A PSCA/PGRN–NF-κB–Integrin–α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential

Zhao, Zhigang; Li, Ermao; Luo, Lianmin; Zhao, Shankun; Liu, Luhao; Wang, Jiamin; Kang, Ran; Luo, Jin-Yan

doi:10.1158/1541-7786.mcr-19-0278

Cited by 25 publications

(21 citation statements)

References 38 publications

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“…Other molecules are also reportedly related to MPC, such as PSCA (prostate stem cell antigen), LZTS1 (leucine zipper tumor suppressor 1), and some miRNAs [2]. PSCA expression tends to be higher in MPC cases [34] and can modulate integrin signals [35] as well as RhoA [36]. LZTS1 expression is reportedly lower in MPC cases [37] and can modulate integrin signaling [38].…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Onuma

Sato

Okuyama

et al. 2021

The Journal of Pathology

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Micropapillary carcinoma (MPC) is a morphologically distinctive form of carcinoma, composed of small nests of cancer cells surrounded by lacunar spaces. Invasive MPC is associated with poor prognosis. The nests of tumor cells in MPC reportedly exhibit reverse polarity, although the molecular mechanisms underlying MPC patterns are poorly understood. Using the cancer tissue‐originated spheroid (CTOS) method, we previously reported polarity switching in colorectal cancer (CRC). When cultured in suspension, the apical membrane promptly switches from the outside surface of the CTOSs to the surface of the lumen inside the CTOSs under extracellular matrix (ECM)‐embedded conditions, and vice versa. Here, we investigated two CTOS lines from CRC patient tumors with MPC lesions. Xenograft tumors from the CTOSs exhibited the MPC phenotype. The MPC‐CTOSs did not switch polarity in vitro. Time‐course analysis of polarity switching using real‐time imaging of the apical membrane revealed that local switching was continually propagated in non‐MPC‐CTOSs, while MPC‐CTOSs were unable to complete the process. Integrin β4 translocated to the outer membrane when embedded in ECM in both MPC and non‐MPC‐CTOSs. Protein levels, as well as the active form of RhoA, were higher in MPC‐CTOSs. The suppression of RhoA activity by GAP overexpression enabled MPC‐CTOSs to complete polarity switching both in vitro and in vivo, while overexpression of active RhoA did not affect polarity switching in non‐MPC‐CTOSs. Pretreatment with a ROCK inhibitor enabled MPC‐CTOSs to complete polarity switching both in vitro and in vivo, although delayed treatment after becoming embedded in ECM failed to do so. Thus, the inability to switch polarity might be a cause of MPC, in which the aberrant activation of RhoA plays a critical role. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Onuma

Sato

Okuyama

et al. 2021

The Journal of Pathology

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“…IHC analysis was performed as described previously by our group. 17 , 18 Briefly, after deparaffinisation, rehydration, antigen retrieval, and blocking endogenous peroxidase activity, the sections were incubated with the primary antibody mouse anti‐DDR1 (Abcam, Cambridge, MA) overnight at 4 °C, followed by adding the secondary biotinylated antibody in PBS for 20 min at room temperature. Finally, sections were treated with streptavidin-HRP in PBS for 30 min at room temperature, and subsequently incubated with diaminobenzidine buffer (Vector Laboratories, Burlingame, CA).…”

Section: Methodsmentioning

confidence: 99%

miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition

Zhao

Luo

et al. 2020

Br J Cancer

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Background The investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear. Methods The current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo. Results We demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3’-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival. Conclusions Our study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

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“…It was previously reported that EphA2 knockdown inhibits NF-κB activation and impairs endothelial permeability ( Carpenter et al, 2012 ). In addition, multiple lines of evidence suggest that PGRN deficiency weakens the adhesion of and tight junctions between endothelial cells and tumor cells, leading to barrier disruption or metastasis ( Jackman et al, 2013 ; Zhao et al, 2020 ). Taken together, we believe that EphA2 might be a crucial player in the initiation of the atherosclerosis process, specifically the recruitment of leukocytes to sites of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway

Tian

Qin

et al. 2021

Front. Pharmacol.

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Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (EphA2), vascular cell adhesion molecule-1 (VCAM-1), and Hcy in patients with arteriosclerosis and investigate their functions in Hcy-injured human umbilical vein endothelial cells (HUVECs). EphA2 knockdown was induced in HUVECs by shRNA lentivirus infection with EphA2-RNAi, and bulk RNA-seq assay was performed. Then we investigated the mechanism underlying the effect of recombinant human PGRN (rhPGRN) combined with shRNA interference of EphA2 on cell proliferation, migration, and angiogenesis in Hcy-injured HUVECs. Results showed that serum EphA2, VCAM-1, and Hcy levels in acute coronary syndrome patients were significantly higher than those in chronic coronary syndrome patients (p = 0.000; p = 0.000; p = 0.033, respectively). In vitro, we demonstrated that knockdown of EphA2 significantly impaired cell adhesion and inhibited HUVECs migration and angiogenesis (p < 0.001), which was associated with reduction in VCAM1 and VE-cadherin (p < 0.05). Hcy modulated the expression of PGRN and EphA2 in a time-and dose-dependent manner. However, rhPGRN ameliorated the Hcy-induced reduction in cell viability and migration (p < 0.05). Mechanistically, we found that PGRN/EphA2 and its downstream AKT/NF-κB signaling might be the primary signal transduction pathways underlying Hcy-induced injury. The present study illustrated that PGRN plays a previously unrecognized role in Hcy-induced endothelial injury, which is achieved through its interaction with EphA2 signaling, implying a promising therapeutic target for cardiovascular disease.

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A PSCA/PGRN–NF-κB–Integrin–α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential

Cited by 25 publications

References 38 publications

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition

Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway

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