Nuclear Factor-κB-Mediated Transforming Growth Factor-β-Induced Expression of Vimentin Is an Independent Predictor of Biochemical Recurrence after Radical Prostatectomy

Abstract

Purpose: Transforming growth factor-β (TGF-β)-mediated epithelial-to-mesenchymal transition (EMT) has been shown to occur in some cancers; however, the pathway remains controversial and varies with different cancers. In addition, the mechanisms by which TGF-β and the EMT contribute to prostate cancer recurrence are largely unknown. In this study, we elucidated TGF-β-mediated EMT as a predictor of disease recurrence after therapy for prostate cancer, which has not been reported before. Experimental Design: We analyzed TGF-β-induced EMT using nuclear factor-κB (NF-κB) as an intermediate mediator in prostate cancer cell lines. A total of 287 radical prostatectomy specimens were evaluated using immunohistochemistry in a high-throughput tissue microarray analysis. Levels of TGF-β signaling components and EMT-related factors were analyzed using specific antibodies. Results were expressed as the percentage of cancer cells that stained positive for a given antibody and were correlated with disease recurrence rates at a mean of 7 years following radical prostatectomy. Results: In prostate cancer cell lines, TGF-β-induced EMT was mediated by NF-κB signaling. Blockade of NF-κB or TGF-β signaling resulted in abrogation of vimentin expression and inhibition of the invasive capability of these cells. There was high risk of biochemical recurrence associated with tumors that displayed high levels of expression of TGF-β1, vimentin, and NF-κB and low level of cytokeratin 18. This was particularly true for vimentin, which is independent of patients' Gleason score. Conclusions: The detection of NF-κB-mediated TGF-β-induced EMT in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-β signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment.Prostate cancer is the most common malignancy in American males and is second only to lung cancer as the leading cause of cancer-specific mortality (1). Metastases are responsible for mortality in prostate cancer patients. Post-treatment serum prostate-specific antigen (PSA) values have been used to identify patients at risk for metastases. In fact, depending on the definition used, the 5-year PSA recurrence rates following either radical prostatectomy or radiation therapy were reported to be up to 31%, and the 10-year clinical recurrence rates in these patients were reported to be ∼75% (2-4). A short time interval to biochemical recurrence, rapid PSA doubling times, and high Gleason scores are all considered high-risk factors for prostate cancer-specific mortality (5, 6). However, these clinical characteristics have not been proven to be useful predictors of clinical outcome in patients with low-grade disease (Gleason score ≤6; refs. 7-9). Therefore,

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…These data are in concordance with our results showing an increased expression in treated tumors of NF-kB subunits and NF-kB-regulated cytokines, such as IL-6, adding support to a body of evidence on the involvement of this pathway in resistance to chemotherapy in prostate cancer (11). On the other hand, NF-kB activation may induce EMT in prostate cancer (34). Although our study did not investigate the potential causal relationship between NF-kB activation and EMT, this last phenomenon was found to be highly relevant in resistance to therapy.…”

“…CD44 and VIM expression in primary tumors has been correlated with adverse prognosis (34,49). Notably, the few patients in our series with ZEB1 þ /CD44 þ tumor cells in primary tumors showed extremely aggressive clinical behavior.…”

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

“…A change in the cellular response to TGF-b is frequently observed in cancer, and there is great interest in the molecular mechanisms responsible for the switch of TGF-b signalling from tumor suppression to tumor promotion (Bierie and Moses, 2006;Inman, 2011). TGF-b1 inhibits proliferation of RWPE-1 cells and BPH-1 benign prostate epithelial cells (Ao et al, 2006), but does not affect proliferation of metastatic PC3 cells or transformed derivatives of BPH-1, where instead it promotes an epithelial-to-mesenchymal transition (Ao et al, 2006;Zhang et al, 2009). An important TGF-b target gene, PMEPA1, has been implicated in this TGF-b switch (Singha et al, 2010), and silencing of PMEPA1 has been shown to reduce RWPE-1 cell proliferation (Liu et al, 2011).…”

KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer

“…A more recent study revealed that JunB was a Smad1-responsive gene and that it was involved in suppression of prostate cancer metastasis (46). On the other hand, the role of NFB transcription factors has been well established in the development and progression of prostate cancer through its effect on apoptosis, invasion, and inflammation and particularly on androgen-independent and recurrent prostate cancer (47)(48)(49)(50). Therefore, ATF3 acts as a modulator of KAI1 transcription through coordinating other endogenous transcription factors as either co-activator or co-repressor, and this mechanism is dependent on the tumor stage and genetic background of tumors.…”