Correlation of Sprouty1 and Jagged1 With Aggressive Prostate Cancer Cells With Different Sensitivities to Androgen Deprivation

Abstract

Prostate cancer is a heterogeneous disease and thus, it is important to understand whether among the heterogeneous collection of cell types, androgen-deprivation insensitive cells exist prior to hormonal manipulation. We established several LNCaP subclones with distinct insensitivities to androgen deprivation from a parental LNCaP cell line. In the resulting clones, the sensitivity to androgen-deprivation negatively correlated with their PSA expression levels. In two of these clones, an androgen insensitive clone, LNCaP-cl1, and an androgen sensitive clone, LNCaP-cl5, the DNA copy number differed significantly, indicating that these clones contain genetically distinct cells. LNCaP-cl1 had higher PSA expression but lower invasiveness and tumor growth potential than LNCaP-cl5. The expression levels of two genes that are known to be regulated by miR-21, an androgen-regulated microRNA, Sprouty1 (SPRY1) and Jagged1 (JAG1) were significantly lower in LNCaP-cl1 than in LNCaP-cl5. Knocking down SPRY1 in LNCaP cells enhanced PSA expression and cell proliferation. JAG1 administration in LNCaP cells enhanced cell invasion and JAG1 knockdown in PC3 cells suppressed cell invasion and tumor formation. These results indicated that the expression differences in SPRY1 and JAG1 may contribute to the phenotypic differences between the LNCaP-cl1 and LNCaP-cl5 clones. In tissue samples, SPRY1 expression levels were significantly lower in prostate cancer patients with PSA recurrence after surgical treatment (P = 0.0076) and JAG1 expression levels were significantly higher in Gleason sum (GS) 8–9 disease than in GS 5–6 (P = 0.0121). In summary a random population of LNCaP cells comprises a heterogeneous group of cells with different androgen-deprivation sensitivities and potential for invasiveness.

Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

“…Furthermore, the model also predicts that the intracellular CLK2, HIPK1-PAGE4, and CLK2-PAGE4 oscillations need not be synchronized across cells. Thus, individual cells in an isogenic population would have varying levels of androgen dependence or independence at a given point in time consequently giving rise to non-genetic phenotypic heterogeneity observed in a seemingly homogenous population of PCa cells [ 134 ]. In other words, androgen dependence represents a trait whose values can display a broad distribution across the population.…”

Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans

“…26, 27, 28 Also, silencing of Jag1 in human prostate cancer cells decreases cell invasion and in vivo tumour growth. 29 However, the functional contribution of Jag1 in ICC development has not been studied to date.…”

Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer

“…For example, in the breast cancer model, Jagged1-mediated Notch activation has been shown to promote tumor cell motility by inducing epithelial-mesenchymal transition (EMT) (19–21); On the other hand, Jagged1 expressed by breast cancer cells were also shown to activate Notch signaling in cells within their microenvironment such as osteoblasts, which secrete growth factors that in turn promotes survival, proliferation, and migration of tumor cells (22, 23). In contrast, the functional significance of Jagged1 upregulation in prostate cancer cells is still inadequately interrogated (12, 24, 25). It remains an open question whether Jagged1 upregulation plays a causative role in tumor progression in vivo or is only a consequence of tumor progression, as Jagged1 itself is a Notch downstream target.…”