scholarly journals Somatic aberrations of BRCA1 gene are associated with progressive and stem cell-like phenotype of prostate cancer

2018 ◽  
Author(s):  
Aleksandra Omari ◽  
Paulina Nastały ◽  
Aneta Bałabas ◽  
Michalina Dąbrowska ◽  
Beata Bielińska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Gleason Score ◽  
Gene Loss ◽  
Epithelial Mesenchymal Transition ◽  
Gene Dosage ◽  
Brca1 Gene ◽  
Ki 67 ◽  
Regional Lymph Nodes ◽  
Mesenchymal Transition

AbstractBackgroundBRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumor entities. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to regional lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and to reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors.MethodsBRCA1 gene dosage was assessed in 2398 tumor samples from 1199 PCa patients using fluorescent in situ hybridization. It was compared to clinic-pathological parameters, patients’ outcome as well as selected proteins (Ki-67, apoptosis marker, cytokeratins, vimentin, E- and N-cadherin, ALDH1 and EGFR) examined by immunohistcohemistry.ResultsBRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T status (p=0.027), Gleason score (p=0.039), shorter time to biochemical recurrence in patients with Gleason score >7 independently of other factors (multivariate analysis, p=0.005) as well as expression of proteins regulating stemness and epithelial-mesenchymal transition i.e. ALDH1 (p=0.021) and EGFR (p=0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p=0.012) and expression of ALDH1 (p=0.014).ConclusionsThe presented results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell-like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain might mark more invasive tumors.

scholarly journals The paracrine induction of prostate cancer progression by caveolin-1

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chun-Jung Lin ◽  
Eun-Jin Yun ◽  
U-Ging Lo ◽  
Yu-Ling Tai ◽  
Su Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Neuroendocrine Differentiation ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
The Impact

Abstract A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer (CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial–mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.

scholarly journals ARRDC4 and UBXN1: Novel Target Genes Correlated with Prostate Cancer Gleason Score

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5209
Author(s):  
Jong Jin Oh ◽  
Jin-Nyoung Ho ◽  
Seok-Soo Byun
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Gleason Score ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Akt Phosphorylation ◽  
Cancer Aggressiveness ◽  
Novel Target

To investigate potential markers of the prostate cancer (PCa) Gleason score (GS), genetic arrays in 841 PCa patients were conducted followed by functional validation in PCa cell lines. A total of 841 PCa patients who received radical prostatectomy (RP) from November 2003 to July 2019 were enrolled. HumanExome BeadChip 12v1-1 (Illumina, Inc.; San Diego, CA, USA) exomic arrays were performed on RP tissue samples. Unconditional logistic regression was used to calculate odds ratios to generate estimates of the relative risk of pathologic GS (≥8); SNPs with the highest association were selected and validated using PCa cell lines (PC3, LNCaP, 22Rv1 and DU145). Following transfection with target-gene siRNA, assays for cell viability, wound healing, and transwell invasion were performed. Mean age of enrolled subjects was 66.34 years and median PSA was 8.43 ng/mL. After RP, 122 patients (14.5%) had pathological Gleason scores ≥8. The results from genotyping with 242,186 SNPs by exomic array revealed that 4 SNPs (rs200944490, rs117555780, rs34625170, and rs61754877) were significantly associated with high pathological GS (≥8) within cut-off level to p < 10−5. The most highly associated rs200944490 in ARRDC4 (p = 1.39 × 10−6) and rs117555780 in UBXN1 (p = 2.92 × 10−5) were selected for further validation. The knockdown of UBXN1 and ARRDC4 led to significantly reduced cell proliferation and suppressed migration and invasiveness in PCa cell lines. Epithelial mesenchymal transition (EMT) markers were significantly down-regulated in si-ARRDC4 and si-UBXN1-transfected cells. The expression levels of PI3K-phosphorylation and Akt phosphorylation and NF-κB were also suppressed following knockdown of UBXN1 and ARRDC4. The rs200944490 (ARRDC4) and rs117555780 (UBXN1) were identified as candidate markers predictive of PCa Gleason score which is strongly associated with cancer aggressiveness. Additional validation in future studies is warranted.

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