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1.
Front Immunol ; 15: 1382661, 2024.
Article in English | MEDLINE | ID: mdl-38558797

ABSTRACT

Introduction: BTBD8 has been identified as a susceptible gene for inflammatory bowel diseases (IBD). However, the function of BTBD8 in normal development and IBD pathogenesis remains unknown. Methods: We administered drinking water with 3% dextran sodium sulfate (DSS) to wild-type (WT) and Btbd8 knockout (KO) mice for seven consecutive days to induce IBD. Subsequently, we further examined whether Btbd8 KO affects intestinal barrier and inflammation. Results: We demonstrated that Btbd8 deficiency partially protects mice from DSS-induced IBD, even though no obvious phenotypes were observed in Btbd8 KO mice. Btbd8 deletion leads to strengthened tight junctions between intestinal epithelial cells, elevated intestinal stem cell activity, and enhanced mucus layer. All these three mechanisms work together to improve the intestinal barrier integrity in Btbd8 KO mice. In addition, Btbd8 deficiency mitigates inflammation by reducing the expression of IL-1ß and IL-6 by macrophages. Discussion: Our studies validate the crucial role of Btbd8 in IBD pathogenesis, and reveal that Btbd8 deficiency may ameliorate DSS-induced IBD through improving the intestinal barrier integrity, as well as suppressing inflammatory response mediated by macrophages. These findings suggest that Btbd8 could be a promising therapeutic target for the treatment of IBD.


Subject(s)
Colitis , Inflammatory Bowel Diseases , Animals , Mice , Intestinal Barrier Function , Colitis/chemically induced , Colitis/genetics , Colitis/drug therapy , Inflammation/genetics , Inflammation/pathology , Intestines/pathology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology
2.
BMC Infect Dis ; 24(1): 368, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38566040

ABSTRACT

OBJECTIVE: Healthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis. METHODS: This observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed. RESULTS: A total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan-Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P = 0.019 and 81.8% vs. 46.9%, P = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P = 0.044). CONCLUSIONS: Our findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients' outcome. TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).


Subject(s)
Carbapenems , Meningitis, Bacterial , Humans , Carbapenems/therapeutic use , Retrospective Studies , Anti-Bacterial Agents/therapeutic use , Gram-Negative Bacteria , Meningitis, Bacterial/drug therapy , Meningitis, Bacterial/microbiology , Delivery of Health Care , Microbial Sensitivity Tests
3.
Int J Mol Sci ; 25(5)2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38473939

ABSTRACT

Embryonic stem cells (ESCs) favor glycolysis over oxidative phosphorylation for energy production, and glycolytic metabolism is critical for pluripotency establishment, maintenance, and exit. However, an understanding of how glycolysis regulates the self-renewal and differentiation of ESCs remains elusive. Here, we demonstrated that protein lactylation, regulated by intracellular lactate, contributes to the self-renewal of ESCs. We further showed that Esrrb, an orphan nuclear receptor involved in pluripotency maintenance and extraembryonic endoderm stem cell (XEN) differentiation, is lactylated on K228 and K232. The lactylation of Esrrb enhances its activity in promoting ESC self-renewal in the absence of the LIF and XEN differentiation of ESCs by increasing its binding at target genes. Our studies reveal the importance of protein lactylation in the self-renewal and XEN differentiation of ESCs, and the underlying mechanism of glycolytic metabolism regulating cell fate choice.


Subject(s)
Embryonic Stem Cells , Endoderm , Endoderm/metabolism , Cell Differentiation/genetics
4.
Cell Commun Signal ; 20(1): 178, 2022 11 14.
Article in English | MEDLINE | ID: mdl-36376959

ABSTRACT

BACKGROUND: Bicalutamide is a nonsteroidal antiandrogen widely used as a first-line clinical treatment for advanced prostate cancer (PCa). Although patients initially show effective responses to bicalutamide treatment, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa (CRPC). This research investigated the roles of the oestrogen receptor α (ERα)-nuclear factor E2-related factor 2 (NRF2) signalling pathway in bicalutamide resistance in PCa cells. METHODS: We performed bioinformatic analysis and immunohistochemical staining on normal and cancerous prostate tissue to evaluate ERα and NRF2 expression and their correlation. Gene expression and localization in PCa cell lines were further investigated using real-time reverse transcription PCR/Western blotting and immunofluorescence staining. We treated PCa cells with the ER inhibitor tamoxifen and performed luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays to understand ERα-dependent NRF2 expression. Overexpression and knockdown of ERα and NRF2 were used to explore the potential role of the ERα-NRF2 signalling axis in bicalutamide resistance in PCa cells. RESULTS: We found that the expression of ERα and NRF2 was positively correlated and was higher in human CRPC tissues than in primary PCa tissues. Treatment with oestrogen or bicalutamide increased the expression of ERα and NRF2 as well as NRF2 target genes in PCa cell lines. These effects were blocked by pretreatment with tamoxifen. ChIP assays demonstrated that ERα directly binds to the oestrogen response element (ERE) in the NRF2 promoter. This binding led to increased transcriptional activity of NRF2 in a luciferase reporter assay. Activation of the ERα-NRF2 signalling axis increased the expression of bicalutamide resistance-related genes. Inhibition of this signalling axis by knockdown of ERα or NRF2 downregulated the expression of bicalutamide resistance-related genes and inhibited the proliferation and migration of PCa cells. CONCLUSIONS: We demonstrated the transcriptional interaction between ERα and NRF2 in CRPC tissues and cell lines by showing the direct binding of ERα to the ERE in the NRF2 promoter under oestrogen treatment. Activation of the ERα-NRF2 signalling axis contributes to bicalutamide resistance in PCa cells, suggesting that the ERα-NRF2 signalling axis is a potential therapeutic target for CRPC. Video Abstract.


Subject(s)
Estrogen Receptor alpha , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Cell Line, Tumor , Estrogen Receptor alpha/metabolism , Estrogens , Gene Expression Regulation, Neoplastic , NF-E2-Related Factor 2/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Tamoxifen/pharmacology
6.
Int J Infect Dis ; 123: 157-165, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35987467

ABSTRACT

OBJECTIVES: This study aimed to evaluate the efficacy and safety of ceftolozane/tazobactam (C/T) plus metronidazole versus meropenem plus placebo for the treatment of complicated intra-abdominal infection (cIAI) in Chinese adult participants. METHODS: In this phase III clinical trial (NCT03830333), Chinese adult participants with cIAI were randomized 1:1 to receive C/T plus metronidazole or meropenem plus placebo. The primary objective was to assess C/T plus metronidazole for noninferiority versus meropenem for clinical response rate at the test of cure (TOC; 28 ± 2 days after study start) visit in the clinically evaluable population. Secondary endpoints included clinical and microbiologic responses at the TOC and end-of-treatment (≤24 hours after last dose) visits and adverse event rates. RESULTS: Clinical cure at the TOC visit in the clinically evaluable population was 95.2% and 93.1% for C/T plus metronidazole and meropenem, respectively (between-treatment difference: 2.1% [95% confidence interval: -4.7%, 8.8%]); thus, noninferiority was met. Clinical responses at the TOC and end-of-treatment visits and microbiologic responses at the TOC visit were consistent with the primary efficacy endpoint. Safety was comparable between study treatment groups. CONCLUSION: In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety.


Subject(s)
Intraabdominal Infections , Metronidazole , Adult , Anti-Bacterial Agents/adverse effects , Cephalosporins/adverse effects , China , Double-Blind Method , Humans , Intraabdominal Infections/drug therapy , Meropenem/adverse effects , Metronidazole/adverse effects , Tazobactam/adverse effects
7.
Front Cell Dev Biol ; 10: 850052, 2022.
Article in English | MEDLINE | ID: mdl-35547809

ABSTRACT

The SEPTIN12 gene has been associated with male infertility. Male Septin12 +/- chimera mice were infertile, supporting the prevailing view that SEPTIN12 haploinsufficiency causes male infertility. In this study, we identified a heterozygous mutation on SEPTIN12, c.72C>A (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). To investigate the role of SEPTIN12 in FF and oocyte activation, we constructed Septin12 knockout mice. Surprisingly, Septin12 -/- male mice, but not Septin12 +/- male mice, are infertile, and have reduced sperm counts and abnormal sperm morphology. Importantly, AOA treatment enhances the 2-cell embryo rate of ICSI embryos injected with Septin12 -/- sperm, indicating that FF caused by male Septin12 deficiency is overcome by AOA. Mechanistically, loss of PLCζ around the acrosome might be the reason for FF of Septin12 -/- sperm. Taken together, our data indicated that homozygous knockout of Septin12, but not Septin12 haploinsufficiency, leads to male infertility and FF.

8.
Development ; 149(12)2022 06 15.
Article in English | MEDLINE | ID: mdl-35608036

ABSTRACT

HBXIP, also named LAMTOR5, has been well characterized as a transcriptional co-activator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation and decreased colony-forming capacity. In addition, both Hbxip-/- ESCs and E7.5 embryos displayed defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, displayed differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/- and p18-/- mice, lacking subunits of the Ragulator complex, also shared similar phenotypes, embryonic lethality and retarded growth around E7-E8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.


Subject(s)
Embryonic Development , Embryonic Stem Cells , Animals , Cell Differentiation/genetics , Embryonic Development/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Mice , Signal Transduction
9.
Cell Commun Signal ; 20(1): 31, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35292057

ABSTRACT

BACKGROUND: Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17ß-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear. METHODS: To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter. RESULTS: CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1+ PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter. CONCLUSIONS: Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Video Abstract.


Subject(s)
Cytochrome P-450 CYP1B1 , Estrogen Receptor alpha , Interleukin-6 , Prostatic Neoplasms, Castration-Resistant , Androgen Antagonists , Androgens , Castration , Catalysis , Cell Line, Tumor , Cytochrome P-450 CYP1B1/metabolism , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Humans , Interleukin-6/metabolism , Male , Neoplastic Stem Cells/metabolism , Prostate/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy
10.
Biomed Res Int ; 2021: 6613439, 2021.
Article in English | MEDLINE | ID: mdl-34337035

ABSTRACT

METHODS: Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. RESULTS: AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 µM vs. lenvatinib 1 µM + alisertib 0.1 µM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). CONCLUSIONS: Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.


Subject(s)
Antineoplastic Agents/therapeutic use , Azepines/therapeutic use , Carcinoma, Hepatocellular/drug therapy , DNA Damage , Liver Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Pyrimidines/therapeutic use , Quinolines/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aurora Kinase A/metabolism , Carcinoma, Hepatocellular/pathology , Cell Death/drug effects , Cell Proliferation/drug effects , Female , Liver Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Models, Biological , Neoplasm Metastasis , Signal Transduction/drug effects , Up-Regulation
11.
J Cell Biochem ; 2021 May 03.
Article in English | MEDLINE | ID: mdl-33938030

ABSTRACT

Cancer-associated fibroblasts (CAFs) can promote the development and metastasis of prostate cancer partly by mediating tumor-associated inflammation. An increasing amount of studies have focused on the functional interactions between CAFs and immune cells in the tumor microenvironment (TME). We previously reported that G protein-coupled receptor 30 (GPR30) was highly expressed in prostate CAFs and plays a crucial role in prostate stromal cell activation. However, the effect and underlying mechanism of GPR30 expression in prostate CAFs affecting the interaction between CAFs and tumor-associated macrophages (TAMs) need further elucidation. Here, we found that, compared with CAF-shControl, CAF-shGPR30 inhibited macrophage migration through transwell migration assays, which should be attributed to the decreased expression of C-X-C motif chemokine ligand 12 (CXCL12). In addition, macrophages treated with a culture medium of CAF-shGPR30 exhibited attenuated M2 polarization with downregulated M2-like markers expression. Moreover, macrophages stimulated with a culture medium of CAF-shGPR30 were less efficient in promoting activation of fibroblast cells and invasion of PCa cells. Finally, cocultured CAF-shGPR30 and macrophages suppressed PCa cell invasion compared to cocultured CAF-shControl and macrophages by decreasing interleukin-6 (IL-6) secretion, and this effect could be abrogated with rescue expression of IL-6. Our results pinpoint the function of GPR30 in prostate CAFs on regulating the CAF-TAM interaction in the TME and provide new insights into PCa therapies via regulating TME.

12.
Nanoscale ; 13(15): 7381-7388, 2021 Apr 21.
Article in English | MEDLINE | ID: mdl-33889884

ABSTRACT

The integration of black phosphorus (BP) with metal phosphides is known to produce high-performance electrocatalysts for oxygen evolution reduction (OER), although increased stability and prevention of the degradation of their lone pairs would be desirable improvements. In this work, cobalt phosphide (CoP)/BP heterostructures were electrochemically synthesized with a two-electrode system, where cobalt ions were generated in situ at a Co anode, and non-aggregated BP nanosheets (NSs) were exfoliated from the bulky BP cathode. With an electrolysis voltage of 30 V, the CoP/BP heterostructure exhibited a superior and stable OER performance (e.g., an overpotential of 300 mV at 10 mA cm-2, which is 41 mV lower than that obtained with a RuO2 catalyst). The CoOx formed in situ during the OER catalysis and remaining CoP synergistically contributed to the enhanced OER performance. The present strategy provides a new electrosynthetic method to prepare stable BP electrocatalysts and also further expands their electrochemical applications.

13.
Front Oncol ; 11: 787953, 2021.
Article in English | MEDLINE | ID: mdl-35096586

ABSTRACT

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.

14.
Nanomaterials (Basel) ; 9(9)2019 Sep 17.
Article in English | MEDLINE | ID: mdl-31533228

ABSTRACT

Food safety is one of the most important and widespread research topics worldwide. The development of relevant analytical methods or devices for detection of unsafe factors in foods is necessary to ensure food safety and an important aspect of the studies of food safety. In recent years, developing high-performance sensors used for food safety analysis has made remarkable progress. The combination of carbon-based nanomaterials with excellent properties is a specific type of sensor for enhancing the signal conversion and thus improving detection accuracy and sensitivity, thus reaching unprecedented levels and having good application potential. This review describes the roles and contributions of typical carbon-based nanomaterials, such as mesoporous carbon, single- or multi-walled carbon nanotubes, graphene and carbon quantum dots, in the construction and performance improvement of various chemo- and biosensors for various signals. Additionally, this review focuses on the progress of applications of this type of sensor in food safety inspection, especially for the analysis and detection of all types of toxic and harmful substances in foods.

15.
Cancer Lett ; 467: 72-84, 2019 12 28.
Article in English | MEDLINE | ID: mdl-31499120

ABSTRACT

Castration-resistant prostate cancer (CRPC) following androgen deprivation therapy remains a major obstacle advanced prostate cancer management. Aromatase catalyzes estrogen from androgens, yet the role of aromatase-generated endogenous estrogen in CRPC is poorly understood. In this study, we assessed the expression and function of aromatase in CRPC. We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets. Bicalutamide treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition. Aromatase knockdown in PC3 cells reduced invasiveness and decreased metastasis-related gene expression. The aromatase inhibitor, letrozole, attenuated tumour metastasis in castrated PC3-xenograft mice. Mechanistically, aromatase-induced endogenous estrogen promoted estrogen receptor-α (ERα) binding to matrix metalloproteinase 12 (MMP12) promoter estrogen response element (ERE). MMP12 co-localized with CD44 on the cell membrane and MMP12 knockdown significantly reduced estradiol-induced PC3 invasion. Taken together, our findings indicated that increased endogenous estrogen, catalysed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis. Thus, aromatase represents a potential novel therapeutic target for CRPC.


Subject(s)
Aromatase/genetics , Aromatase/metabolism , Estrogen Receptor alpha/metabolism , Estrogens/metabolism , Matrix Metalloproteinase 12/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Aged , Anilides/administration & dosage , Anilides/pharmacology , Animals , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hyaluronan Receptors/metabolism , Letrozole/administration & dosage , Letrozole/pharmacology , Male , Mice , Middle Aged , Neoplasm Metastasis , Nitriles/administration & dosage , Nitriles/pharmacology , PC-3 Cells , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Tosyl Compounds/administration & dosage , Tosyl Compounds/pharmacology , Up-Regulation/drug effects
16.
Cell Commun Signal ; 17(1): 50, 2019 05 23.
Article in English | MEDLINE | ID: mdl-31122254

ABSTRACT

BACKGROUND: Prostate cancer (PCa) is the second leading cause of mortality and a leading cause of malignant tumors in males. Prostate cancer stem cells (PCSCs) are likely the responsible cell types for cancer initiation, clinical treatment failure, tumor relapse, and metastasis. Estrogen receptor alpha (ERα) is mainly expressed in the basal layer cells of the normal prostate gland and has key roles in coordinating stem cells to control prostate organ development. Here, we investigated the roles of the estrogen-ERα signaling pathway in regulating PCSCs. METHODS: Correlation of CD49f and ERα/NOTCH1 was analyzed in human clinical datasets and tissue samples. Flow cytometry was used to sort CD49fHi and CD49fLow cells. EZH2 recruitment by ERα and facilitation of ERα binding to the NOTCH1 promoter was validated by Co-IP and ChIP. Primary tumor growth, tumor metastasis and sensitivity to 17ß-estradiol (E2) inhibitor (tamoxifen) were evaluated in castrated mice. RESULTS: ERα expression was significantly higher in CD49fHi prostate cancer basal stem-like cells (PCBSLCs), which showed basal and EMT features with susceptibility to E2 treatment. ERα-induced estrogen effects were suggested to drive the NOTCH1 signaling pathway activity via binding to the NOTCH1 promoter. Moreover, EZH2 was recruited by ERα and acted as a cofactor to assist ERα-induced estrogen effects in regulating NOTCH1 in PCa. In vivo, E2 promoted tumor formation and metastasis, which were inhibited by tamoxifen. CONCLUSIONS: Our results implicated CD49f+/ERα + prostate cancer cells associated with basal stem-like and EMT features, named EMT-PCBSLCs, in heightened potential for promoting metastasis. NOTCH1 was regulated by E2 in CD49fHi EMT-PCBSLCs. These results contribute to insights into the metastatic mechanisms of EMT-PCBSLCs in PCa.


Subject(s)
Epithelial-Mesenchymal Transition , Estrogen Receptor alpha/metabolism , Prostatic Neoplasms/metabolism , Receptor, Notch1/metabolism , Animals , Cell Line, Tumor , Enhancer of Zeste Homolog 2 Protein/metabolism , Humans , Integrin alpha6/metabolism , Male , Mice , Mice, Inbred BALB C , Neoplasm Metastasis , Neoplastic Stem Cells/metabolism , Phenotype , Prostatic Neoplasms/pathology , Receptor, Notch1/genetics
17.
Int J Mol Med ; 41(2): 1147-1155, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29207197

ABSTRACT

Prostate cancer (PCa) is a leading cause of cancer­associated mortality in men; however, the factors that contribute to disease development have yet to be fully elucidated. Previous studies have suggested that prohibitin-2 (PHB2), which is a multifunctional protein that contributes to various cellular processes, is positively correlated with malignant progression of PCa; however, the molecular mechanisms underlying the effects of PHB2 on the enhancement of cell migration have not been identified. The present study induced overexpression and knockdown of PHB2 in PCa cell lines (PC3 and DU145) with the aim of examining the effects of PHB2 on PCa cell migration via wound healing assays. The results indicated that PHB2 overexpression promoted migration of both cell lines. AKT serine/threonine kinase 2 (AKT2), which interacts with PHB2, has been reported to participate in cell migration; therefore, the present study examined the effects PHB2 overexpression and knockdown on AKT2 in PCa cells. The present study demonstrated that overexpression of PHB2 reduced the expression of AKT2, whereas PHB2 knockdown increased AKT2 expression in both PCa cell lines. In addition, knockdown of PHB2 enhanced the protein stability of AKT2. Furthermore, AKT2 overexpression resulted in a significant decrease in migration, whereas AKT2 knockdown promoted migration of PC3 and DU145 PCa cells. The combined overexpression of PHB2 and AKT2 inhibited migration of both cell lines, thus suggesting that AKT2 overexpression abolished PHB2-induced migration. Mechanistically, the present study suggested that PHB2 may promote PCa cell migration by inhibiting the expression of AKT2. These results provide information regarding the role of PHB2 in PCa migration and malignancy.


Subject(s)
Cell Movement/genetics , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins c-akt/genetics , Repressor Proteins/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , Prohibitins , Prostatic Neoplasms/pathology
18.
Oncotarget ; 8(38): 64471-64480, 2017 Sep 08.
Article in English | MEDLINE | ID: mdl-28969086

ABSTRACT

PURPOSE: This study was conducted to review the efficacy and safety of Apatinib in stage IV sarcoma patients who failed previous chemotherapy. MATERIALS AND METHODS: The clinical information on 16 patients with stage IV sarcomas who failed in prior chemotherapy and subsequently received Apatinib treatment was collected. Apatinib was given 500mg/daily and 4 weeks as a cycle. All patients had at least one measurable extracranial tumor according to Response Evaluation Criteria In Solid Tumors 1.0 criteria. Progression free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment-related adverse effects (AEs) were reviewed and evaluated. RESULTS: Patients was administered Apatinib for 0 to 9 cycles with the median of 3.2 cycles. Median follow-up time was 8.4 months (1 to 12 months). Ten of 16 patients received at least 1 complete cycle of Apatinib treatment were eligible for the efficacy analysis. The median PFS was 8.84 months. Two patients achieved partial response (PR) and 6 patients achieved stable disease (SD). Two patients were evaluated as progression disease (PD) and one patient died of disease progression. The ORR was 20.0% (2/10) and the DCR was 80.0% (8/10). The most common grade 3/4 treatment-related AEs were hypertension (18.7%), hand-foot syndrome (12.5%) and proteinuria (6.3%). No drug-related severe AEs occurred. CONCLUSION: CApatinib treatment in this exploratory study exhibited objective efficacy and manageable toxicity in stage IV sarcoma patients who failed in chemotherapy. This result supports future random controlled trial to further define Apatinib activity in stage IV sarcomas.

19.
Prostate ; 77(14): 1424-1437, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28850686

ABSTRACT

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is involved in pathogenesis of human benign prostatic hyperplasia (BPH). Estrogenic signaling pathways may stimulate the induction of EMT. However, the details of estradiol (E2) and estrogen receptors (ERs) effects on EMT, as well as E2-induced modulation of benign prostatic epithelial cell phenotype in vitro have not been completely clarified. METHODS: The effects of E2 on EMT markers and cytokeratins (CKs) expression were evaluated in benign epithelial cell lines BPH-1 and RWPE-1, which were cultured both in two-dimensional (2D) culture and three-dimensional (3D) culture model using hanging drop technique or 3D Matrigel model. ER antagonist, ICI182,780, was used to confirm the regulatory effects of E2 on EMT and phenotypic modulation. In 3D culture, immunohistochemical stainings were performed to detect the specific phenotype of cells that underwent EMT in acinar-like spheroids formed by RWPE-1. To illustrate the exact function of ERs in E2-induced EMT and phenotypic modulation, specific short interfering RNAs (siRNAs), and agonists were used to knockdown or activate individual ERs, respectively. RESULTS: E2-induced EMT was observed both in 2D and 3D culture, with related regulation of EMT markers expression at both mRNA and protein level. In addition, E2 down-regulated luminal cell type markers CK18 and CK8 and up-regulated basal cell type markers CK5 and CK14. E2 also increased intermediate type markers CK15 and CK17, while it attenuated CK19 in 3D culture. ICI182,780 blocked E2-induced EMT and cell phenotypic switching. In 3D Matrigel culture, Vimentin was co-expressed with ERα and CK17, as well as with SMemb, which is related to cell status switching and proliferation. Knockdown of ERα but not GPR30 inhibited EMT, while ERß knockdown facilitated EMT process. Knockdown of ERα blocked E2-induced EMT both in RWPE-1 and BPH-1. MRNA expression of EMT markers was stimulated by ERα-specific agonist PPT and inhibited by ERß-specific agonist DPN. CONCLUSIONS: Estrogenic effect mediated by ERα can promote EMT. E2 is also an inductive factor of cell phenotypic switching. Cell type modulation is associated with E2-induced EMT in benign prostatic epithelial cells. Taken together the results support a contribution of estrogens to the pathogenesis of BPH in elderly men.


Subject(s)
Epithelial-Mesenchymal Transition , Prostatic Hyperplasia , Prostatic Neoplasms , Receptors, Estrogen , Cell Line, Tumor , Cell Movement/drug effects , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/physiology , Estradiol/pharmacology , Estrogens/pharmacology , Humans , Male , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/metabolism , Signal Transduction/physiology
20.
Stem Cell Investig ; 4: 21, 2017.
Article in English | MEDLINE | ID: mdl-28447036

ABSTRACT

Liposarcomas (LPS) are among the most common soft tissue sarcomas, originating from adipocytes. Treatment for LPS typically involves surgical resection and radiation therapy, while the use of conventional cytotoxic chemotherapy for unresectable or metastatic LPS remains controversial. This review summarizes the results of recent translational research and trials of novel therapies targeting various genetic and molecular aberrations in different subtypes of LPS. Genetic aberrations such as the 12q13-15 amplicon, genetic amplification of MDM2, CDK4, TOP2A, PTK7, and CHEK1, point mutations in CTNNB1, CDH1, FBXW7, and EPHA1, as the fusion of FUS-DDIT3/EWSR1-DDIT3 are involved in the pathogenesis LPS and represent potential therapeutic candidates. Tyrosine kinase inhibitors targeting MET, AXL, IGF1R, EGFR, VEGFR2, PDGFR-ß and Aurora kinase are effective in certain types of LPS. Abnormalities in the PI3K/Akt signaling pathway deregulation of C/EBP-α and its partner PPAR-γ, and the interaction between calreticulin (CRT) and CD47 are also promising therapeutic targets. These promising new approaches may help to supplement existing treatments for LPS.

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