2013
DOI: 10.1002/path.4170
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G‐Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1

Abstract: Metastatic spread in Ewing sarcomas (ES) is frequent and haematogenous. G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis is specifically over-expressed in ES among sarcoma, but also up-regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64 expression in ES by RNA interference impaired colony formation in vitro and suppressed local tumour growth and metastasis in Rag2(-/-) γC (-/-) mice. Microarray analysis af… Show more

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Cited by 58 publications
(69 citation statements)
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“…Furthermore, there is also evidence that MMP1 is a direct target of EWS / ETS proteins, as a previous study has shown that EWS-ETV1 (ER81) and EWS-FLI1 fusion proteins can interact with the MMP1 promoter and collaborate with c-Jun and the cofactor p300 to activate MMP1 gene transcription in vitro [49]: But in our hands, EWS-FLI1 knock down suppressed MMP1 expression only in A673 cells but not in other ES lines. Previous results of our laboratory already indicated a strong contribution of MMP1 to metastasis of ES and its possible induction via several, presumably independent pathways that so far was not understood [5, 38, 39]. In line with these observations, knock down of HOXD11 or HOXD13 significantly suppressed metastasis in a xeno-transplant model in immune deficient Rag2 −/− γ C −/− mice.…”
Section: Discussionsupporting
confidence: 75%
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“…Furthermore, there is also evidence that MMP1 is a direct target of EWS / ETS proteins, as a previous study has shown that EWS-ETV1 (ER81) and EWS-FLI1 fusion proteins can interact with the MMP1 promoter and collaborate with c-Jun and the cofactor p300 to activate MMP1 gene transcription in vitro [49]: But in our hands, EWS-FLI1 knock down suppressed MMP1 expression only in A673 cells but not in other ES lines. Previous results of our laboratory already indicated a strong contribution of MMP1 to metastasis of ES and its possible induction via several, presumably independent pathways that so far was not understood [5, 38, 39]. In line with these observations, knock down of HOXD11 or HOXD13 significantly suppressed metastasis in a xeno-transplant model in immune deficient Rag2 −/− γ C −/− mice.…”
Section: Discussionsupporting
confidence: 75%
“…As shown in Figure 5C, A673 and SK-N-MC HOXD10 , HOXD11 and HOXD13 shRNA infectants revealed a significant contribution of at least HOXD11 and HOXD13 to in vitro invasiveness. Recent results of our laboratory already indicated a strong contribution of MMP1 to invasion and metastasis of ES and its possible induction via several, presumably independent pathways [5, 38, 39]. Subsequent analysis of MMP1 expression in these HOXD shRNA infectants demonstrated a strong induction of MMP1 expression by all three HOXD genes (Figure 5D, see Supplementary Material, Figure S5B) signifying that the reduced invasive potential of HOXD11 or HOXD13 and probably HOXD10 silenced ES cells may be mediated at least in part via MMP1.…”
Section: Resultsmentioning
confidence: 99%
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“…Consistent with the phenotypic changes, mEHT coordinately impacted a restricted number of defined oncogenic pathways that acted in concert to decrease cell proliferation and induce apoptosis, thereby providing a rationale for the therapeutic use of mEHT in HCC. Specifically, the expression level of SEPT4, which is involved in pro-apoptotic activity and growth suppression [12] was induced, whereas a key regulator of invasiveness and metastasis GPR64 [13] was repressed in RNA level. Subsequent Western blot analysis confirmed the common increase of the SEPT4 tumour suppressor in addition to a concomitant increase in CDK inhibitor p21 and decrease in both pro-caspase 3 and pro-caspase 7 (Figure 6(A)), thereby accelerating apoptotic signalling in the HepG2 and Huh7 cell lines.…”
Section: The Molecular Mechanisms Underlying the Growth Inhibitory Efmentioning
confidence: 98%
“…As shown in Figure 5C, A673 and SK-N-MC HOXD10, HOXD11 and HOXD13 shRNA infectants revealed a significant contribution of at least HOXD11 and HOXD13 to in vitro invasiveness. Recent results of our laboratory already indicated a strong contribution of MMP1 to invasion and metastasis of ES and its possible induction via several, presumably independent pathways [5,38,39]. Figure S5B) signifying that the reduced invasive potential of HOXD11 or HOXD13 and probably HOXD10 silenced ES cells may be mediated at least in part via MMP1.…”
Section: Hoxd Genes Promote Es Growth and Invasivenessmentioning
confidence: 99%