The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

Hu, Yufeng; Su, Hexiu; Li, Xu; Guo, Guoli; Cheng, Lan; Qin, Renyi; Qing, Guoliang; Liu, Hudan

doi:10.1158/1535-7163.mct-14-0501

Cited by 25 publications

(21 citation statements)

References 30 publications

(31 reference statements)

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“…Moreover, intestinal mast cells require the expression of Notch2 in order to localize to the epithelium [ 104 ]. In pancreatic cancer, the NOTCH1-JAGGED2 interaction itself, but not canonical Notch signaling, is known to promote metastasis [ 105 ].…”

Section: In Vivo Roles Of Notch-mediated Cell Amentioning

confidence: 99%

Notch-Mediated Cell Adhesion

Murata

Hayashi

2016

Biology

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Notch family members are generally recognized as signaling molecules that control various cellular responses in metazoan organisms. Early fly studies and our mammalian studies demonstrated that Notch family members are also cell adhesion molecules; however, information on the physiological roles of this function and its origin is limited. In this review, we discuss the potential present and ancestral roles of Notch-mediated cell adhesion in order to explore its origin and the initial roles of Notch family members dating back to metazoan evolution. We hypothesize that Notch family members may have initially emerged as cell adhesion molecules in order to mediate multicellularity in the last common ancestor of metazoan organisms.

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Section: In Vivo Roles Of Notch-mediated Cell Amentioning

confidence: 99%

Notch-Mediated Cell Adhesion

Murata

Hayashi

2016

Biology

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“…Upon binding of a ligand (jagged 1, jagged 2, delta-like 1 or delta-like 1, 3 or 4) to the cell surface Notch receptors (Notch1-4), the intracellular domain of Notch (NICD) is cleaved and translocated to the nucleus to induce the expression of target genes including Hes1, Hes5, Hey1 and HeyL [14]. Dysfunction of the Notch signaling pathway may block differentiation and lead to malignant transformation [15–17]. Many alterations in Notch signaling are reported in osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

Fan

Fang

et al. 2016

Oncotarget

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Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance.

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“…Next, we examined several oncogenic and stemness‐related markers, which have been implicated in pancreatic tumorigenesis in garcinol‐treated PANC‐1 SP cells. We found that garcinol treatment was able to dose dependently suppress Mcl‐1 (prosurvival factor) , EZH2 (a metastatic marker) , ABCG2 (drug resistance), Gli‐1 and cleaved Notch‐1 representatives of Sonic Hedgehog , and Notch stemness signaling pathways (Fig. C), suggesting garcinol targets multiple signaling pathways in PANC‐1 SP cells.…”

Section: Resultsmentioning

confidence: 87%

Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

Huang

Lin

Huang

et al. 2017

Biotech and App Biochem

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Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs.

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The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

Cited by 25 publications

References 30 publications

Notch-Mediated Cell Adhesion

Notch-Mediated Cell Adhesion

Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

Garcinol downregulates Notch1 signaling via modulating miR‐200c and suppresses oncogenic properties of PANC‐1 cancer stem‐like cells

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