, and other inflammatory pseudotumor. The main treatment of inflammatory myofibroblastic tumor patients is through surgical complete excision of the lesion.
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http://dx.doi.org/10.4103/0973-1482.163872DOI Listing
August 2015