Publications by authors named "Xiaoren Zhang"

40 Publications

Full-dimensional quantum dynamics study of isotope effects for the H + NH/ND/NHD and H/D/HD + NH reactions.

J Chem Phys 2021 Feb;154(7):074301

State Key Laboratory of Molecular Reaction Dynamics and Center for Theoretical and Computational Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People's Republic of China.

A full-dimensional quantum dynamical study for the bimolecular reactions of hydrogen molecules with amino radicals for different isotopologues is reported. The nonreactive amino radical is described by two Radau vectors that are very close to the valence bond coordinates. Potential-optimized discrete variable representation basis is used for the vibrational coordinates of the amino radical. Starting from the reaction H + NH, we study the isotope effects for the two reagents separately, i.e., H + NH/ND/NHD and H/D/HD + NH. The effects of different vibrational mode excitations of the reagents on the reactivities are studied. Physical explanations about the isotope effects are also provided thoroughly including the influence of vibrational energy differences between the different isotopologues and the impact of the tunneling effect.
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http://dx.doi.org/10.1063/5.0040002DOI Listing
February 2021

The critical role of T cells in glucocorticoid-induced osteoporosis.

Cell Death Dis 2020 Dec 14;12(1):45. Epub 2020 Dec 14.

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, Jiangsu, 215123, China.

Glucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.
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http://dx.doi.org/10.1038/s41419-020-03249-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791068PMC
December 2020

Chitinase-3 like-protein-1 function and its role in diseases.

Signal Transduct Target Ther 2020 09 14;5(1):201. Epub 2020 Sep 14.

Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China.

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4 T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.
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http://dx.doi.org/10.1038/s41392-020-00303-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490424PMC
September 2020

Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer.

J Exp Clin Cancer Res 2020 Aug 28;39(1):172. Epub 2020 Aug 28.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.

Background: Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored.

Methods: Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222-succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments.

Results: Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration.

Conclusions: Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC.
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http://dx.doi.org/10.1186/s13046-020-01681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455916PMC
August 2020

Reversible acetylation modulates dishevelled-2 puncta formation in canonical Wnt signaling activation.

Signal Transduct Target Ther 2020 07 6;5(1):115. Epub 2020 Jul 6.

Institutes of Biology and Medical Sciences, Soochow University Medical College, 215000, Suzhou, Jiangsu, China.

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http://dx.doi.org/10.1038/s41392-020-00229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338394PMC
July 2020

Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer.

Signal Transduct Target Ther 2020 05 1;5(1):52. Epub 2020 May 1.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200025, China.

Wnt/β-catenin signaling plays a critical role in colorectal cancer (CRC) tumorigenesis and the homeostasis of colorectal cancer stem cells (CSCs), but its molecular mechanism remains unclear. B-cell lymphoma 3 (Bcl-3), a member of the IκB family, is overexpressed in CRC and promotes tumorigenicity. Here, we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling. Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential for β-catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to β-catenin and enhances the acetylation of β-catenin at lysine 49 (Ac-K49-β-catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from β-catenin, thus interrupting Wnt/β-catenin activity. In CRC clinical specimens, Bcl-3 expression negatively correlates with the overall survival of CRC patients. A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin. Collectively, our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin, which serves as a promising therapeutic target for CRC.
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http://dx.doi.org/10.1038/s41392-020-0138-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193563PMC
May 2020

Critical role of histone H3 lysine 27 demethylase Kdm6b in the homeostasis and function of medullary thymic epithelial cells.

Cell Death Differ 2020 Oct 28;27(10):2843-2855. Epub 2020 Apr 28.

Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou, 510000, China.

Medullary thymic epithelial cells (mTECs) play a central role in the establishment of T cell central immunological tolerance by promiscuously expressing tissue-restricted antigens (TRAs) and presenting them to developing T cells, leading to deletion of T cells responding to self-antigens. However, molecular mechanisms especially epigenetic regulation of mTEC homeostasis and TRA expression remain elusive. Here we show that the H3K27 demethylase Kdm6b is essential to maintain the postnatal thymic medulla by promoting mTEC survival and regulating the expression of TRA genes. Moreover, mice lacking Kdm6b developed pathological autoimmune disorders. Mechanically, Kdm6b exerted its function by reducing repressive H3K27 trimethylation (H3K27me3) at the promoters of anti-apoptotic gene Bcl2 and a set of Aire-dependent TRA genes. Thus, our findings reveal a dual role of Kdm6b in the regulation of mTEC-mediated T cell central tolerance.
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http://dx.doi.org/10.1038/s41418-020-0546-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493893PMC
October 2020

PBX1 expression in uterine natural killer cells drives fetal growth.

Sci Transl Med 2020 04;12(537)

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.

Abundant decidual natural killer (dNK) cells at the maternal-fetal interface are important during early pregnancy. However, functional subsets of dNK cells remain poorly understood. We describe a CD49aPBX homeobox 1 (PBX1) dNK cell subset that promotes fetal development in humans and mice. The expression of PBX1 in dNK cells is up-regulated via the activated AKT1 pathway through the interaction of major histocompatibility complex G with the immunoglobulin-like transcript 2 receptor. PBX1 drives pleiotrophin and osteoglycin transcription in dNK cells, further promoting fetal development. Decreased PBX1 expression or the PBX1 mutant correlated with fetal growth restriction and pregnancy failure in patients with unexplained recurrent spontaneous abortion (URSA). Inactivation of in mouse dNK cells impairs fetal development by decreasing growth-promoting factors from CD49aPBX1 dNK cells. Impairment of PBX1 in dNK cells has positive correlation with URSA pathogenesis and may provide a potential marker for this condition.
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http://dx.doi.org/10.1126/scitranslmed.aax1798DOI Listing
April 2020

PBX1 promotes development of natural killer cells by binding directly to the Nfil3 promoter.

FASEB J 2020 05 19;34(5):6479-6492. Epub 2020 Mar 19.

Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.

The transcription factor nuclear factor interleukin-3-regulated protein (NFIL3, also called E4BP4) is crucial for commitment of natural killer (NK) cells from common lymphoid progenitors (CLPs). However, the identity of the factor that can regulate NFIL3 directly during the NK-cell development is not known. Here, we reveal that pre-B-cell leukemia transcription factor 1 (PBX1) can upregulate the NFIL3 expression directly. We used conditional knockout mice in which PBX1 in hematopoietic cells was specifically absent. The number of NK-committed progenitor pre-NKP cells and rNKP cells was reduced significantly in the absence of PBX1, which was consistent with NFIL3 deficiency. Also, the NFIL3 expression in NK cells was decreased if PBX1 was absent. We demonstrated that PBX1 was bound directly to the promoter of Nfil3 and facilitated transcription. Upon knockout of the binding site of PBX1 in the Nfil3 promoter, mice showed fewer NK-precursor cells and NK cells, just like that observed in Nfil3 knockout mice. Furthermore, asparagine N286 in the homeodomain of PBX1 controlled the binding of PBX1 to the Nfil3 promoter. Collectively, these findings demonstrate that the transcription factor PBX1 promotes the early development of NK cells by upregulating the Nfil3 expression directly.
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http://dx.doi.org/10.1096/fj.202000121RDOI Listing
May 2020

Feshbach resonances in the F + HO → HF + OH reaction.

Nat Commun 2020 Jan 13;11(1):223. Epub 2020 Jan 13.

State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.

Transiently trapped quantum states along the reaction coordinate in the transition-state region of a chemical reaction are normally called Feshbach resonances or dynamical resonances. Feshbach resonances trapped in the HF-OH interaction well have been discovered in an earlier photodetchment study of FHO; however, it is not clear whether these resonances are accessible by the F + HO reaction. Here we report an accurate state-to-state quantum dynamics study of the F + HO → HF + OH reaction on an accurate newly constructed potential energy surface. Pronounced oscillatory structures are observed in the total reaction probabilities, in particular at collision energies below 0.2 eV. Detailed analysis reveals that these oscillating structures originate from the Feshbach resonance states trapped in the hydrogen bond well on the HF(v' = 2)-OH vibrationally adiabatic potentials, producing mainly HF(v' = 1) product. Therefore, the resonances observed in the photodetchment study of FHO are accessible to the reaction.
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http://dx.doi.org/10.1038/s41467-019-14097-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957676PMC
January 2020

Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses.

Nat Commun 2019 07 3;10(1):2935. Epub 2019 Jul 3.

Affiliated Cancer Hospital & Institute, Guangzhou Medical University, 510000, Guangzhou, China.

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.
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http://dx.doi.org/10.1038/s41467-019-11002-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610088PMC
July 2019

Fibrotic liver microenvironment promotes Dll4 and SDF-1-dependent T-cell lineage development.

Cell Death Dis 2019 06 5;10(6):440. Epub 2019 Jun 5.

The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Soochow University Medical College, Suzhou, China.

The reconstitution of the T-cell repertoire and quantity is a major challenge in the clinical management of HIV infection/AIDS, cancer, and aging-associated diseases. We previously showed that autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4 T-cell count in AIDS patients also suffering from decompensated liver cirrhosis. In the current study, we characterized T-cell reconstitution in a mouse model of liver fibrosis induced by CCl and found that T-cell reconstitution after BMT via hepatic portal vein was also greatly enhanced. The expression of Dll4 (Delta-like 4), which plays an important role in T-cell progenitor expansion, was elevated in hepatocytes of fibrotic livers when compared to normal livers. This upregulation of Dll4 expression was found to be induced by TNFα in an NFκB-dependent manner. Liver fibroblasts transfected with Dll4 (LF-Dll4) also gained the capacity to promote T-cell lineage development from hematopoietic stem cells (HSCs), resulting in the generation of DN2 (CD4 and CD8 DN 2) and DN3 T-cell progenitors in vitro, which underwent a normal maturation program when adoptively transferred into Rag-2 deficient hosts. We also demonstrated a pivotal role of SDF-1 produced by primary liver fibroblasts (primary LF) in T-lineage differentiation from HSCs. These results suggest that Dll4 and SDF-1 in fibrotic liver microenvironment could promote extrathymic T-cell lineage development. These results expand our knowledge of T-cell development and reconstitution under pathological conditions.
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http://dx.doi.org/10.1038/s41419-019-1630-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549170PMC
June 2019

Elevating H3K27me3 level sensitizes colorectal cancer to oxaliplatin.

J Mol Cell Biol 2020 02;12(2):125-137

The Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, 227 Chongqing South Road, Shanghai, China.

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
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http://dx.doi.org/10.1093/jmcb/mjz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109602PMC
February 2020

A pilot study of new promising non-coding RNA diagnostic biomarkers for early-stage colorectal cancers.

Clin Chem Lab Med 2019 06;57(7):1073-1083

Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, P.R. China.

Background Diagnostic biomarkers for the detection of colorectal cancers (CRCs) are lacking. Recent studies have demonstrated that circulating long non-coding RNAs have the potential to serve as biomarkers for the detection of cancers. We analyzed the significance of lncRNAs 91H, PVT-1 and MEG3 in the detection of CRC. Methods We examined the expression levels of 13 candidate lncRNAs in the plasma of 18 CRC patients and 20 non-cancerous controls. Then, we validated our findings by determining the expression levels of six promising lncRNAs in CRC tissues and normal colorectal tissues. Finally, we evaluated the clinical relevance of lncRNAs 91H, PVT-1 and MEG3 in the plasma of 58 CRC patients and 56 non-cancerous controls. Results Our data revealed that the expression levels of lncRNAs 91H, PVT-1 and MEG3 were significantly higher in plasma samples from CRC patients than in those from non-cancerous controls. The combination of 91H, PVT-1 and MEG3 could discriminate CRC patients from non-cancerous controls with an area under the receiver-operating curve (AUC) of 0.877 at a cut-off value of 0.3816, with a sensitivity of 82.76% and 78.57% specificity. More importantly, the combination of lncRNAs shows more sensitivity in the detection of early-stage CRC than the combination of CEA and CA19-9, biomarkers currently used for CRC detection (p < 0.0001). Conclusions lncRNAs 91H, PVT-1 and MEG3 are promising diagnostic biomarkers for early-stage CRC.
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http://dx.doi.org/10.1515/cclm-2019-0052DOI Listing
June 2019

STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation.

EMBO J 2019 03 15;38(6). Epub 2019 Feb 15.

Institutes of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu, China

T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.
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http://dx.doi.org/10.15252/embj.201899595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418461PMC
March 2019

POH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity.

Nat Commun 2018 10 12;9(1):4225. Epub 2018 Oct 12.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China.

Inflammasome activation is essential for host defence against invading pathogens, but is also involved in various forms of inflammatory diseases. The processes that control inflammasome activity are thus important for averting excessive immune responses and tissue damage. Here we show that the deubiquitinase POH1 negatively regulates the immune response triggered by inflammasome activation. POH1 deficiency in macrophages enhances mature IL-1β production without significant alterations in inflammasome priming and ASC-caspase-1 activation. In WT macrophages, POH1 interacts with and deubiquitinates pro-IL-1β by decreasing the K63-linked polyubiquitin chains, as well as decreases the efficacy of pro-IL-1β cleavage. Furthermore, myeloid cell-specific deletion of POH1 aggravates lipopolysaccharide-induced systemic inflammation and alum-induced peritonitis inflammatory responses in vivo. Our study thereby reveals that POH1-mediated deubiquitination of pro-IL-1β is an important regulatory event that restrains inflammatory responses for the maintenance of immune homeostasis.
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http://dx.doi.org/10.1038/s41467-018-06455-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185913PMC
October 2018

Bcl-3 promotes proliferation and chemosensitivity in BL1 subtype of TNBC cells.

Acta Biochim Biophys Sin (Shanghai) 2018 Nov;50(11):1141-1149

Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.

Bcl-3 is an established oncogene in diverse malignant tumors. In this study, we investigated a dual role of Bcl-3 in BL1-subtype triple-negative breast cancer (TNBC). The BL1-subtype TNBC is featured by increasing cell cycle gene expression and the highest sensitivity to chemotherapy among all subtypes. Bcl-3 is associated with a better prognosis in BL1 patients. Bcl-3 knockdown in BL1 cell MDA-MB-468 induces the inhibition of cell proliferation and the G1/S transition arrest by promoting p27 and reducing the expressions of c-Myc and skp2 at mRNA and protein levels. Meanwhile, Bcl-3 enhances the sensitivity of MDA-MB-468 to chemotherapeutics ABX and PTX. Furthermore, the regulation mechanisms are restricted to BL1 cell and do not occur in SUM159PT, a typical MSL subtype of TNBC cell. These data suggest that Bcl-3 may be a potential clinical biomarker for diagnosis, treatment, and prognosis of patients with BL1-subtype TNBC.
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http://dx.doi.org/10.1093/abbs/gmy117DOI Listing
November 2018

Alternative NF-κB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3.

Oncogene 2018 11 4;37(44):5887-5900. Epub 2018 Jul 4.

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200025, China.

Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27 protein level, which inhibits CRC cell proliferation and retards CRC xenograft growth. Conversely, overexpression of RelB increases proliferation of CRC cells. In addition, we revealed a significant correlation between Bcl-3 and RelB in CRC tissues. The expression of RelB was consistent with the expression of Bcl-3 and the phosphorylation of Bcl-3 downstream proteins p-Akt (S473) and p-GSK3β (S9). Bcl-3 overexpression can restore the phenotype changes caused by RelB knockdown. Importantly, we demonstrated that alternative NF-κB transcriptional factor (p52:RelB) can directly bind to the promoter region of Bcl-3 gene and upregulate its transcription. Moreover, the expression of RelB, NF-κB2 p52, and Bcl-3 was associated with poor survival of CRC patients. Taken together, these results represent that alternative NF-κB signaling may function as an oncogenic driver in CRC, and also provide new ideas and research directions for the pathogenesis, prevention, and treatment of other inflammatory-related diseases.
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http://dx.doi.org/10.1038/s41388-018-0363-4DOI Listing
November 2018

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis.

Cancer Res 2018 06 12;78(11):2825-2838. Epub 2018 Mar 12.

Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation. CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2314DOI Listing
June 2018

Bcl-3 is a novel biomarker of renal fibrosis in chronic kidney disease.

Oncotarget 2017 Nov 9;8(57):97206-97216. Epub 2017 Oct 9.

Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.

Progressive renal fibrosis in chronic kidney disease (CKD) greatly contributes to end-stage renal failure and is associated with high mortality. The identification of renal fibrosis biomarkers for the diagnosis and the monitoring of disease progression in CKD is urgently needed. Whole-transcriptomic analysis of renal tissues in a unilateral ureteral obstruction (UUO) mouse model revealed that the mRNA level of Bcl-3, an atypical member of the IκB family, was induced 6.3-fold 2 days after UUO. Compared with renal tissues in sham-operated mice, increases in Bcl-3 mRNA and protein in the renal tissues in the UUO model were accompanied with increases in other markers of renal fibrosis, including human epididymis protein 4 (HE4), a recently identified biomarker of renal fibrosis. Immunohistochemical analysis revealed that both Bcl-3 and HE4 were located in the plasma of renal tubule cells. Serum protein levels of Bcl-3 and HE4 rose with the development of renal fibrosis in UUO mouse model. We found that the serum protein levels of both HE4 and Bcl-3 were elevated in CKD patients compared with healthy controls. Moreover, a significant positive correlation between Bcl-3 and HE4 (r = 0.939, p < 0.0001) was observed in CKD patients. These data suggest that Bcl-3 can serve as a novel valuable biomarker of renal fibrosis in CKD.
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http://dx.doi.org/10.18632/oncotarget.21692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722556PMC
November 2017

Heterologous expression, purification and function of the extracellular domain of human RANK.

BMC Biotechnol 2017 Dec 4;17(1):87. Epub 2017 Dec 4.

Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Background: Receptor activator of NF-κB ligand (RANKL)/RANK signaling essentially functions within the skeletal system, particularly participating in osteoclastogenesis and bone resorption. In addition, this signaling pathway has also been shown to influence tumor progression as well as the development and function of the immune system. Therefore, blocking the interaction between RANKL and RANK is a new therapeutic approach to prevent bone-related diseases and cancer.

Results: The coding sequence encoding the extracellular domain of human RANK (RANK-N) was codon optimized for Pichia pastoris and cloned into the pPIC9K vector, and the recombinant plasmid was then transformed into P. pastoris. The expression of RANK-N protein was confirmed using SDS-PAGE with Coomassie Brilliant Blue stain and western blotting. Recombinant RANK-N protein was purified by a multistep process including ultrafiltration (UF), Sephadex G-50 size-exclusion chromatography and Q-Sepharose Fast Flow ion exchange chromatography, which resulted in a purity >95%. We found that the RANK-N protein can block RANKL-RANK signaling both in vitro and in vivo. Furthermore, using a patient-derived xenograft of human colon cancer, we found that the recombinant RANK-N protein can inhibit the growth of colorectal cancer.

Conclusions: The results show that a simple system to express and purify functional RANK-N protein has been developed. This work has thus laid a foundation for further research and clinical applications of RANK-N protein in treating bone-related diseases or even colorectal cancer.
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http://dx.doi.org/10.1186/s12896-017-0405-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716252PMC
December 2017

microRNA-449a modulates medullary thymic epithelial cell differentiation.

Sci Rep 2017 Nov 21;7(1):15915. Epub 2017 Nov 21.

Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Medullary thymic epithelial cells (mTECs) ectopically express a diversity of peripheral tissue-restricted antigens (PTAs) and provide unique cues for the expansion, maturation and selection of a repertoire of functionally diverse T lymphocytes. Genetic deletion of all mature microRNAs in thymic epithelial cells (TECs) results in premature thymic involution, progressive disorganisation of the thymic epithelium, and alteration in thymic T cell lineage commitment, consequently eliciting autoimmune disorders. In the present study, we identified that microRNA-449a (miR-449a), a member of miR-449 cluster, regulated mTEC differentiation. Expression of miR-449a was induced by RANK ligand in mouse fetal thymus. In in vitro studies, overexpression of miR-449a induced thymic epithelial progenitor cells (TEPCs) differentiation into mature mTECs. Despite abundant expression of miR-449a in developing thymus, miR-449a-mutant mice exhibited normal thymic development. This might be partially due to in miR-449a-mutant thymus the up-regulation of miR-34a which shared similar seed sequence with miR-449a. However, thymic expression of miR-449/34 sponge which was able to neutralize the function of miR-449/34 family members significantly reduced the number of mature Ly51MHCII mTECs. Taken together, our data suggested that miR-449a modulated mTEC differentiation, and members of miR-34 cluster functioned redundantly to rescue miR-449a deficiency in thymus development.
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http://dx.doi.org/10.1038/s41598-017-16162-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698406PMC
November 2017

Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation.

Mol Cell 2017 Jan 5;65(2):296-309. Epub 2017 Jan 5.

Institute of Health Sciences, Chinese Academy of Sciences, Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China. Electronic address:

In mammalian cells, histone deacetylase (HDAC) and Sirtuin (SIRT) are two families responsible for removing acetyl groups from acetylated proteins. Here, we describe protein deacetylation coupled with deacetylimination as a function of lysyl oxidase (LOX) family members. LOX-like 3 (Loxl3) associates with Stat3 in the nucleus to deacetylate and deacetyliminate Stat3 on multiple acetyl-lysine sites. Surprisingly, Loxl3 N-terminal scavenger receptor cysteine-rich (SRCR) repeats, rather than the C-terminal oxidase catalytic domain, represent the major deacetylase/deacetyliminase activity. Loxl3-mediated deacetylation/deacetylimination disrupts Stat3 dimerization, abolishes Stat3 transcription activity, and restricts cell proliferation. In Loxl3-/- mice, Stat3 is constitutively acetylated and naive CD4 T cells are potentiated in Th17/Treg cell differentiation. When overexpressed, the SRCR repeats from other LOX family members can catalyze protein deacetylation/deacetylimination. Thus, our findings delineate a hitherto-unknown mechanism of protein deacetylation and deacetylimination catalyzed by lysyl oxidases.
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http://dx.doi.org/10.1016/j.molcel.2016.12.002DOI Listing
January 2017

Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis.

Cell Death Dis 2016 12 1;7(12):e2508. Epub 2016 Dec 1.

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China.

Transforming growth factor beta (TGFβ) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the IκB family, serves as a critical regulator in TGFβ signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGFβ signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGFβ treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis.
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http://dx.doi.org/10.1038/cddis.2016.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5261001PMC
December 2016

miR-449a inhibits colorectal cancer progression by targeting SATB2.

Oncotarget 2017 Nov 28;8(60):100975-100988. Epub 2016 Jul 28.

Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, 200031, China.

miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.
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http://dx.doi.org/10.18632/oncotarget.10900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731849PMC
November 2017

Expression, purification and biological characterization of the extracellular domain of CD40 from Pichia pastoris.

BMC Biotechnol 2016 Jan 25;16. Epub 2016 Jan 25.

Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Rm. 1126, Biological Research Life Building A, Yueyang Rd 320, Shanghai, 200031, China.

Background: CD40, also called Bp50, is a novel member of the TNF receptor superfamily. Based on its important role in multiple physiological and pathological processes, the CD40 signaling pathway has become a vital target for treating transplantation, autoimmune diseases and cancers. This study generated a protein fragment that disrupts this signaling pathway.

Results: A DNA fragment encoding the extracellular domain of CD40 (CD40-N) has been codon-optimized and cloned into pPIC9K to create a Pichia pastoris expression and secretion strain. SDS-PAGE and Western blotting assays using the culture media from methanol-induced expression strains showed that recombinant CD40-N, a 27 kDa glycosylated protein, was secreted into the culture broth. The recombinant protein was purified to more than 90 % using Sephadex G-50 size-exclusion chromatography and Q Sepharose Fast Flow ion exchange. Finally, 120 mg of the protein was obtained at a relatively high purity from 3 l supernatant. Binding assay (ITC200 assay) shown the direct interaction of CD40-N and CD40 agonist antibody (G28-5). The bioactivity of recombinant CD40-N was confirmed by its ability to disrupt non-canonical NF-κB signaling activated by CD40 agonist antibody or CD40 ligand and to inhibit ant-CD40 agonist antibody-induced TNF-alpha expression in BJAB cells in vitro. In addition, our data indicate that the protein has curative potential in treating dextran sulfate sodium (DSS)-induced colitis in vivo.

Conclusions: The results show that the experimental procedure we have developed using P. pastoris can be used to produce large amounts of active CD40-N for research and industrial purposes. The protein fragment we have acquired has potential to be used in research or even treating inflammation diseases such as colitis.
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http://dx.doi.org/10.1186/s12896-016-0237-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727258PMC
January 2016

The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation.

J Mol Cell Biol 2015 Dec 3;7(6):505-16. Epub 2015 Apr 3.

Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China

Interleukin (IL) 17-producing T helper (Th17) cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases, such as multiple sclerosis, psoriasis, and ulcerative colitis. Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently, the participation of epigenetic modifications in the differentiation process has yet to be elucidated. We demonstrated here that histone H3 lysine-27 (H3K27) demethylation, predominantly mediated by the H3K27 demethylase Jmjd3, crucially regulated Th17 cell differentiation. Activation of naïve CD4(+) T cells immediately induced high expression of Jmjd3. Genetic depletion of Jmjd3 in CD4(+) T cells specifically impaired Th17 cell differentiation both in vitro and in vivo. Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficient CD4(+) T cells. Importantly, Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro. At the molecular level, Jmjd3 directly bound to and reduced the level of H3K27 trimethylation (me3) at the genomic sites of Rorc, which encodes the master Th17 transcription factor Rorγt, and Th17 cytokine genes such as Il17, Il17f, and Il22. Therefore, our studies established a critical role of Jmjd3-mediated H3K27 demethylation in Th17 cell differentiation and suggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.
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http://dx.doi.org/10.1093/jmcb/mjv022DOI Listing
December 2015

OVA12, a novel tumor antigen, promotes cancer cell growth and inhibits 5-fluorouracil-induced apoptosis.

Cancer Lett 2015 Feb 15;357(1):141-151. Epub 2014 Nov 15.

Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chong-Qing Road, Shanghai 200025, China. Electronic address:

To achieve a better understanding of mechanisms that underlie carcinogenesis and to identify novel target molecules for diagnosis and therapy of carcinoma, we previously identified 24 distinct gene clones by immunoscreening of a cDNA library derived from an ovarian cancer patient through SEREX analysis. Among these genes we focused on a novel gene termed OVA12 and which putatively encodes a 114-amino-acid protein. In the present study, we found that OVA12 was ubiquitously overexpressed in diverse human tumor cell lines. Interestingly, we noticed that overexpression of OVA12 promoted proliferation of cancer cells in vitro and accelerated tumor growth in nude mice as compared to controls. Conversely, specific downregulation of OVA12 inhibited tumor cell proliferation and tumor growth both in vitro and in vivo. Furthermore, OVA12 inhibited 5-FU-induced apoptosis through specific upregulation of Mcl-1 and survivin. These results demonstrate that OVA12 is able to promote tumor growth, suggesting that this antigen might be a new potential target for development of cancer therapy.
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http://dx.doi.org/10.1016/j.canlet.2014.11.023DOI Listing
February 2015

A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFκB and STAT3 in colorectal cancer cells.

Gastroenterology 2014 Oct 12;147(4):847-859.e11. Epub 2014 Jun 12.

Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Background & Aims: Constitutive activation of the transcription factors nuclear factor κB (NF-κB) and STAT3 is involved in the development and progression of human colorectal cancer (CRC). Little is known about how these factors become activated in cancer cells. We investigated whether microRNA miR-221 and miR-222 regulate NF-κB and signal transducer and activator of transcription 3 (STAT3) activation in human CRC cell lines.

Methods: CRC cell lines (HCT116 and RKO) were transfected with miR-221 or miR-222 mimics or inhibitors. The activity levels of NF-κB and STAT3 were measured in dual luciferase reporter assays. We used immunoblot and real-time polymerase chain reaction analyses to measure protein and messenger RNA (mRNA) levels. Cells were analyzed by proliferation, viability, and flow cytometry analyses. Mice were given injections of azoxymethane, followed by dextran sodium sulfate, along with control lentivirus or those expressing mRNAs that bind miR-221 and miR-222 (miR-221/miR-222 sponge). The levels of miR-221 and miR-222 as well as RelA, STAT3, and PDLIM2 mRNAs were measured in 57 paired CRC and adjacent nontumor tissues from patients.

Results: In CRC cell lines, mimics of miR-221 and miR-222 activated NF-κB and STAT3, further increasing expression of miR-221 and miR-222. miR-221 and miR-222 bound directly to the coding region of RelA mRNA, increasing its stability. miR-221 and miR-222 also reduced the ubiquitination and degradation of the RelA and STAT3 proteins by binding to the 3' untranslated region of PDLIM2 mRNA (PDLIM2 is a nuclear ubiquitin E3 ligase for RelA and STAT3). Incubation of CRC cells with miR-221 and miR-222 inhibitors reduced their proliferation and colony formation compared with control cells. In mice with colitis, injection of lentiviruses expressing miR-221/miR-222 sponges led to formation of fewer tumors than injection of control lentiviruses. Human CRC tissues had higher levels of miR-221 and miR-222 than nontumor colon tissues; increases correlated with increased levels of RelA and STAT3 mRNAs. Levels of PDLIM2 mRNA were lower in CRC than nontumor tissues.

Conclusions: In human CRC cells, miR-221 and miR-222 act in a positive feedback loop to increase expression levels of RelA and STAT3. Antagonism of miR-221 and miR-222 reduces growth of colon tumors in mice with colitis.
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http://dx.doi.org/10.1053/j.gastro.2014.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839969PMC
October 2014

The tumor promoter and NF-κB modulator Bcl-3 regulates splenic B cell development.

J Immunol 2013 Dec 15;191(12):5984-92. Epub 2013 Nov 15.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Bcl-3 is an atypical member of the family of IκB proteins. Unlike the classic members, Bcl-3 functions as a nuclear transcriptional cofactor that may, depending on context, promote or suppress genes via association with p50/NF-κB1 or p52/NF-κB2 homodimers. Bcl-3 is also an oncogene, because it is a partner in recurrent translocations in B cell tumors, resulting in deregulated expression. Bcl-3 functions, however, remain poorly understood. We have investigated the role of Bcl-3 in B cells and discovered a previously unknown involvement in the splenic development of these cells. Loss of Bcl-3 in B cells resulted in significantly more marginal zone (MZ) and fewer follicular (FO) B cells. Conversely, transgenic expression of Bcl-3 in B cells generated fewer MZ and more FO B cells. Both Bcl-3(-/-) FO and MZ B cells were more responsive to LPS stimulation compared with their wild-type counterparts, including increased proliferation. By contrast, Bcl-3(-/-) FO B cells were more prone to apoptosis upon BCR stimulation, also limiting their expansion. The data reveal Bcl-3 as a regulator of B cell fate determination, restricting the MZ path and favoring the FO pathway, at least in part, via increased signal-specific survival of the latter, a finding of relevance to its tumorigenic activity.
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http://dx.doi.org/10.4049/jimmunol.1300611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868497PMC
December 2013