Plasminogen activator inhibitor type‐1 (<i>PAI‐1</i>) polymorphism 4G/5G is associated with prostate cancer among men with a positive family history

Jorgenson, Eric; Deitcher, Steven R.; Cicek, Mine S.; Liu, Xin; Plummer, Sarah J.; Casey, Graham; Witte, John S.

doi:10.1002/pros.20512

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…The highest expression was found in the Runx2‐HTY mutant, indicating that disruption of Runx2–Smad signaling can induce more osteoblastic‐related gene expression. It is noteworthy that PAI‐1, an inhibitor of tumor growth, was present at very high levels in the Runx2‐HTY‐expressing cells (fourfold compared to WT), while Runx2‐ΔC had levels even lower than ‐WT, again correlating with opposing tumor size in these groups (Fig. ).…”

Section: Resultsmentioning

confidence: 91%

“…Disruption of the Runx2–Smad interaction significantly reduced tumor growth by blocking TGFβ‐induced SMAD interaction with Runx2. Also contributing to the lowest tumor burden in the Runx2‐HTY was the high expression of the TGFβ‐regulated gene PAI‐1 that is an inhibitor of prostate tumor growth . Of note, osteoblastic disease still occurred in the small tumors formed by the Runx2‐HTY‐expressing PC3 cells, indicating that other factors contribute to woven bone formation in the tumors generated by these cells that do not require Runx2–Smad signaling.…”

Section: Discussionmentioning

confidence: 99%

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Runx2–smad signaling impacts the progression of tumor‐induced bone disease

Zhang

Akech

Browne

et al. 2014

Intl Journal of Cancer

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Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT expressing cells resulted in predominantly osteolytic disease, while cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and of woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Runx2–smad signaling impacts the progression of tumor‐induced bone disease

Zhang

Akech

Browne

et al. 2014

Intl Journal of Cancer

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“…The 4G/4G genotype confers an increase in the risk of mortality in adult patients with septic shock due to a greater organ failure, and it is also associated with higher IL‐1, TNF‐α, and PAI‐1 plasma concentration and increased severity in these patients [68]. PAI‐1 may play an important role in growth, angiogenesis, and metastasis of some types of tumours such as prostate cancer and breast cancer [69, 70]. The 4G/4G genotype is also significantly associated with increased risk of myocardial infarction [71], arterial hypertension [72], early onset of coronary heart disease [73], and pneumonia [63].…”

Section: The 4g/5g Polymorphism Of the Plasminogen Activator Inhibitomentioning

confidence: 99%

Plasminogen activator inhibitor‐1 and asthma: role in the pathogenesis and molecular regulation

Paek

2009

Clin Experimental Allergy

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Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at -675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases.

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“…Controls were mainly matched on sex and age, of which 17 were hospital based [21], [22], [23], [24], [29], [30], [31], [32], [33], [35], [36], [37], [38], [40], [41], [42], [43], 8 were population based [20], [25], [26], [27], [28], [34], [39]. Furthermore, 10 studies were conducted with subjects >500 in both case and control groups [20], [25], [26], [27], [28], [29], [34], [39], [40]. Diverse genotyping methods were used, including PCR–RFLP, TaqMan, allele-specific PCR, MassARRAY, and two parallel PCR.…”

Section: Resultsmentioning

confidence: 99%

PAI-1 4G/5G Polymorphism Contributes to Cancer Susceptibility: Evidence from Meta-Analysis

Wang

Cao

Wang³

et al. 2013

PLoS ONE

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BackgroundThe plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results.MethodsA meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I2 test.ResultsOverall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03–1.18, I2 = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06–1.39, I2 = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04–1.18, I2 = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09–1.59, I2 = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04–1.21, I2 = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05–1.21, I2 = 25.3%).ConclusionsThe results of the present meta-analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer.

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Plasminogen activator inhibitor type‐1 (PAI‐1) polymorphism 4G/5G is associated with prostate cancer among men with a positive family history

Abstract: These observations suggest that the 4G/5G polymorphism in PAI-1 may explain some of the increased risk and earlier mean age of onset of prostate cancer due to a positive family history.

Cited by 8 publications

References 20 publications

Runx2–smad signaling impacts the progression of tumor‐induced bone disease

Runx2–smad signaling impacts the progression of tumor‐induced bone disease

Plasminogen activator inhibitor‐1 and asthma: role in the pathogenesis and molecular regulation

PAI-1 4G/5G Polymorphism Contributes to Cancer Susceptibility: Evidence from Meta-Analysis

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