The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma
Jérémy H. RaymondMarie PouteauxValérie PetitZackie AktaryFlavie LucianiMaria WehbePatrick GizziClaire BourbanIgor MartianovIrwin DavidsonCatherine TomasettoFlorence Mahuteau‐BetzerB. VergierLionel LarueVéronique Delmas
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Summary Although tremendous progress has been made in understanding the mechanisms leading to cancer, those governing metastases are still poorly understood. E-cadherin (Ecad) is a cell-cell adhesion molecule essential for tissue homeostasis, and its loss often correlates with the dissemination of human cancers. However, whether and how the loss of Ecad triggers the full metastatic program is largely unknown. Here, we show that the loss of Ecad promotes melanoma lung metastases in females. The loss of Ecad, after the induction of estrogen receptor α (ERα) expression, activates gastrin-releasing peptide receptor (GRPR) expression. GRPR promotes cellular processes essential for metastasis formation through G□ q and YAP1 signaling and its pharmacological inhibition reduces metastasis in vivo . This study reveals an Ecad-ERα-GRPR metastatic sex dimorphism axis in melanoma that is conserved in human breast cancer and provides proof of concept that the G-coupled receptor GRPR is a therapeutic target for metastasis.Keywords:
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<p>Figure S1. The correlation analysis between ADAM12 and YAP1.(A) The correlation analysis between ADAM12 and YAP1 in CRC based on the TCGA-COAD data. (B) The correlation analysis between ADAM12 and YAP1 in CRC patients. (C) CRC patients with high YAP1 expression showed markedly lower 2000-days survival than those with low YAP1 expression. (D) Western blot analysis of ADAM12 in T84 cells with YAP1 knockdown.</p>
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<p>Figure S1. The correlation analysis between ADAM12 and YAP1. (A) The correlation analysis between ADAM12 and YAP1 in CRC based on the TCGA-COAD data. (B) The correlation analysis between ADAM12 and YAP1 in CRC patients. (C) CRC patients with high YAP1 expression showed markedly lower 2000-days survival than those with low YAP1 expression. (D) Western blot analysis of ADAM12 in T84 cells with YAP1 knockdown.</p>
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ABSTRACT Melanoma with rapid progression towards metastasis has become the deadliest form of skin cancer. However, the mechanism of melanoma growth and metastasis is still unclear. Here, we found that miRNA-138 was lowly expressed and hypoxia-inducible factor 1α (HIF1α) was highly expressed in patients’ melanoma tissue compared with the paracancerous tissues, and they had a significant negative correlation (r=−0.877, P<0.001). Patients with miRNA-138low/HIF1αhigh signatures were predominant in late stage III/IV of melanoma. Further, bioinformatic analysis demonstrated that miRNA-138 directly targeted HIF1α. We found that the introduction of pre-miRNA-138 sequences to A375 cells reduced HIF1α mRNA expression and suppressed cell proliferation, migration and invasion. Overexpression of miRNA-138 or inhibition of HIF1α significantly suppressed the growth and metastasis of melanoma in vivo. Our study demonstrates the role and clinical relevance of miRNA-138 and HIF1α in melanoma cell growth and metastasis, providing a novel therapeutic target for suppression of melanoma growth and metastasis.
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Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.
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YAP1(Yes-associated protein 1)is a molecular of Hippo pathway. In early studies, researchers found that YAP1 was inactive when Hippo pathway was well functional. When some molecules mutated in Hippo pathway, YAP1 was hyperactivated. Hyperactivated YAP1 could promote cell proliferation, metastasis, cell survival and maintain the activity of stem cell. Because hyperactivated YAP1 can promote the occurrence and progress of tumor, YAP1 was defined as an oncoprotein. Recently, researchers found that YAP1 variants were associated with survival rates of small-cell lung cancer patients. YAP1 interacted with catenin and Kras to regulate infiltration and metastasis of cancer cell. And some micro RNAs could interact with YAP1. Based on the function of YAP1, we can find some therapeutic strategies and targets for cancer treatment. This paper summarize the studies of YAP1 and provide some evidence for basic and clinical research of cancer therapy.
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<p>Figure S1. The correlation analysis between ADAM12 and YAP1. (A) The correlation analysis between ADAM12 and YAP1 in CRC based on the TCGA-COAD data. (B) The correlation analysis between ADAM12 and YAP1 in CRC patients. (C) CRC patients with high YAP1 expression showed markedly lower 2000-days survival than those with low YAP1 expression. (D) Western blot analysis of ADAM12 in T84 cells with YAP1 knockdown.</p>
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AbstractBy immunological methods, we show that the monoclonal antibody 6D5 which reacts specifically with Xenopus laevis XB/U-cadherin, also binds to mouse P-cadherin and to chicken B-cadherin but not to the respective E-cadherins (L-CAM) or other "classical" cadherins in these species. In the first extracellular domain, three amino acid residues are identified that are shared by frog XB/U-cadherin, chicken B-cadherin and mammalian P-cadherins but not by the other "classical" cadherins. With few exceptions, the other cadherins possess residues at these positions that are also characteristic of each type of cadherin. Moreover, the expression patterns of P-, B-, and XB/U-cadherin in mouse, chicken and frog are more similar to each other than they are to those of the E-cadherins, L-CAM or other classical cadherins. Taken together, our results suggest that mammalian P-cadherins, chicken B-cadherin and frog XB/U-cadherin are closely related, if not homologous, molecules. A number of differences in the expression patterns between P-, B-, and XB/U-cadherin indicate that these molecules assume differential morphogenetic roles in different species.Key Words: cell-cell adhesioncalcium-dependentcadherin superfamilyexpression analysiscross-species homologuesphylogenesis
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<p>Figure S1. The correlation analysis between ADAM12 and YAP1. (A) The correlation analysis between ADAM12 and YAP1 in CRC based on the TCGA-COAD data. (B) The correlation analysis between ADAM12 and YAP1 in CRC patients. (C) CRC patients with high YAP1 expression showed markedly lower 2000-days survival than those with low YAP1 expression. (D) Western blot analysis of ADAM12 in T84 cells with YAP1 knockdown.</p>
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<p>Figure S1. The correlation analysis between ADAM12 and YAP1.(A) The correlation analysis between ADAM12 and YAP1 in CRC based on the TCGA-COAD data. (B) The correlation analysis between ADAM12 and YAP1 in CRC patients. (C) CRC patients with high YAP1 expression showed markedly lower 2000-days survival than those with low YAP1 expression. (D) Western blot analysis of ADAM12 in T84 cells with YAP1 knockdown.</p>
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