Silencing of TGF-β1 in tumor cells impacts MMP-9 in tumor microenvironment.
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ABSTRACT:
SUBMITTER: Moore-Smith LD
PROVIDER: S-EPMC5561077 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Matrix metalloproteinase (MMP)-2 and MMP-9, also known as gelatinases or type IV collagenases, are recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. Latent MMP-2 (proMMP-2) is activated by membrane type 1 MMP (MT1-MMP) on the cell surface of tumor cells. We previously reported that cell-bound proMMP-9 is activated by the MT1-MMP/MMP-2 axis in HT1080 cells treated with concanavalin A in the presence of exogenous proMMP-2. However, the regulatory mechanism of proMMP-9 activation remains largely unknown. Transforming growth factor (TGF)-β1 is frequently overexpressed in tumor tissues and is associated with tumor aggressiveness and poor prognosis. In this study, we examined the role of TGF-β1 on MT1-MMP-mediated proMMP-9 activation using human oral squamous cell carcinoma cells. TGF-β1 significantly increased the expression of MMP-9. By adding exogenous proMMP-2, TGF-β1-induced proMMP-9 was activated during collagen gel culture, which was suppressed by the inhibition of TGF-β1 signaling or MT1-MMP activity. This MT1-MMP-mediated proMMP-9 activation was needed to facilitate TGF-β1-induced cell invasion into collagen gel. Thus, TGF-β1 may facilitate MT1-MMP-mediated MMP-9 activation and thereby stimulate invasion of tumor cells in collaboration with MT1-MMP and MMP-2.
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Project description:TGF‑β1 is a pleiotropic cytokine that can either promote or inhibit cancer development and progression. It was previously found that TGF‑β1 can regulate the expression of several microRNAs (miR or miRNA) involved in the progression of renal cell carcinoma (RCC). Therefore, the present study aimed to analyze the effects of TGF‑β1 on the global RCC miRNome. It was found that TGF‑β1 can regulate a complex network consisting of miRNAs and mRNAs involved in RCC transformation. In particular, TGF‑β1 was revealed to regulate the proliferation of RCC cells while concomitantly modifying the expression of oncogenic regulators, including avian erythroblastosis virus E26 (V‑Ets) oncogene homolog‑1 (ETS1). In addition, TGF‑β1 was demonstrated to regulate the expression of a number of miRNAs including miR‑30c‑5p, miR‑155‑5p, miR‑181a‑5p and miR‑181b‑5p. By contrast, TGF‑β1 reciprocally modified the expression of genes encoding TGF‑β1 receptors and SMADs, indicating a novel regulatory feedback mechanism mediated through the miRNAs. These data suggested that ETS1 served different roles in different subtypes of RCC tumors, specifically by functioning as an oncogene in clear cell RCC while as a tumor suppressor in papillary RCC.
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Project description:BackgroundAccording to WHO 2020, CAD is the second leading cause of death in Indonesia with death cases reaching 259,297 or 15.33% of total deaths. Unfortunately, most of the patients of CAD in Indonesia did not match the golden period or decline to be treated with Percutaneous Coronary Intervention (PCI). Based on the recent study, there were increases in MMP-9, NOX2, and TGF-β1 in STEMI patients which contribute to cardiac remodeling. Moreover, there is controversy regarding the benefit of late PCI (12-48 hours after onset of STEMI) in stable patients. Lately, colchicine is widely used in cardiovascular disease. This study was conducted to explore the effect of colchicine to reduce MMP- 9, NOX2, and TGF-β1 levels after myocardial infarction in stable patients.MethodIn this clinical trial study, we assessed 129 STEMI patients, about 102 patients who met inclusion criteria were randomized into four groups. Around 25 patients received late PCI (12-48 h after the onset of chest pain), optimal medical treatment (OMT) for STEMI, and colchicine; 24 patients received late PCI and OMT; 22 patients didn't get the revascularization (No Revas), OMT, and colchicine; and 31 patients received No Revas and OMT only. The laboratory test for MMP-9, NOX2, and TGF-β1 were tested in Day-1 and Day-5. The data were analyzed using Mann-Whitney.ResultsA total of 102 patients with mean age of 56 ± 9.9, were assigned into four groups. The data analysis showed significant results within No Revas + OMT + Colchicine group versus No Revas + OMT + Placebo in MMP-9 (Day-1: p = 0.001; Day-5: p = 0.022), NOX2 (Day-1: p = 0.02; Day-5: p = 0.026), and TGF-β1 (Day-1: p = 0.00; Day-5: p = 0.00) with the less three markers in OMT + Colchicine group than OMT + Placebo group. There were no significant differences within the late PCI + OMT + colchicine group and PCI + OMT + Placebo group.ConclusionsColchicine could significantly reduce MMP-9, NOX2, and TGF-β1 levels in stable STEMI patients. So that, colchicine could be a potential agent in STEMI patients and prevent cardiac remodeling events.
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