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  • Chang, Antao  (10)
  • 2020-2024  (10)
  • 1
    Online Resource
    Online Resource
    CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism
    Wiley ; 2023
    In:  Advanced Science Vol. 10, No. 6 ( 2023-02)
    Details
    In: Advanced Science, Wiley, Vol. 10, No. 6 ( 2023-02)
    Abstract: CD73, a cell surface‐bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5′‐AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase‐independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small‐molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non‐steroidal anti‐inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL‐Kras G12D/+ , LSL‐Trp53 R172H/+ , and Pdx‐1‐Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti‐CD73 therapy, when used alone or in combination with gemcitabine‐based chemotherapy regimen, for metastatic PDAC.
    Type of Medium: Online Resource
    ISSN: 2198-3844 , 2198-3844
    URL: Issue
    URL: Article
    DOI: 10.1002/advs.v10.6
    DOI: 10.1002/advs.202206335
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2808093-2
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  • 2
    Online Resource
    Online Resource
    A novel isoform of ATOH8 promotes the metastasis of breast cancer by regulating RhoC
    Oxford University Press (OUP) ; 2021
    In:  Journal of Molecular Cell Biology Vol. 13, No. 1 ( 2021-04-10), p. 59-71
    Details
    In: Journal of Molecular Cell Biology, Oxford University Press (OUP), Vol. 13, No. 1 ( 2021-04-10), p. 59-71
    Abstract: Metastases are the main cause of cancer-related mortality in breast cancer. Although significant progress has been made in the field of tumor metastasis, the exact molecular mechanisms involved in tumor metastasis are still unclear. Here, we report that ATOH8-V1, a novel isoform of ATOH8, is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients. Forced expression of ATOH8-V1 dramatically enhances, while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines. Moreover, ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC, which in turn enhances the metastasis of breast cancer. Altogether, our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis, suggesting that ATOH8-V1 is a potential therapeutic target for treatment of metastatic cancers.
    Type of Medium: Online Resource
    ISSN: 1759-4685
    URL: Article
    DOI: 10.1093/jmcb/mjaa050
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2500949-7
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  • 3
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    SDCBP promotes pancreatic cancer progression by preventing YAP1 from β-TrCP-mediated proteasomal degradation
    BMJ ; 2023
    In:  Gut Vol. 72, No. 9 ( 2023-09), p. 1722-1737
    Details
    In: Gut, BMJ, Vol. 72, No. 9 ( 2023-09), p. 1722-1737
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression. Design We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study. Results The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses β-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP. Conclusions SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from β-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2022-327492
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1492637-4
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  • 4
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    Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Experimental & Clinical Cancer Research Vol. 42, No. 1 ( 2023-05-04)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 42, No. 1 ( 2023-05-04)
    Abstract: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. Methods We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. Results High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. Conclusions Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-023-02671-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2430698-8
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  • 5
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    Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma
    China Anti-cancer Association ; 2023
    In:  Cancer Biology & Medicine ( 2023-06-27), p. 1-28
    Details
    In: Cancer Biology & Medicine, China Anti-cancer Association, ( 2023-06-27), p. 1-28
    Abstract: Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. Methods: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. Results: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. Conclusions: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.
    Type of Medium: Online Resource
    ISSN: 2095-3941
    URL: Article
    DOI: 10.20892/j.issn.2095-3941.2023.0039
    Language: Unknown
    Publisher: China Anti-cancer Association
    Publication Date: 2023
    detail.hit.zdb_id: 2676322-9
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  • 6
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    DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 6 ( 2021-03-19), p. 1403-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 6 ( 2021-03-19), p. 1403-
    Abstract: Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13061403
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 7
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    Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma
    Elsevier BV ; 2022
    In:  Cancer Letters Vol. 548 ( 2022-11), p. 215864-
    Details
    In: Cancer Letters, Elsevier BV, Vol. 548 ( 2022-11), p. 215864-
    Type of Medium: Online Resource
    ISSN: 0304-3835
    URL: Article
    DOI: 10.1016/j.canlet.2022.215864
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 195674-7
    detail.hit.zdb_id: 2004212-7
    SSG: 12
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  • 8
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    BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis
    Springer Science and Business Media LLC ; 2023
    In:  Signal Transduction and Targeted Therapy Vol. 8, No. 1 ( 2023-07-14)
    Details
    In: Signal Transduction and Targeted Therapy, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2023-07-14)
    Abstract: VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3’UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.
    Type of Medium: Online Resource
    ISSN: 2059-3635
    URL: Article
    DOI: 10.1038/s41392-023-01478-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2886872-9
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  • 9
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    Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy
    Elsevier BV ; 2024
    In:  Gastroenterology ( 2024-3)
    Details
    In: Gastroenterology, Elsevier BV, ( 2024-3)
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1053/j.gastro.2024.02.046
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
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  • 10
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    Table_1.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Oncology Vol. 12 ( 2022-2-21)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-2-21)
    Abstract: Some patients with pancreatic ductal adenocarcinoma (PDAC) are prone to rapid recurrence or metastasis after radical resection. However, evaluation methods for effectively identifying these patients are lacking. In this study, we established perioperative serum scoring systems to screen patients with early recurrence and poor prognosis. Methods We systematically analysed 44 perioperative serum parameters, including systemic inflammatory parameters, coagulation system parameters, tumor markers, and 18 clinicopathological characteristics of 218 patients with radical resection in our centre. Univariate Cox regression and LASSO regression models were used to screen variables. Kaplan-Meier survival analysis was used to compare relapse-free survival and overall survival. Multivariate Cox regression was used to evaluate the independent risk variables. AUC and C-index were used to reveal the effectiveness of the models. In addition, the effectiveness was also verified in an independent cohort of 109 patients. Results Preoperative systemic immune coagulation cascade (SICC) (including increased neutrophil to lymphocyte ratio, decreased lymphocyte to monocyte ratio, increased platelet and fibrinogen) and increased postoperative tumor markers (TMs) (CA199, CEA and CA242) were independent risk factors for early recurrence of resectable pancreatic cancer. On this basis, we established the preoperative SICC score and postoperative TMs score models. The patients with higher preoperative SICC or postoperative TMs score were more likely to have early relapse and worse prognosis. The nomogram based on preoperative SICC, postoperative TMs, CACI, smoking index, vascular cancer embolus and adjuvant chemotherapy can effectively evaluate the recurrence rate (AUC 1 year : 0.763, AUC 2 year : 0.679, AUC 3 year : 0.657) and overall survival rate (AUC 1 year : 0.770, AUC 3 year : 0.804, AUC 5 year : 0.763). Conclusion Preoperative SICC and postoperative TMs can help identify resectable PDAC patients with early recurrence and poor prognosis.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2022.841819
    DOI: 10.3389/fonc.2022.841819.s001
    DOI: 10.3389/fonc.2022.841819.s002
    DOI: 10.3389/fonc.2022.841819.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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