المؤلفون: Feng-Wei Chen, Yung-Ling Wu, Chao-Chun Cheng, Yu-Wei Hsiao, Jhih-Ying Chi, Liang-Yi Hung, Chih-Peng Chang, Ming-Derg Lai, Ju-Ming Wang

المصدر: Journal of Biomedical Science, Vol 31, Iss 1, Pp 1-19 (2024)

مصطلحات موضوعية: PTX3, Cancer-associated fibroblasts, M2-like macrophages, Colon cancer, Immunosuppression, Medicine

الوصف: Abstract Background The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear. Methods Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization. Results Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization. Conclusions PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1423-0127Test

الوصول الحر: https://doaj.org/article/fc78de390566478a976181459c9e7cc0Test

المؤلفون: Yan-Ting Chen, Ainun Nizar Masbuchin, Yi-Hsien Fang, Ling-Wei Hsu, Sheng-Nan Wu, Chia-Jui Yen, Yen-Wen Liu, Yu-Wei Hsiao, Ju-Ming Wang, Mohammad Saifur Rohman, Ping-Yen Liu

المصدر: Biomedicine & Pharmacotherapy, Vol 157, Iss , Pp 113962- (2023)

مصطلحات موضوعية: Cardiomyocytes, Hepatocellular carcinoma, Mitochondrial respiration, Pentraxin 3, Tyrosine kinase inhibitors, Cardiooncology, Therapeutics. Pharmacology, RM1-950

الوصف: Background: Hepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models. Objectives: We sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity. Methods: We used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers. Results: Significantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis. Conclusions: TKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332222013518Test; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/4b9f21f742054723871db3bdd038be28Test

المؤلفون: Jhih‐Ying Chi, Yu‐Wei Hsiao, Hsin‐Yin Liang, Tang‐Hsiu Huang, Feng‐Wei Chen, Chen‐Yang Chen, Chiung‐Yuan Ko, Chao‐Chun Cheng, Ju‐Ming Wang

المصدر: Clinical and Translational Medicine, Vol 12, Iss 11, Pp n/a-n/a (2022)

مصطلحات موضوعية: CD44, pentraxin 3, pulmonary fibrosis, Medicine (General), R5-920

الوصف: Background Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. Methods Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin‐exposed conditional Ptx3‐deficient and PTX3‐neutralizing antibody (αPTX3i)‐treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44‐involved PTX3‐induced fibrosis in HFL1 and primary mouse fibroblasts. Results PTX3 was upregulated in the lungs and plasma of bleomycin‐exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin‐exposed conditional Ptx3‐deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen‐expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K‐AKT1, NF‐κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic‐based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin‐induced pulmonary fibrosis. Conclusions The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2001-1326Test

الوصول الحر: https://doaj.org/article/7c28c937591e40f2831b2a6e44ccd2bdTest

المؤلفون: Ruo-Yu Chen, Chia-Jui Yen, Yih-Jyh Lin, Ju-Ming Wang, Ting-Fen Tasi, Yu-Chuan Huang, Yao-Wen Liu, Hung-Wen Tsai, Ming-Hao Lee, Liang-Yi Hung

المصدر: Cell Death and Disease, Vol 12, Iss 11, Pp 1-13 (2021)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1β and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/b386d754e434499abdb65528261eadb2Test

المؤلفون: Jhih-Ying Chi, Yu-Wei Hsiao, Hai-Ling Liu, Xin-Juan Fan, Xiang-Bo Wan, Tsung-Lin Liu, Sheng-Jou Hung, Yi-Ting Chen, Hsin-Yin Liang, Ju-Ming Wang

المصدر: Cell Death Discovery, Vol 7, Iss 1, Pp 1-16 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671

الوصف: Abstract Cancer-associated fibroblasts (CAFs) play an essential role in supporting cancer progression. However, the details and consequent effects in response to the communication between CAFs and angiogenesis remain largely uninvestigated, especially in anticancer drug treatments. We found that cisplatin and 5-fluorouracil could induce fibroblast differentiation toward myofibroblasts via CCAAT/enhancer-binding protein delta (CEBPD) and consequently promote proliferation, migration, and in vitro tube formation of vascular endothelial cells and angiogenesis in vivo. Stromal-cell-derived factor 4 (SDF4) is responsive to anticancer drugs via CEBPD activation in CAFs and contributes to create a permissive environment for tumor cell angiogenesis and promotion of distant metastasis. Importantly, we demonstrated that SDF4 interacts with CXCR4 to trigger VEGFD expression through the activation of the ERK1/2 and p38 pathways in endothelial cells. Taken together, our novel findings support that SDF4 can be a therapeutic target in inhibition of angiogenesis for chemotherapy drug-administrated cancer patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2058-7716Test

الوصول الحر: https://doaj.org/article/757da9e997c74013b8992407199a400bTest

المؤلفون: Shao-Ming Wang, Wen-Chi Lin, Hong-Yi Lin, Yen-Lin Chen, Chiung-Yuan Ko, Ju-Ming Wang

المصدر: Cell Death Discovery, Vol 7, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671

الوصف: Abstract Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2058-7716Test

الوصول الحر: https://doaj.org/article/f9a3756aada94693983fc579086e1793Test

المؤلفون: Jyun-Yi Du, Hong-Yue Lai, Yu-Wei Hsiao, Jhih-Ying Chi, Ju-Ming Wang

المصدر: Journal of Immunology Research, Vol 2022 (2022)

مصطلحات موضوعية: Immunologic diseases. Allergy, RC581-607

الوصف: Background. Since food avoidance is currently the only way to prevent allergic reactions to shrimp, a better understanding of molecular events in the induction and progression of allergy, including food allergy, is needed for developing strategies to inhibit allergic responses. Pentraxin 3 (PTX3) is rapidly produced directly from inflammatory or damaged tissues and is involved in acute immunoinflammatory responses. However, the role of PTX3 in the development of immediate IgE-mediated shrimp allergy remains unknown. Methods. Wild-type BALB/c mice were immunized intraperitoneally and were challenged with shrimp extract. Serum IgE and PTX3 levels were analyzed. RBL-2H3 cells were stimulated with either dinitrophenyl (DNP) or serum of shrimp-allergic mice, and markers of degranulation, proinflammatory mediators, and phosphorylation of signal proteins were analyzed. We further examined the effect of PTX3 in shrimp extract-induced allergic responses in vitro and in vivo. Results. Mice with shrimp allergy had increased PTX3 levels in the serum and small intestine compared with healthy mice. PTX3 augmented degranulation, the production of proinflammatory mediators, and activation of the Akt and MAPK signaling pathways in mast cells upon DNP stimulation. Furthermore, the expression of transcription factor CCAAT/enhancer-binding protein delta (CEBPD) was elevated in PTX3-mediated mast cell activation. Finally, the PTX3 inhibitor RI37 could attenuate PTX3-induced degranulation, proinflammatory mediator expression, and phosphorylation of the Akt and MAPK signaling. Conclusions. The results suggested that PTX3 can facilitate allergic responses. Our data provide new insight to demonstrate that PTX3 is a cause of allergic inflammation and that RI37 can serve as a therapeutic agent in shrimp allergy.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2314-7156Test

الوصول الحر: https://doaj.org/article/548cc66e89294ec1bac45a77ecda345bTest

المؤلفون: Yu‐Wei Hsiao, Jhih‐Ying Chi, Chien‐Feng Li, Lei‐Yi Chen, Yi‐Ting Chen, Hsin‐Yin Liang, Yu‐Chih Lo, Jhen‐Yi Hong, Chin‐Pin Chuu, Liang‐Yi Hung, Jyun‐Yi Du, Wen‐Chang Chang, Ju‐Ming Wang

المصدر: Clinical and Translational Medicine, Vol 12, Iss 1, Pp n/a-n/a (2022)

مصطلحات موضوعية: CD44 and tumour microenvironment, NF‐κB, pentraxin 3 (PTX3), triple‐negative breast cancer cells (TNBC), Medicine (General), R5-920

الوصف: Abstract Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple‐negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF‐β1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF‐κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA‐MB‐231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA‐MB‐231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2001-1326Test

الوصول الحر: https://doaj.org/article/57e2d11844154b1fb091704d1e6bfcd8Test

المؤلفون: Wei-Jan Wang, Hong-Yue Lai, Fei Zhang, Wan-Jou Shen, Pei-Yu Chu, Hsin-Yin Liang, Ying-Bin Liu, Ju-Ming Wang

المصدر: JCI Insight, Vol 6, Iss 15 (2021)

مصطلحات موضوعية: Endocrinology, Hepatology, Medicine

الوصف: Obesity is a risk factor for gallbladder cancer (GBC) development, and it correlates with shorter overall survival. Leptin, derived from adipocytes, has been suggested to contribute to the growth of cancer cells; however, the detailed mechanism of leptin in GBC drug resistance remains uninvestigated. In this study, our finding that patients with GBC with a higher BMI were associated with increased GBC risks, including shortened survival, is clinically relevant. Moreover, obese NOD/SCID mice exhibited a higher circulating concentration of leptin, which is associated with GBC growth and attenuated gemcitabine efficacy. We further revealed that leptin can inhibit gemcitabine-induced GBC cell death through myeloid cell leukemia 1 (MCL1) activation. The transcription factor C/EBP δ (CEBPD) is responsive to activated STAT3 (pSTAT3) and contributes to MCL1 transcriptional activation upon leptin treatment. In addition, MCL1 mediates leptin-induced mitochondrial fusion and is associated with GBC cell survival. The findings in this study suggest the involvement of the pSTAT3/CEBPD/MCL1 axis in leptin-induced mitochondrial fusion and survival and provide a potentially new therapeutic target to improve the efficacy of gemcitabine in patients with GBC.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/f7a4ee5f9e7b482c844150683c673d32Test

المؤلفون: Chia-Jui Yen, Shu-Ting Yang, Ruo-Yu Chen, Wenya Huang, Kazuaki Chayama, Ming-Hao Lee, Shiang-Jie Yang, Hong-Sheng Lai, Hsin-Yi Yen, Yu-Wei Hsiao, Ju-Ming Wang, Yih-Jyh Lin, Liang-Yi Hung

المصدر: Journal of Biomedical Science, Vol 26, Iss 1, Pp 1-14 (2019)

مصطلحات موضوعية: Hepatocarcinogenesis, CPAP, HBx, NF-κB, Inflammation, Medicine

الوصف: Abstract Background Our previous report suggested that centrosomal P4.1-associated protein (CPAP) is required for Hepatitis B virus (HBV) encoded non-structure protein X (HBx)-mediated nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activation. CPAP is overexpressed in HBV-associated hepatocellular carcinoma (HCC); however, the interaction between CPAP and HBx in HBV-HCC remains unclear. Methods The mRNA expression of CPAP and HBx was analyzed by quantitative-PCR (Q-PCR). NF-κB transcriptional activity and CPAP promoter activity were determined using a reporter assay in Huh7 and Hep3B cells. Immunoprecipitation (IP) and in situ proximal ligation assay (PLA) were performed to detect the interaction between CPAP and HBx. Chromatin-IP was used to detect the association of cAMP response element binding protein (CREB) and HBx with the CPAP promoter. Cell proliferation was measured using cell counting kit CCK-8, Bromodeoxyuridine (5-bromo-2′-deoxyuridine, BrdU) incorporation, and clonogenic assays. The tumorigenic effects of CPAP were determined using xenograft animal models. Results HBx can transcriptionally up-regulate CPAP via interacting with CREB. Overexpressed CPAP directly interacted with HBx to promote HBx-mediated cell proliferation and migration; SUMO modification of CPAP was involved in interacting with HBx. Knocked-down expression of CPAP decreased the HBx-mediated tumorigenic effects, including cytokines secretion. Interestingly, overexpressed CPAP maintained the HBx protein stability in an NF-κB-dependent manner; and the expression levels of CPAP and HBx were positively correlated with the activation status of NF-κB in HCC. Increased expression of CPAP and CREB mRNAs existed in the high-risk group with a lower survival rate in HBV-HCC. Conclusion The interaction between CPAP and HBx can provide a microenvironment to facilitate HCC development via enhancing NF-κB activation, inflammatory cytokine production, and cancer malignancies. This study not only sheds light on the role of CPAP in HBV-associated HCC, but also provides CPAP as a potential target for blocking the hyper-activated NF-κB in HCC.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12929-019-0534-9Test; https://doaj.org/toc/1423-0127Test

الوصول الحر: https://doaj.org/article/1987785a2d1240ffbec7f6dee6b577aeTest