c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells

Hou, Yongzhong; Okamoto, Chikako; Okada, Kiyotaka; Kawao, Naoyuki; Kawata, Shuhei; Ueshima, Shigeru; Matsuo, Osamu

doi:10.1016/j.cardiores.2007.02.033

Cited by 16 publications

(5 citation statements)

References 29 publications

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“…Several other studies have reported the importance of MMPs in PCa cell proliferation, invasion, and metastasis (Quigley et al, 2018;Wegiel et al, 2008) (Wyganowska-Swią tkowska et al, 2019. Of note, we found that hemeinduced c-MYC levels control the expression of uPA, similar to hypoxia-induced uPA expression (Hou et al, 2007). Because of its role in the process of extracellular matrix degradation, uPA is a poor prognostic marker for PCa, and its expression levels have been associated with distant metastasis and tumor progression (Duffy, 2002;Nassir, 2020;Shariat et al, 2007).…”

Section: Discussionsupporting

confidence: 70%

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

Canesin

Ruscio

et al. 2020

Cell Reports

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SUMMARY Hemopexin (Hx) is a scavenger of labile heme. Herein, we present data defining the role of tumor stroma-expressed Hx in suppressing cancer progression. Labile heme and Hx levels are inversely correlated in the plasma of patients with prostate cancer (PCa). Further, low expression of Hx in PCa biopsies characterizes poorly differentiated tumors and correlates with earlier time to relapse. Significantly, heme promotes tumor growth and metastases in an orthotopic murine model of PCa, with the most aggressive phenotype detected in mice lacking Hx. Mechanistically, labile heme accumulates in the nucleus and modulates specific gene expression via interacting with guanine quadruplex (G4) DNA structures to promote PCa growth. We identify c-MYC as a heme:G4-regulated gene and a major player in heme-driven cancer progression. Collectively, these results reveal that sequestration of labile heme by Hx may block heme-driven tumor growth and metastases, suggesting a potential strategy to prevent and/or arrest cancer dissemination.

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Section: Discussionsupporting

confidence: 70%

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

Canesin

Ruscio

et al. 2020

Cell Reports

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“…Under this condition, certain types of ECM-degrading enzymes play a critical role in promoting the migration and subsequent metastasis of cancer cells [13–15]. A well-characterized example of such enzymes is the uPA, a serine proteinase which is overexpressed in many human cancers in a manner associated with their malignancy [16, 17]. Therefore, we hypothesized that the stimulatory effect of semaphorin 5A on tumor invasion and migration is associated with the expression of uPA.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 5A Promotes Gastric Cancer Invasion/Metastasis via Urokinase-Type Plasminogen Activator/Phosphoinositide 3-Kinase/Protein Kinase B

et al. 2013

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BackgroundSemaphorin 5A, a member of the semaphorin family, was originally identified as an axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, less information is currently available as to the involvement of uPA in the semaphorin 5A-induced metastasis and invasion of gastric cancer cells.AimThe present study was designed to test whether semaphorin 5A mediates the invasion and metastasis of gastric cancer via PI3K/Akt/uPA signaling.MethodsThe semaphorin 5A-overexpressing cell was established from the gastric cancer cell line AGS. The effect of semaphorin 5A on the expression of uPA was evaluated by ELISA and Western blotting as well as RT-PCR assays, respectively. Synthetic or natural inhibitors and dominant-negative mutants were used to determine the hierarchical relationship between semaphorin 5A, PI3K/Akt and uPA in the invasion and metastasis of gastric cancer.ResultsOverpression of semaphorin 5A enhanced the expression of uPA, and synthetic or natural inhibitors of uPA abolished semaphorin 5A-induced cell migration and invasion. Semaphorin 5A overexpression promoted the phosphorylation of Akt. Blocking effects of PI3K/Akt using pharmacologic inhibitors, dominant-negative mutants abolished the ability of semaphorin 5A to induce uPA expression and cell invasion and migration.ConclusionSemaphorin 5A could promote invasion and metastasis of gastric cancer through the PI3K/Akt/uPA signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy.

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“…The fibrinolytic activity of PAs was analysed by fibrin zymography, as previously described (33). Briefly, the damaged portions of the livers from u-PA +/+ or u-PA -/mice were harvested on day 0 (before the experiment) and days 4 and 7 after photoillumination and homogenised in ice-cold extraction buffer containing 10 mM sodium phosphate buffer, 150 mM NaCl, 1% Triton X-100, 0.1% so-dium dodecyl sulfate, and 0.5% sodium deoxycholate (pH 7.2).…”

Section: Fibrin Zymographymentioning

confidence: 99%

Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice

Kawao¹,

Nagai²,

Tamura³

et al. 2011

Thromb Haemost

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Urokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated macrophages were analysed histologically. Fibrinolytic activity at the damaged site was also examined by fibrin zymography. In wild-type mice, the extent of damage decreased gradually until day 14 and was associated with an accumulation of macrophages at the border of the damaged site. In addition, the macrophages that accumulated near the damaged tissue expressed CD206, a marker of highly phagocytic macrophages, on day 7. Further, macrophages that were adjacent to CD206-positive cells expressed inducible nitric oxide synthase (iNOS), a pro-inflammatory marker. u-PA activity increased at the damaged site on days 4 and 7, which distributed primarily at the border region. In contrast, in u-PA-deficient mice, the decrease in damage size and the accumulation of macrophages were impaired. Further, neither CD206 nor iNOS was expressed in the macrophages that accumulated at the border region in u-PA-deficient mice. Mice deficient for the gene encoding either u-PA receptor (u-PAR) or tissue-type plasminogen activator experienced normal recovery during liver repair. These data indicate that u-PA mediates the accumulation of macrophages and their phenotypic heterogeneity at the border of damaged sites through u-PAR-independent mechanisms.

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c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells

Abstract: The results show that c-Myc was essential for hypoxia-induced uPA expression and activity, resulting in VSMC migration and invasion. In addition, Bcl2 enhanced the c-Myc-mediated uPA/MMP-2 pathway.

Cited by 16 publications

References 29 publications

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

Semaphorin 5A Promotes Gastric Cancer Invasion/Metastasis via Urokinase-Type Plasminogen Activator/Phosphoinositide 3-Kinase/Protein Kinase B

Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice

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