Abstract
Cell migration drives cell invasion and metastatic progression in prostate cancer and is a major cause of mortality and morbidity. However the mechanisms driving cell migration in prostate cancer patients are not fully understood. We previously identified the cancer-associated cell migration protein Tetraspanin 1 (TSPAN1) as a clinically relevant androgen regulated target in prostate cancer. Here we find that TSPAN1 is acutely induced by androgens, and is significantly upregulated in prostate cancer relative to both normal prostate tissue and benign prostate hyperplasia (BPH). We also show for the first time, that TSPAN1 expression in prostate cancer cells controls the expression of key proteins involved in cell migration. Stable upregulation of TSPAN1 in both DU145 and PC3 cells significantly increased cell migration and induced the expression of the mesenchymal markers SLUG and ARF6. Our data suggest TSPAN1 is an androgen-driven contributor to cell survival and motility in prostate cancer.
Highlights
Cancer, in its most aggressive form, is a disease of uncontrolled cell growth, and a disease of inappropriate cell migration
Using a time course and real-time PCR we found that androgen mediated induction of the Tetraspanin 1 (TSPAN1) gene could be detected in LNCaP cells 9 hours after androgen exposure suggesting it is directly regulated by the androgen receptor (AR)
Androgen-mediated induction of TSPAN1 expression in LNCaP cells was induced by treatment with a range of R1881 concentrations for 24 hours, consistent with TSPAN1 induction occurring under physiological androgen concentrations within the prostate (Fig. 1B), and was blocked by treatment with the AR antagonist CasodexR (Fig. 1C)
Summary
In its most aggressive form, is a disease of uncontrolled cell growth, and a disease of inappropriate cell migration. Prognostic heterogeneity is an important feature of prostate cancer; while some prostate cancers can progress very rapidly, others can remain indolent for many years, there a major unmet clinical need to identify new biomarkers to help distinguish indolent from aggressive disease[6]. We identified a set of nearly 700 genes which were reciprocally regulated between the two datasets and so were strong candidates to be clinically relevant androgen-regulated genes in prostate cancer. This set of 700 genes included the gene for the cancer-associated cell migration protein Tetraspanin 1 (TSPAN1) which had not previously been shown to be regulated by androgens in prostate cancer. Our findings are in agreement with numerous studies showing that TSPAN1 is upregulated in several other cancer types[15, 17, 25,26,27,28], but are in contrast to a recent publication suggesting that decreased TSPAN1 is linked to prostate cancer progression[29]
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