Function of JunB in Transient Amplifying Cell Senescence and Progression of Human Prostate Cancer

Abstract

Purpose: Replicative senescence in cells acts as a barrier against excessive proliferation and carcinogenesis. Transient amplifying cells (TAC) are a subset of basal cell populations within the prostate from which cancers are thought to originate; therefore, we focused on prostate TAC to investigate the molecular mechanisms by which theTAC may be able to evade senescence. Experimental Design: TAC clones were isolated from each zone within the whole prostate and analyzed in flow cytometry. Prostate cancer cells were transfected with junB small interfering RNA (siRNA) and examined by chorioallantoic membrane assay for cancer invasion. Immunohistochemical analysis was done in primary and metastatic prostate cancer specimens. Results: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence. TAC clones with reduced p16 expression successfully bypassed this phase. We further found close correlation between the levels of junB and p16 expression. Repeated transfection of junB siRNA in prostaticTAC allowed the cells to escape senescence presumably through inactivation of p16/pRb. The chorioallantoic membrane invasion assay showed much lower in invasive cancer cells with high expression of junB; conversely, silencing of junB by transfection with junB siRNA promoted invasion.We also found that metastatic prostate cancers, as well as cancers with high Gleason scores, showed significantly low junB immunopositivity. Conclusions: JunB is an essential upstream regulator of p16 and contributes to maintain cell senescence that blocks malignant transformation of TAC. JunB thus apparently plays an important role in controlling prostate carcinogenesis and may be a new target for cancer prevention and therapy.

Loss of JUNB/AP-1 promotes invasive prostate cancer

“…As seen in Figure 1a, areas with normal prostate epithelia displayed low or undetectable JUNB, whereas areas with low-grade prostate cancer showed strong staining. Remarkably, and consistent with a previous report, 13 JUNB was almost undetectable in the areas where the tumour had progressed to high grade ( Figure 1a).…”

“…Transient-amplifying cells (TACs) area subset of basal cells from which prostate cancer is thought to originate and in human samples, JUNB was suggested to maintain TAC senescence. 13 Although the number of TACs was not different between Pten ΔP and noninvasive JunB Decreased p21 CIP1 expression between primary and metastatic prostate cancer was also observed in publicly available human patient data sets (Supplementary Figure 3f). Furthermore, p21 CIP1 and JUNB expressions positively correlated, suggesting an interaction between these two genes and prostate cancer progression (Figure 3f) data indicate that, both in mouse models and in patients, loss of JunB likely affects the proliferation and senescence of the neoplastic prostatic epithelium by decreasing p16 Ink4a and p21 CIP1 expressions.…”

“…13 Here, we show that JunB is downregulated in high-grade human prostate cancer. Moreover, using genetically modified mouse models, we demonstrate that although the loss of Junb in the prostate epithelium does not affect prostate homeostasis, combined loss of Junb and Pten even in a limited number of adult cells, leads to early-onset and invasive prostate cancer.…”

JunB and PTEN in prostate cancer: ‘loss is nothing else than change’

“…8 Conversely, depletion of JunB in prostatic transient amplifying cells in vitro promoted escape from senescence through the inactivation of p16/pRb. 9 This is consistent with the tumorsuppressive functions of JunB in the myeloid and lymphoid lineages. 10,11 In this issue, Thomsen et al investigated the role of JunB in the PSA-Cre mediated Pten knockout mouse model, which enables the investigation of the time window from low-grade prostate intraepithelial neoplasia (PIN) to high-grade PIN lesions, which is of special human relevance.…”

JunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in Transforming Growth Factor-β (TGF-β)-induced Inhibition of Cell Proliferation

“…JunD, along with Fra1 and Fra2, has also been reported to be essential in prostate cancer proliferation and confers protection against radiation-induced cell death (47). In a recent report, JunB was shown to play an important role in maintaining cell senescence that blocks malignant prostate cell transformations (48) and has been shown to be a potent activator of KAI1 (49). Jun proteins by themselves or in combination with members of the Fos proteins have also been implicated in the actions of androgens (50,51), atmospheric pollutants (52), growth factors (53), phytochemicals (54 -56), peroxides (57), isothiocyanates (58), glycoproteins (59), and, most recently, proteasome inhibitors (60).…”