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To characterize the iPS87 cell line, cells were stained with antibodies to various markers of stem cells including ALDH7A1, LGR5, Oct4, Nanog, Sox2, Androgen Receptor, and Retinoid X Receptor. click here These markers were found to be expressed by iPS87 cells, and the high tumorigenicity in SCID mice of iPS87 was confirmed by histopathology. This research thus characterizes the iPS87 cell line as a cancer-inducing, stem cell-like cell line, which can be used in the development of novel treatments for prostate cancer.Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the full-length hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2, and Spondin1. Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.Previous studies have demonstrated that CTCs do not travel in the bloodstream alone, but rather are accompanied by clusters of stromal cells such as cancer associated fibroblasts (CAFs). Our laboratory has confirmed the presence of CAFs in the peripheral blood of prostate cancer (PC) patients. The observation that CAFs disseminate with CTCs prompts the examination of the role of CAFs in CTC survival under physiological shear stress during the dissemination process using a clinically relevant, three-dimensional (3D) co-culture model. In this study, we found that "reactive CAFs" induce shear resistance to prostate tumor cells via intercellular contact and soluble derived factors. In addition, these reactive CAFs conserve the proliferative capability of tumor cells in the presence of high magnitude fluid shear stress (FSS). This reactive CAF phenotype emerges from normal fibroblasts (NF), which take on the CAF phenotype when co-cultured with tumor cells. The reactive CAFs showed higher expression of α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) compared to differentiated CAFs, when co-cultured with PC cells at the same experimental conditions. Together, we found that the activation mechanism of NF to CAF comprises different stages that progress from a reactive to quiescent cellular state in which these two states are differentiated by the fluctuation of intensity in CAF markers. Here we determined that a reactive state of CAFs proved to be important for supporting tumor cell survival and proliferation. These findings suggest the use of CAFs as a marker for cancer progression and a potential target for novel cancer therapeutics to treat metastatic disease. Copyright © 2020 Ortiz-Otero et al.Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRA-induced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRA-induced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRA-induced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine. Copyright © 2020 Rashid et al.The p16 tumor suppressor is coded by CDKN2A (9p21) and plays an important role during carcinogenesis and tumor progression in numerous tumor entities. The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC). Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence in-situ hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data. p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC. In SCC p16 immunostaining correlated with low tumor stage (P = 0.014). In AC Ki67 positivity was associated with high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005). Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; P = 0.009) and negative p16 immunostaining (P = 0.026).
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