Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

Park, Deokbum; Kim, Youngmi; Kim, Hyun-Ah; Kim, Kyungjong; Lee, Yun‐Sil; Choe, Jongseon; Hahn, Jang-Hee; Lee, Hansoo; Jeon, Jongwook; Choi, Chulhee; Kim, Young‐Myeong; Jeoung, Dooil

doi:10.1007/s10059-012-2294-1

Cited by 136 publications

(102 citation statements)

References 73 publications

(66 reference statements)

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“…HA increases PAI-1 expression in a concentration-dependent manner in human vascular smooth muscle cells (Marutsuka et al 1998) and a positive correlation exists between HA and PAI-1 produced by human aortic endothelial cells incubated with C-reactive protein (Devaraj et al 2009). In human umbilical vein endothelial cells, high-molecular-weight HA induces activation of the TGF-β receptor I and expression of PAI-1 (Park et al 2012). In combination with these previous findings, our data suggest that the TGF-β-induced HA secretion at high cell densities may facilitate the cell densitydependent PAI-1 stimulation in OFs.…”

Section: Discussionsupporting

confidence: 75%

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Galgoczi

Jeney

Gazdag

et al. 2016

Journal of Endocrinology

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During the course of Graves’ orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorβ(TGF-β). We examined the effects of increasing cell densities and TGF-β on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-β stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-β. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO.

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Section: Discussionsupporting

confidence: 75%

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Galgoczi

Jeney

Gazdag

et al. 2016

Journal of Endocrinology

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“…The binding of various abnormally expressed CD44 molecules to the receptor HA promotes the secretion of MMPs, resulting in ECM degradation, which is closely associated with axillary lymph node metastasis, increased angiogenesis, prognosis and drug resistance (17)(18)(19)(20)(21)(22). It has been shown that HA binds to the CD44 variant that is widely distributed on the surface of the cell membrane during tumor progression, which induces the activation of ankyrin and small G-protein Rho, and the activation of the PI3K-AKT signaling pathway, thereby leading to enhanced tumor cell adhesion, growth, migration and invasion, and resultant tumor progression (23).…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

et al. 2014

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Abstract. CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose-dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.

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“…Some abnormally expressed CD44 receptors bind hyaluronan, which promotes the secretion of matrix metalloproteinases (MMPs), resulting in extracellular matrix degradation which is closely associated with tumor angiogenesis, axillary lymph node metastasis, and prognosis [21][22][23]. It has been reported that during tumor progression, hyaluronan binds to CD44 isoforms which are extensively expressed on the surface of the cell membrane, and mediates the activation of ankyrin and Rho small G protein, further activating the PI3K-AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Expression of Novel CD44st and MMP2 in NSCLC Tissues and Their Clinical Significance

Zhang

Hai

et al. 2017

Oncol Res Treat

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Background: Abnormal expression of some CD44 molecules in tumor tissues can induce the degradation of the extracellular matrix, and is closely associated with axillary lymph node metastasis, angiogenesis, cancer progression, and drug resistance. Patients and Methods: We measured and confirmed the expression of CD44st and MMP2 mRNAs and proteins in the cancer tissues and adjacent normal tissues of postoperative non-small cell lung cancer (NSCLC) patients with either adenocarcinoma (n = 72) or squamous cell carcinoma (n = 53) using quantitative reverse transcription polymerase chain reaction, gene sequencing, and immunohistochemical analysis. Results: CD44st and MMP2 expression were closely associated with the histopathological classification, lymph node metastasis, and TNM stage of the tumors, and the difference was statistically significant (p < 0.05). The median overall survival (OS) for the high CD44st expression group was 30.52 months (95% confidence interval (CI) 24.02-36.15); for the low expression group it was 43.23 months (95% CI 31.81-52.02) (p = 0.020). The median OS for the high MMP-2 expression group was 30.53 months (95% CI 26.69-33.31); for the low expression group it was 40.06 months (95% CI 33.55-46.45) (p = 0.022). Conclusion: The rates of CD44st and MMP2 expression were higher in squamous cell carcinomas than in adenocarcinomas, were closely associated with lymph node metastasis and TNM stage, and affected patients' prognoses.

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Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

Cited by 136 publications

References 73 publications

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

Expression of Novel CD44st and MMP2 in NSCLC Tissues and Their Clinical Significance

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