Publications by authors named "Chundong Yu"

56 Publications

SRC-3 deficiency protects host from Listeria monocytogenes infection through increasing ROS production and decreasing lymphocyte apoptosis.

Int Immunopharmacol 2021 Apr 12;96:107625. Epub 2021 Apr 12.

Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China. Electronic address:

Listeria monocytogenes is the third major cause of death among food poisoning. Our previous studies have demonstrated that steroid receptor coactivator 3 (SRC-3) plays a critical protective role in host defense against extracellular bacterial pathogens such as Escherichia coli and Citrobacter rodentium. However, its role involved in intracellular bacterial pathogen infection remains unclear. Herein, we found that SRC-3 mice are more resistant to L. monocytogenes infection after tail intravenous injection with L. monocytogenes compared with wild-type mice. After infecting with L. monocytogenes, SRC-3 mice exhibited decreased mortality rate, decreased bacterial load, less body weight loss, less proinflammatory cytokines and less severe tissue damage compared with wild-type mice. SRC-3 mice produced more ROS and decreased L. monocytogenes-induced lymphocyte apoptosis. Mechanically, SRC-3 mice displayed decreased expressions of negative regulator of ROS (NRROS) and interferon (IFN)-β and its target genes such as Daxx, Mx1 and TRAIL associated with apoptosis. Taken together, SRC-3 deficiency can protect host from L. monocytogenes infection through increasing ROS production and decreasing lymphocyte apoptosis via affecting the expressions of NRROS and IFN-β.
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http://dx.doi.org/10.1016/j.intimp.2021.107625DOI Listing
April 2021

Correction to: Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression.

Oncogene 2021 Mar;40(12):2336-2337

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

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http://dx.doi.org/10.1038/s41388-021-01678-9DOI Listing
March 2021

Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.

J Biol Chem 2020 11 24:100121. Epub 2020 Nov 24.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China;. Electronic address:

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.
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http://dx.doi.org/10.1074/jbc.RA120.015335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948496PMC
November 2020

Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation.

Theranostics 2021 1;11(4):1672-1689. Epub 2021 Jan 1.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.
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http://dx.doi.org/10.7150/thno.47390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778610PMC
January 2021

Steroid Receptor Coactivator-3 Is Required for Inhibition of the Intestinal Muscularis Inflammatory Response of Postoperative Ileus in Mice.

Inflammation 2021 Jan 4. Epub 2021 Jan 4.

Department of Gastrointestinal Surgery, Ward 3 Areas of Cancer Center, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, 361003, China.

Inflammation theory has suggested that the pathogenesis of postoperative ileus (POI) involves the steroid receptor coactivator-3 (SRC-3). Therefore, we investigated the role of SRC-3 in the muscles of the small intestine using a mouse POI model. Here, we reported that intestinal manipulation (IM) significantly reduced the extent of phenol red migration in the entire gastrointestinal tract, and the calculated geometric center (GC) value in wild-type (WT) mice at 24 h after surgery was higher than that in the knockout (KO) mice and in the sham-operated control group. The expression of SRC-3 was upregulated in the mouse intestinal muscularis at 24 h after surgical manipulation, and the mRNA and protein levels of inflammatory cytokines were upregulated compared with those in the control group. At 24 h after IM, the number of neutrophils in the experimental group was significantly higher than that in the control group; in the IM group, the number of neutrophils in the SRC-3 mice was markedly higher than that in the WT mice. At 24 h after IM, the myeloperoxidase (MPO) activity in the experimental group was significantly higher than that in the control group. In the IM group, the MPO activity of the SRC-3 mice was markedly higher than that of the WT mice. In summary, proinflammatory cytokines, the number of neutrophils, and the MPO activity were significantly increased in the muscularis of the jejunum and ileum of KO mice after IM compared with those of the WT mice, indicating that SRC-3 might play a protective role in POI.
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http://dx.doi.org/10.1007/s10753-020-01409-4DOI Listing
January 2021

MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and suppresses Nrf2 signaling.

EMBO Rep 2021 Jan 4;22(1):e50854. Epub 2021 Jan 4.

Department of Pharmacy, National University of Singapore, Singapore, Singapore.

Nrf2 signaling is vital for protecting cells against oxidative stress. However, its hyperactivation is frequently found in liver cancer through excessive build-up of p62/SQSTM1 bodies that sequester Keap1, an adaptor of the E3-ubiquitin ligase complex for Nrf2. Here, we report that the Bax-binding protein MOAP-1 regulates p62-Keap1-Nrf2 signaling through disruption of p62 bodies. Upon induction of cellular stresses that stimulate formation of p62 bodies, MOAP-1 is recruited to p62 bodies and reduces their levels independent of the autophagy pathway. MOAP-1 interacts with the PB1-ZZ domains of p62 and interferes with its self-oligomerization and liquid-liquid phase separation, thereby disassembling the p62 bodies. Loss of MOAP-1 can lead to marked upregulation of p62 bodies, enhanced sequestration of Keap1 by p62 and hyperactivation of Nrf2 antioxidant target genes. MOAP-1-deficient mice exhibit an elevated tumor burden with excessive levels of p62 bodies and Nrf2 signaling in a diethylnitrosamine (DEN)-induced hepatocarcinogenesis model. Together, our data define MOAP-1 as a negative regulator of Nrf2 signaling via dissociation of p62 bodies.
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http://dx.doi.org/10.15252/embr.202050854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788458PMC
January 2021

Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression.

Oncogene 2020 11 28;39(47):7076-7091. Epub 2020 Sep 28.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a key role in cancer progression by enhancing glycolysis through activating the transcription of glycolytic genes. JMJD2D, a histone demethylase that specifically demethylates H3K9me2/3, can promote colorectal cancer (CRC) progression. However, it is unknown whether JMJD2D could promote CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. In this study, we found that downregulation of JMJD2D inhibited the glycolysis in CRC cells through suppressing HIF1 signaling pathway to downregulate glycolytic gene expression. Restoring HIF1 signaling by enforced expression of HIF1α in JMJD2D-knockdown CRC cells partially recovered CRC cell glycolysis, proliferation, migration, invasion, xenograft growth, and metastasis, suggesting that JMJD2D promotes CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. JMJD2D activated HIF1 signaling pathway through three different mechanisms: JMJD2D cooperated with the transcription factor SOX9 to enhance mTOR expression and then to promote HIF1α translation; JMJD2D cooperated with the transcription factor c-Fos to enhance HIF1β transcription; JMJD2D interacted and cooperated with HIF1α to enhance the expression of glycolytic gene. The demethylase-defective mutant of JMJD2D could not induce the expression of mTOR, HIF1α, HIF1β, and glycolytic genes, suggesting that the demethylase activity of JMJD2D is important for glycolysis through activating HIF1 signaling. Clinically, a highly positive correlation between the expression of JMJD2D and mTOR, HIF1β, and several glycolytic genes in human CRC specimens was identified. Collectively, our study reveals an important role of JMJD2D in CRC progression by enhancing glycolysis through activating HIF1 signaling pathway.
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http://dx.doi.org/10.1038/s41388-020-01483-wDOI Listing
November 2020

Demethylase-independent function of JMJD2D as a novel antagonist of p53 to promote Liver Cancer initiation and progression.

Theranostics 2020 11;10(19):8863-8879. Epub 2020 Jul 11.

Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, China.

As a histone demethylase, JMJD2D can enhance gene expression by specifically demethylating H3K9me2/3 and plays an important role in promoting colorectal cancer progression. However, its role in liver cancer remains unclear. The expression of JMJD2D was examined in human liver cancer specimens and non-tumorous liver tissues by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in liver cancer cells using small hairpin RNAs, and cells were analyzed with Western blot, real-time PCR, cell viability, colony formation, and flow cytometry assays. Cells were also grown as tumor xenografts in nude mice, and the tumor cell proliferation and apoptosis were measured by immunohistochemical analysis. The relationship between JMJD2D and p53 was studied by co-immunoprecipitation, chromatin immunoprecipitation, and electric mobility shift assay. Wild-type and JMJD2D-knockout mice were intraperitoneally injected with diethylnitrosamine (DEN) to induce liver tumors and the liver cancer initiation and progression were investigated. JMJD2D was frequently upregulated in human liver cancer specimens compared with non-tumorous liver tissues. The overall survival of liver cancer patients with high JMJD2D expression was significantly decreased compared to that with low JMJD2D expression. JMJD2D knockdown reduced liver cancer cell proliferation and xenograft tumor growth, sensitized cells to chemotherapeutic drug-induced apoptosis, and increased the expression of cell cycle inhibitor p21 and pro-apoptosis gene PUMA. Genetically, JMJD2D deficiency protected mice against DEN-induced liver cancer initiation and progression. Knockout of tumor suppressor p53 significantly reduced the effects of JMJD2D knockdown on cell proliferation, apoptosis, and the expression of p21 and PUMA, suggesting that JMJD2D regulates liver cancer cell functions in part through inhibiting p53 signaling pathway. Mechanistically, JMJD2D directly interacted with p53 and inhibited p53 recruitment to the p21 and PUMA promoters in a demethylation activity-independent manner, implicating a demethylase-independent function of JMJD2D as a novel p53 antagonist. In addition, JMJD2D could activate Wnt/β-catenin signaling to promote liver cancer cell proliferation. Our study demonstrates that JMJD2D can antagonize the tumor suppressor p53 and activate an oncogenic signaling pathway (such as Wnt/β-catenin signaling pathway) simultaneously to promote liver cancer initiation and progression, suggesting that JMJD2D may serve as a novel target for liver cancer treatment.
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http://dx.doi.org/10.7150/thno.45581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392006PMC
July 2020

Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling.

Oncogene 2020 04 24;39(16):3336-3353. Epub 2020 Feb 24.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.
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http://dx.doi.org/10.1038/s41388-020-1219-2DOI Listing
April 2020

Steroid receptor coactivator 3 inhibits hepatitis B virus gene expression through activating Akt signaling to prevent HNF4α nuclear translocation.

Cell Biosci 2019 13;9:64. Epub 2019 Aug 13.

1Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361012 Fujian China.

Background: Chronic hepatitis B virus (HBV) infection is one of the most serious global public health problems. The role of steroid receptor coactivator 3 (SRC-3) in HBV biosynthesis is unknown. The aim of this study is to investigate the function of SRC-3 in regulating HBV biosynthesis both in vitro and in vivo and to identify the underlying mechanism.

Results: In this study, we found that knockdown of SRC-3 could increase the levels of HBV mRNA and HBV proteins HBsAg and HBeAg in human liver cancer cell line HepG2 transfected with pHBV1.3 plasmids. In contrast, enforced expression of SRC-3 in SRC-3-knockdown HepG2 cells reduced the levels of HBV mRNA and HBV proteins HBsAg and HBeAg. Knockdown of SRC-3 dampened the Akt signaling, which has been shown to play a negative role in HBV transcription. Ectopic expression of constitutively activated Akt impaired the enhancement of HBV transcription by SRC-3 knockdown, indicating that SRC-3 inhibits HBV transcription by enhancing Akt signaling. Both SRC-3 and constitutively activated Akt could inhibit hepatocyte nuclear factor 4α (HNF4α)-mediated upregulation of HBV core promoter activity by preventing HNF4α nuclear translocation. Consistent with the in vitro results, in an in vivo chronic HBV replication mouse model developed by hydrodynamic injection of pHBV1.3 plasmids into mouse tail vein, enforced expression of SRC-3 in mouse liver reduced the levels of HBV mRNA in the liver and HBV antigens in serum, whereas knockout of SRC-3 in mouse increased the levels of HBV mRNA in the liver and HBV antigens in the serum.

Conclusion: Our study suggests that SRC-3 inhibits HBV gene expression by activating Akt signaling to prevent HNF4α nuclear translocation.
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http://dx.doi.org/10.1186/s13578-019-0328-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692928PMC
August 2019

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

Dev Cell 2019 02 7;48(4):460-474.e9. Epub 2019 Feb 7.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China. Electronic address:

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.
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http://dx.doi.org/10.1016/j.devcel.2018.12.021DOI Listing
February 2019

SRC-3 protects intestine from DSS-induced colitis by inhibiting inflammation and promoting goblet cell differentiation through enhancement of KLF4 expression.

Int J Biol Sci 2018 3;14(14):2051-2064. Epub 2018 Nov 3.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Goblet cell loss, which leads to the reduction of mucin secretion, is a hallmark of ulcerative colitis (UC). We previously reported that steroid receptor coactivator 3 (SRC-3), a transcriptional coactivator, contributes to host defense against by recruiting neutrophils, suggesting a role of SRC-3 in intestine homeostasis. However, the biological role of SRC-3 in UC remains unclear. Here, we showed that SRC-3 mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis compared with wild-type mice after oral administration of 2% DSS dissolved in drinking water. After oral administration of 2% DSS, SRC-3 mice displayed higher mortality rate, significant body weight loss, and higher clinical symptom scores compared to wild-type mice. SRC-3 mice suffered a severe loss of mature colonic goblet cells, leading to more severe histopathology and more proinflammatory cytokine production. Mechanistically, SRC-3 mice exhibited a decreased expression of transcription factor KLF4 in the colons, which is responsible for colonic goblet cell differentiation and maturation. At the molecular level, SRC-3 cooperated with c-Fos to promote KLF4 expression at the transcriptional level. These results demonstrate that SRC-3 can ameliorate DSS-induced colitis by inhibiting inflammation and promoting colonic goblet cell differentiation and maturation through enhancing the expression of transcriptional factor KLF4, which is responsible for colonic goblet cell differentiation and maturation.
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http://dx.doi.org/10.7150/ijbs.28576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299374PMC
September 2019

Histone Demethylase JMJD2D Interacts With β-Catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice.

Gastroenterology 2019 03 23;156(4):1112-1126. Epub 2018 Nov 23.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China. Electronic address:

Background & Aims: Wnt signaling contributes to the development of colorectal cancer (CRC). We studied interactions between lysine demethylase 4D (KDM4D or JMJD2D) and β-catenin, a mediator of Wnt signaling, in CRC cell lines and the effects on tumor formation in mice.

Methods: We obtained colorectal tumor specimens and surrounding nontumor colon tissues (controls) from patients undergoing surgery in China; levels of JMJD2D were measured by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in CRC (CT26, HCT116, and SW480 cells) using small hairpin RNAs, and cells were analyzed with viability, flow cytometry, colony formation, and transwell migration and invasion assays. Cells were also grown as tumor xenografts in nude mice or injected into tail veins or spleens of mice, and metastases were measured. We performed promoter activity, co-immunoprecipitation, and chromatin immunoprecipitation assays. We also performed studies with Apc and JMJD2D-knockout mice; these mice were crossed, and colorectal tumor formation in offspring (ApcJmjd2d and ApcJmjd2d) was analyzed. JMJD2D-knockout and wild-type (control) mice were given azoxymethane followed by dextran sodium sulfate to induce colitis-associated CRC; some mice were given the JMJD2D inhibitor 5-chloro-8-hydroxyquinoline (5-c-8HQ) or vehicle to examine the effects of 5-c-8HQ on intestinal tumor formation.

Results: Levels of JMJD2D were significantly higher in human colorectal tumors than in control tissues and correlated with levels of proliferating cell nuclear antigen. JMJD2D knockdown reduced CRC cell proliferation, migration, and invasion, as well as growth of xenograft tumors and formation of metastases in mice. JMJD2D was required for expression of β-catenin in CRC cell lines; ectopic expression of JMJD2D increased the promoter activities of genes regulated by β-catenin (MYC, CCND1, MMP2, and MMP9). We found that JMJD2D and β-catenin interacted physically and that JMJD2D demethylated H3K9me3 at promoters of β-catenin target genes. JMJD2D-knockout mice developed fewer colitis-associated colorectal tumors than control mice, and their tumor tissues had lower levels of β-catenin, MYC, cyclin D1, and proliferating cell nuclear antigen than tumors from control mice. ApcJmjd2d mice developed fewer and smaller colon tumors than Apc mice. Mice given 5-c-8HQ developed smaller and fewer colitis-associated tumors, with lower levels of cell proliferation, than mice given vehicle. Apc mice given 5-c-8HQ also developed fewer tumors in intestines and colons than mice given vehicle.

Conclusions: Levels of the histone demethylase JMJD2D are increased in human colorectal tumors compared with nontumor colon tissues. JMJD2D interacts with β-catenin to activate transcription of its target genes and promote CRC cell proliferation, migration, and invasion, as well as formation of colorectal tumors in mice.
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http://dx.doi.org/10.1053/j.gastro.2018.11.036DOI Listing
March 2019

Roles of Steroid Receptor Coactivator 3 in Host Defense Against Bacterial Pathogens.

Crit Rev Immunol 2018 ;38(3):245-252

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors such as the estrogen receptor and the androgen receptor and several other transcription factors to enhance their effects on target gene expression. SRC-3 plays important roles in many developmental, physiological, and pathologic events, including body growth, mammary gland development, energy homeostasis, inflammatory regulation, and cancer initiation and progression. SRC-3 has been suggested to be involved in host defense against bacterial pathogens. In this review, we summarize the roles of SRC-3 in host defense against peritoneal and enteric bacterial infection and discuss the potential clinical implications.
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http://dx.doi.org/10.1615/CritRevImmunol.2018026300DOI Listing
August 2019

Histone demethylase JMJD1A promotes colorectal cancer growth and metastasis by enhancing Wnt/β-catenin signaling.

J Biol Chem 2018 07 25;293(27):10606-10619. Epub 2018 May 25.

From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China,

The histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression. JMJD1A has been shown to promote colorectal cancer (CRC) progression, but its molecular role in CRC is unclear. Here, we report that JMJD1A is overexpressed in CRC specimens and that its expression is positively correlated with that of proliferating cell nuclear antigen (PCNA). JMJD1A knockdown decreased the expression of proliferative genes such as c-, cyclin D1, and , suppressed CRC cell proliferation, arrested cell cycle progression, and reduced xenograft tumorigenesis. Furthermore, JMJD1A knockdown inhibited CRC cell migration, invasion, and lung metastasis by decreasing matrix metallopeptidase 9 (MMP9) expression and enzymatic activity. Moreover, bioinformatics analysis of GEO profile datasets revealed that JMJD1A expression in human CRC specimens is positively correlated with the expression of Wnt/β-catenin target genes, including c-, cyclin D1, and Mechanistically, JMJD1A enhanced Wnt/β-catenin signaling by promoting β-catenin expression and interacting with β-catenin to enhance its transactivation. JMJD1A removed the methyl groups of H3K9me2 at the promoters of c- and genes. In contrast, the JMJD1A variant, which lacked demethylase activity, did not demethylate H3K9me2 at these promoters, failed to assist β-catenin to induce the expression of Wnt/β-catenin target genes, and failed to promote CRC progression. These findings suggest that JMJD1A's demethylase activity is required for Wnt/β-catenin activation. Of note, high JMJD1A levels in CRC specimens predicted poor cancer outcomes. In summary, JMJD1A promotes CRC progression by enhancing Wnt/β-catenin signaling, implicating JMJD1A as a potential molecular target for CRC management.
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http://dx.doi.org/10.1074/jbc.RA118.001730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036217PMC
July 2018

Apoptosis is induced by docosahexaenoic acid in breast cancer cells via death receptor and mitochondria-mediated pathways.

Mol Med Rep 2017 Jul 1;16(1):978-982. Epub 2017 Jun 1.

Department of Cardiothoracic Surgery, Qingdao Center Medical Group, Qingdao, Shandong 266033, P.R. China.

In the present study, the antitumor effect of n‑3 fatty acid was evaluated, and the effect of docosahexaenoic acid (DHA) on the induction of apoptosis and its underlying mechanism were examined. Flow cytometry and western blot analysis were performed to analyze apoptosis and the expression of protein factors in human breast cancer cells. The data revealed that DHA inhibited the viability of MCF‑7 breast cancer cells in vitro, and promoted cell death by the induction of apoptosis. DHA decreased the expression of B‑cell lymphoma 2 (Bcl‑2), whereas the expression of Bcl‑2‑associated X protein was increased. DHA was also shown to promote the release of Smac/Diablo and cytochrome c from the mitochondria. DHA increased the levels of cleaved caspase‑8, ‑9 and ‑3. Additionally, the protein expression of tumor necrosis factor‑related apoptosis‑inducing ligand, death receptor 4 and Fas were increased following DHA treatment. In conclusion, DHA caused apoptosis of the human breast cancer cells in vitro through the death receptor and mitochondria‑mediated pathways. The results of this study encourage further investigation of the effect of fish oil on the prevention and treatment of human breast cancer.
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http://dx.doi.org/10.3892/mmr.2017.6678DOI Listing
July 2017

E3 ubiquitin ligase FBW7α inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E.

Oncol Rep 2017 Mar 7;37(3):1627-1636. Epub 2017 Feb 7.

Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.

FBW7 (F-box and WD repeat domain-containing 7), also known as CDC4, AGO and SEL10, is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase. It is a recognized tumor suppressor because it targets multiple oncoproteins for ubiquitination-mediated destruction and its mutations are frequently identified in a variety of human malignancies. However, the function of FBW7 in proliferation of cholangiocarcinoma (CCA) remains unknown. We found that overexpression of FBW7α induced CCA cell arrest in G1 phase of cell cycle and inhibited cell proliferation in vitro and CCA xenograft tumor growth, suggesting that FBW7α is a tumor suppressor in CCA progression. Overxpression of FBW7α resulted in the protein degradation of its substrates such as c-Myc and cyclin E which promote CCA cell proliferation. Restoration of the expression of c-Myc, but not cyclin E, rescued the proliferation of FBW7α-overexpression CCA cells. These results suggest that FBW7α plays an essential inhibitory role in CCA progression, indicating that targeting FBW7α substrate c-Myc may be a potential strategy for CCA treatment.
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http://dx.doi.org/10.3892/or.2017.5432DOI Listing
March 2017

Steroid Receptor Coactivator 3 Contributes to Host Defense against Enteric Bacteria by Recruiting Neutrophils via Upregulation of CXCL2 Expression.

J Immunol 2017 02 4;198(4):1606-1615. Epub 2017 Jan 4.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China;

Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors and some other transcription factors to enhance their effects on target gene transcription. We reported previously that SRC-3-deficient (SRC-3) mice are extremely susceptible to Escherichia coli-induced septic peritonitis as a result of uncontrolled inflammation and a defect in bacterial clearance. In this study, we observed significant upregulation of SRC-3 in colonic epithelial cells in response to Citrobacter rodentium infection. Based on these findings, we hypothesized that SRC-3 is involved in host defense against attaching and effacing bacterial infection. We compared the responses of SRC-3 and wild-type mice to intestinal C. rodentium infection. We found that SRC-3 mice exhibited delayed clearance of C. rodentium and more severe tissue pathology after oral infection with C. rodentium compared with wild-type mice. SRC-3 mice expressed normal antimicrobial peptides in the colons but exhibited delayed recruitment of neutrophils into the colonic mucosa. Accordingly, SRC-3 mice showed a delayed induction of CXCL2 and CXCL5 in colonic epithelial cells, which are responsible for neutrophil recruitment. At the molecular level, we found that SRC-3 can activate the NF-κB signaling pathway to promote CXCL2 expression at the transcriptional level. Collectively, we show that SRC-3 contributes to host defense against enteric bacteria, at least in part via upregulating CXCL2 expression to recruit neutrophils.
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http://dx.doi.org/10.4049/jimmunol.1600300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296398PMC
February 2017

Decreased expression of the CHD5 gene and its clinicopathological significance in breast cancer: Correlation with aberrant DNA methylation.

Oncol Lett 2016 Nov 16;12(5):4021-4026. Epub 2016 Sep 16.

Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong 266021, P.R. China.

Chromodomain helicase DNA binding protein 5 (CHD5) has been identified as a tumor suppressor in mouse models. Downregulation of CHD5 gene expression is frequently observed in breast cancer cells and tissues. This may be explained by deletions or other mutations; however, alternative mechanisms require investigation. Therefore, the present study evaluated whether CHD5 aberrant methylation has a role in primary breast tumors. A total of 389 patients with primary breast cancer (including 252 paraffin-embedded specimens and 137 fresh-frozen samples) were enrolled in the present study. In the current study, reverse transcription-polymerase chain reaction (RT-PCR) and nested-methylation-specific PCR were used to analyze the mRNA expression and promoter methylation of CHD5 genes in a large cohort of breast cancer patients, and to investigate their associations with the clinicopathological features of tumors. CHD5 expression was significantly suppressed in breast cancer tissues compared with normal breast tissues when analyzed by RT-PCR. Furthermore, DNA methylation of CHD5 was more prevalent in breast tumors than in normal tissues. CHD5 mRNA levels correlated with the degree of CHD5 methylation in breast cancer tissues. Clinicopathological correlation analysis revealed that CHD5 promoter methylation was associated with estrogen receptor and progesterone receptor status. Thus, downregulation of CHD5, mediated by abnormal methylation, may contribute to the development and progression of breast cancer.
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http://dx.doi.org/10.3892/ol.2016.5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104224PMC
November 2016

Long term effect and safety of Wharton's jelly-derived mesenchymal stem cells on type 2 diabetes.

Exp Ther Med 2016 Sep 26;12(3):1857-1866. Epub 2016 Jul 26.

Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Cellular therapies offer novel opportunities for the treatment of type 2 diabetes mellitus (T2DM). The present study evaluated the long-term efficacy and safety of infusion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) on T2DM. A total of 61 patients with T2DM were randomly divided into two groups on the basis of basal therapy; patients in group I were administered WJ-MSC intravenous infusion twice, with a four-week interval, and patients in group II were treated with normal saline as control. During the 36-month follow-up period, the occurrence of any adverse effects and the results of clinical and laboratory examinations were recorded and evaluated. The lack of acute or chronic adverse effects in group I was consistent with group II.. Blood glucose, glycosylated hemoglobin, C-peptide, homeostasis model assessment of pancreatic islet β-cell function and incidence of diabetic complications in group I were significantly improved, as compared with group II during the 36-month follow-up. The results of the present study demonstrated that infusion of WJ-MSC improved the function of islet β-cells and reduced the incidence of diabetic complications, although the precise mechanisms are yet to be elucidated. The infusion of WJ-MSC may be an effective option for the treatment of patients with type 2 diabetes.
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http://dx.doi.org/10.3892/etm.2016.3544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997981PMC
September 2016

Histone acetyl transferase GCN5 promotes human hepatocellular carcinoma progression by enhancing AIB1 expression.

Cell Biosci 2016 2;6:47. Epub 2016 Aug 2.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 Fujian China.

Background: General control non-depressible 5 (GCN5) is a crucial catalytic component of a transcriptional regulatory complex that plays important roles in cellular functions from cell cycle regulation to DNA damage repair. Although GCN5 has recently been implicated in certain oncogenic roles, its role in liver cancer progression remains vague.

Results: In this study, we report that GCN5 was overexpressed in 17 (54.8 %) of 31 human hepatocellular carcinoma (HCC) specimens. Down-regulation of GCN5 inhibited HCC cell proliferation and xenograft tumor formation. GCN5 knockdown decreased the protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and amplified in breast cancer 1 (AIB1), but increased the protein levels of cell cycle inhibitor p21(Cip1/Waf1) in HepG2 cells. GCN5 regulated AIB1 expression, at least in part, by cooperating with E2F1 to enhance AIB1 transcription. Consistently, GCN5 expression was positively correlated with AIB1 expression in human HCC specimens in two GEO profile datasets.

Conclusion: Since AIB1 plays a promoting role in HCC progression, our results propose that GCN5 promotes HCC progression at least partially by regulating AIB1 expression. This study implicates that GCN5 might be a potential molecular target for HCC diagnosis and treatment.
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http://dx.doi.org/10.1186/s13578-016-0114-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969657PMC
August 2016

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders.

J Cell Sci 2016 06 27;129(11):2261-72. Epub 2016 Apr 27.

Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China

Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs.
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http://dx.doi.org/10.1242/jcs.183889DOI Listing
June 2016

Downregulation of amplified in breast cancer 1 contributes to the anti-tumor effects of sorafenib on human hepatocellular carcinoma.

Oncotarget 2016 May;7(20):29605-19

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.

Multi-kinase inhibitor sorafenib represents a major breakthrough in the therapy of advanced hepatocellular carcinoma (HCC). Amplified in breast cancer 1 (AIB1) is frequently overexpressed in human HCC tissues and promotes HCC progression. In this study, we investigated the effects of sorafenib on AIB1 expression and the role of AIB1 in anti-tumor effects of sorafenib. We found that sorafenib downregulated AIB1 protein expression by inhibiting AIB1 mRNA translation through simultaneously blocking eIF4E and mTOR/p70S6K/RP-S6 signaling. Knockdown of AIB1 significantly promoted sorafenib-induced cell death, whereas overexpression of AIB1 substantially diminished sorafenib-induced cell death. Downregulation of AIB1 contributed to sorafenib-induced cell death at least in part through upregulating the levels of reactive oxygen species in HCC cells. In addition, resistance to sorafenib-induced downregulation of AIB1 protein contributes to the acquired resistance of HCC cells to sorafenib-induced cell death. Collectively, our study implicates that AIB1 is a molecular target of sorafenib and downregulation of AIB1 contributes to the anti-tumor effects of sorafenib.
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http://dx.doi.org/10.18632/oncotarget.8812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045420PMC
May 2016

Environmental tobacco smoke and pancreatic cancer: a case-control study.

Int J Clin Exp Med 2015 15;8(9):16729-32. Epub 2015 Sep 15.

Department of General Surgery, The Affiliated Hospital of Qingdao University Qingdao, China.

Background: It has been conformed that active smoking is an established risk factor for pancreatic cancer, but the role of environmental tobacco smok (passive smoking) in pancreatic cancer remains unclear. We intended to study the relationship between passive smoking and pancreatic cancer.

Methods: From Oct. 1991 to Sep. 2014, A hospital-based case-control study on pancreatic cancer was conducted from the inpatient of five hospitals. 1076 cases pancreatic cancer patients. History of exposure to environmental tobacco smoke was assessed through questionnaires. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.

Results: During 23 years of follow-up (1991-2014), 1076 patients were diagnosed with pancreatic cancer (686 men and 390 women). Compared to paternal smoking (RR, 0.97; 95% CI, 0.77-1.21; P = 0.084), maternal smoking significantly increased the risk of pancreatic cancer (R, 1.56; 95% CI, 1.13-1.98; P = 0.018). Although the risk associated with maternal smoking remained elevated compared to the never smokers (RR, 1.49; 95% CI, 1.07-2.27), there was no statistical significance.

Conclusions: The positive association with maternal smoking suggests that environmental tobacco smoke, potentially in utero or in early life, may be associated with pancreatic cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659100PMC
December 2015

Predictive value of CD44 and CD24 for prognosis and chemotherapy response in invasive breast ductal carcinoma.

Int J Clin Exp Pathol 2015 1;8(9):11287-95. Epub 2015 Sep 1.

Department of Breast Surgery, The Affiliated Hospital of Qingdao University Qingdao, China.

Objective: Cells with unique phenotypes and stem cell-like properties have been found to exist in breast cancer. The aim of the present study was to study the relationship of CD24, CD44, CD44(+)/CD24(-/low) and CD44(-)/CD24(+) tumor phenotypes' with clinico-pathological features, chemotherapy response and with prognosis.

Methods: The study included paraffin-embedded tissues of 140 primary and secondary invasive ductal carcinoma samples. All the patients received routine chemotherapy. Expression of CD24, CD44, ER, PR, and Her2 were assayed immunohistochemically. We applied double-staining immunohistochemistry for the detection of CD44(+)/CD24(-/low), CD44(+)/CD24 (+), CD44(-)/CD24(-) and CD44(-)/CD24(+) cells. The association between the proportions of CD44(+)/CD24(-/low) and CD44(-)/CD24(+) and clinicopathological features, chemotherapy response and with prognosis of these patients was evaluated.

Results: CD24 expression was not significantly associated with tumor characteristics, but was significantly associated with poor prognostic variables including ER-, PR-, HER2(+) and triple negative (TN) phenotype; There was no association of CD44 with nodal status, age or HER2 expression. In the correlation analysis, CD24 expression was positively associated with chemotherapy response (P = 0.018), however, CD44 expression was not associated with pathological response to chemotherapy When both markers are considered, the CD44(+)/CD24(-) phenotype had the poor prognosis. The proportion of CD44+/CD24- tumor cells was significantly associated with lymph node involvement, recurrent or metastatic tumors and ER/PR status. High CD44(+)/CD24(-) phenotype had poor response to chemotherapy. The median disease-free survival (DFS) of patients with and without CD44(+)/CD24(-/low) tumor cells were 19.8 ± 2.6 months and 31.7 ± 4.2 months, and the median overall survival (OS) of patients with and without CD44(+)/CD24(-/low) tumor cells were 33.5 ± 2.8 months and 51.4 ± 3.9 months, respectively, and with both univariate and multivariate analyses showing that the proportion of CD44(+)/CD24(-/low) tumor cells was strongly correlated with DFS and OS. However, the CD44(-)/CD24(+), CD44(+)/CD24(+), CD44(-)/CD24 (-) phenotype had no relation with prognosis.

Conclusion: There was significant correlation between CD44(+)/CD24(-/low) tumor cell prevalence and tumor metastasis, prognosis and chemotherapy response. The CD44(+)/CD24(-) phenotype may be an important factor for malignant relapse following surgical resection and chemotherapy in patients with invasive ductal carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637668PMC
September 2016

Selection and Application of DNA Aptamer Against Oncogene Amplified in Breast Cancer 1.

J Mol Evol 2015 Dec 12;81(5-6):179-85. Epub 2015 Oct 12.

State Key Laboratory of Physical Chemistry of Solid Surfaces, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Collaborative Innovation Center of Chemistry for Energy Materials, Key Laboratory for Chemical Biology of Fujian Province, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, People's Republic of China.

Amplified in breast cancer 1 (AIB1), also known as steroid receptor coactivator 3 (SRC-3), is a transcriptional coactivator that interacts with nuclear receptors and other transcription factors to enhance their effects on target gene transcription. AIB1, which acts as a major oncogene, is highly expressed in many human cancers, and has been demonstrated to be a key regulator for tumor initiation, progression, metastasis, invasion, and survival. Recruitment of the transcriptional factor CBP/p300 by CBP/p300-interaction domain (CID) of AIB1 is essential for its transcriptional activation function. In this research, we isolated a DNA aptamer AY-3 that binds to AIB1-CID from a random oligonucleotide library using in vitro screening technology-Systematic Evolution of Ligands by EXponential enrichment (SELEX). The binding affinity of the aptamer to AIB1-CID fusion protein is in the nanomolar range. More importantly, the aptamer was found to disrupt in the interaction between p300 and AIB1. This aptamer has great potential to serve as a therapeutic agent for cancer by inhibiting the coactivation of AIB1.
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http://dx.doi.org/10.1007/s00239-015-9703-yDOI Listing
December 2015

Associations of miR-146a and miR-146b expression and breast cancer in very young women.

Cancer Biomark 2015 ;15(6):881-7

Breast Cancer Center, Shandong Cancer Hospital, Jinan, Shandong, China.

Background: MicroRNAs (miRNA) expression profiles might be useful novel biomarkers for tumor diagnostic and histological characterization.

Objective: Associations of miR-146 expression and breast cancer in very young women needed to be elucidated.

Methods: We investigated expressions of miR-146a, miR-146b and IL-6 in tissues between 120 young women with primary breast cancer and 130 patients with breast fibroadenoma by RT-PCR. The associations between the expression of miR-146, IL-6 and clinical parameters of breast cancer were analyzed.

Results: Levels of miR-146a and miR-146b in breast cancer tissues were lower while level of IL-6 was higher compared to the fibroadenoma tissues and pericancerous breast tissues (P< 0.05). Positive associations were found between levels of miR-146a/b and IL-6 in breast cancer tissues and ER-PgR-, HER2/neu-, Ki-67 index ≥ 20%, tumor size > 2 cm, positive distant metastasis and lymph node metastasis, advanced clinical TNM stages (III-IV) and basal-like phenotype (P< 0.05).

Conclusion: Down-regulations of miR-146a and miR-146b expression in breast tissues were related to development and deterioration of breast cancer. miR-146a and miR-146b might act as potential biomarkers for young women with breast cancer.
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http://dx.doi.org/10.3233/CBM-150532DOI Listing
October 2016

Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling.

J Biol Chem 2015 Jul 16;290(30):18596-608. Epub 2015 Jun 16.

From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, the Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China,

Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator not only for steroid receptors, such as androgen receptor and estrogen receptor, but also for other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in liver cancer progression remains unknown. In this study, we report that SRC-1 was overexpressed in 25 (62.5%) of 40 human hepatocellular carcinoma (HCC) specimens. Down-regulation of SRC-1 decreased HCC cell proliferation and impaired tumor maintenance in HCC xenografts. Knockdown of SRC-1 reduced protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and the oncogene c-Myc. Knockout of SRC-1 in mice reduced diethylnitrosamine/CCl4-induced tumor formation in the liver and the expression of c-Myc and PCNA in liver tumors. SRC-1 promoted c-Myc expression, at least in part, by directly interacting with β-catenin to enhance Wnt/β-catenin signaling. Consistent with these results, the expression of SRC-1 was positively correlated with PCNA expression in human HCC specimens, and the expression levels of c-Myc in SRC-1-positive HCC specimens were higher than in SRC-1-negative HCC specimens. In addition, SRC-1 and SRC-3 were co-overexpressed in 47.5% of HCC specimens, and they cooperated to promote HCC cell proliferation. Simultaneous down-regulation of SRC-1 and SRC-3 dramatically inhibited HCC cell proliferation. Our results demonstrate that SRC-1 promotes HCC progression by enhancing Wnt/β-catenin signaling and suggest that SRC-1 is a potential therapeutic molecular target for HCC.
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http://dx.doi.org/10.1074/jbc.M115.640490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513118PMC
July 2015

Inhibitory effects of Mycoepoxydiene on macrophage foam cell formation and atherosclerosis in ApoE-deficient mice.

Cell Biosci 2015 26;5:23. Epub 2015 May 26.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang-An South Road, Xiamen, Fujian 360112 China.

Background: Mycoepoxydiene (MED) is a polyketide that can be isolated from a marine fungus and is associated with various activities, including antitumor and anti-inflammatory functions. However, its effects on atherosclerosis remain unknown. Macrophage-derived foam cells play crucial roles in the initiation and progression of atherosclerotic plaques. In this study, we investigated the effects of MED on oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and activation, and on high fat diet (HFD)-induced atherosclerosis in ApoE-deficient (ApoE (-/-) ) mice.

Results: Our findings show that MED could significantly inhibit ox-LDL-induced macrophage foam cell formation and suppress the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is a receptor for ox-LDL. Additionally, MED could significantly inhibit the secretion of proinflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Mechanistically, MED inhibited NF-κB activation by blocking IκB-α degradation and reducing NF-κB DNA binding activity. Moreover, MED dramatically reduced the occurrence of HFD-induced atherosclerotic lesions in ApoE (-/-) mice.

Conclusions: Our study shows that MED can inhibit macrophage foam cell formation and activation by inhibiting NF-κB activation, thereby protecting ApoE (-/-) mice from HFD-induced atherosclerosis. Our findings suggest that MED might be a potential lead compound for the development of antiatherosclerotic therapeutics.
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http://dx.doi.org/10.1186/s13578-015-0017-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455339PMC
June 2015

Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling.

Oncogene 2015 Jul 29;34(30):3935-3945. Epub 2014 Sep 29.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Aberrant activation of Notch signaling has an essential role in colorectal cancer (CRC) progression. Amplified in breast cancer 1 (AIB1), also known as steroid receptor coactivator 3 or NCOA3, is a transcriptional coactivator that promotes cancer cell proliferation and invasiveness. However, AIB1 implication in CRC progression through enhancing Notch signaling is unknown. In this study, we found that several CRC cell lines expressed high levels of AIB1, and knockdown of AIB1 decreased cell proliferation, colony formation and tumorigenesis of these CRC cells. Specifically, knockdown of AIB1 inhibited cell cycle progression at G1 phase by decreasing the mRNA levels of cyclin A2, cyclin B1, cyclin E2 and hairy and enhancer of split (Hes) 1. Furthermore, AIB1 interacted with Notch intracellular domain and Mastermind-like 1 and was recruited to the Hes1 promoter to enhance Notch signaling. Downregulation of AIB1 also decreased CRC cell invasiveness in vitro and lung metastasis in vivo. Besides that, knockout of AIB1 in mice inhibited colon carcinogenesis induced by azoxymethane/dextran sodium sulfate treatment. The mRNA levels of cyclin B1 and Hes5 were downregulated, but p27, ATOH1 and MUC2 were upregulated in the colon tumors from AIB1-deficient mice compared with those from wild-type mice. Thus, our results signify the importance of AIB1 in CRC and demonstrate that AIB1 promotes CRC progression at least in part through enhancing Notch signaling, suggesting that AIB1 is a potential molecular target for CRC treatment.
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http://dx.doi.org/10.1038/onc.2014.324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377317PMC
July 2015