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In primary prostate cancer, the common multifocality and heterogeneity are major obstacles in finding robust prognostic tissue biomarkers. The long noncoding RNA SCHLAP1 has been suggested, but its prognostic value has not been investigated in the context of tumor heterogeneity. In the present study, expression of SCHLAP1 was investigated using real-time RT-PCR in a multisampled series of 778 tissue samples from radical prostatectomies of 164 prostate cancer patients (median follow-up time 7.4 y). The prognostic value of SCHLAP1 was evaluated with biochemical recurrence as endpoint. In total, 29% of patients were classified as having high expression of SCHLAP1 in at least one malignant sample. Among these, inter- and intrafocal heterogeneity was detected in 72% and 56%, respectively. High expression of SCHLAP1 was shown to be a predictor of biochemical recurrence in both uni- and multivariable cox regression analyses (P < 0.001 and P = 0.02). High expression of SCHLAP1 was also significantly associated with adverse clinicopathological characteristics, including grade group, high pT stage, invasive cribriform growth/intraductal carcinoma of the prostate, and reactive stroma. In conclusion, high expression of SCHLAP1 in at least one malignant sample is a robust prognostic biomarker in primary prostate cancer. For the first time, high SCHLAP1 expression has been associated with the aggressive histopathologic feature reactive stroma. The expression of SCHLAP1 is highly heterogeneous, and analysis of multiple samples is therefore crucial in determination of the SCHLAP1 status of a patient., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Ethidium bromide (EtBr) is an intercalating agent, which binds tightly to mitochondrial DNA (mtDNA) during replication, and so blocks the function of mitochondria. EtBr inserts itself between the stacked bases in double-stranded DNA and specifically inhibits mtDNA transcription and replication by deleting RNA primers required for initiating mtDNA replication. In this study, the authors wanted to examine whether blocking mtDNA replication with EtBr could change the expression of stenmness genes and the expression of the immuneregulator B7-H3 in prostate cancer cell lines in vitro. Both PC-3 and DU145 prostate cancer cell lines were treated with 50 and 500 ng/mL of EtBr for 2 weeks. There was no difference in growth between EtBr-treated and control cells after 1 week. A slightly slower growth was observed for both cell lines during the second week of culture with EtBr compared to controls. After 2 weeks of culture with EtBr both cell lines showed increased expression of the stemness-related genes ABCG2, Oct3/4, Nanog1/Nanogp8, and CD44. Concomitantly, a dose-dependent increase of B7-H3 protein expression in both cell lines was identified and verified by both flow cytometry and immunocytochemistry. In conclusion, blocking mtDNA replication by EtBr induces increased expression of stemness genes, such as Oct3/4, Nanog, CD44, and ABCG2, in addition to the immune regulator B7-H3 in PC-3 and DU145 prostate cancer cell lines. The findings indicate that mitochondrial function may be associated with stemness of cancer cells and/or maintenance of a cancer stem cell phenotype. The finding of increased B7-H3 expression may be associated with the immunosuppression of cancer cells. [ABSTRACT FROM AUTHOR]

Androgen plays a vital role in prostate cancer development. However, it is not clear whether androgens influence stem-like properties of prostate cancer, a feature important for prostate cancer progression. In this study, we show that upon DHT treatment in vitro, prostate cancer cell lines LNCaP and PC-3 were revealed with higher clonogenic potential and higher expression levels of stemness related factors CD44, CD90, Oct3/4 and Nanog. Moreover, sex hormone binding globulin (SHBG) was also simultaneously upregulated in these cells. When the SHBG gene was blocked by SHBG siRNA knock-down, the induction of Oct3/4, Nanog, CD44 and CD90 by DHT was also correspondingly blocked in these cells. Immunohistochemical evaluation of clinical samples disclosed weakly positive, and areas negative for SHBG expression in the benign prostate tissues, while most of the prostate carcinomas were strongly positive for SHBG. In addition, higher levels of SHBG expression were significantly associated with higher Gleason score, more seminal vesicle invasions and lymph node metastases. Collectively, our results show a role of SHBG in upregulating stemness of prostate cancer cells upon DHT exposure in vitro, and SHBG expression in prostate cancer samples is significantly associated with poor clinicopathological features, indicating a role of SHBG in prostate cancer progression. [ABSTRACT FROM AUTHOR]

Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier's performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer with a cribriform pattern, including invasive cribriform carcinoma (ICC) and/or intraductal carcinoma (IDC) is associated with a poor prognosis, and the underlying mechanisms are unclear. Therefore, we aimed to identify biomarkers for this feature. Using a radical prostatectomy cohort, we performed within-patient differential expression analyses with RNA sequencing data to compare samples with a cribriform pattern to those with non-cribriform Gleason pattern 4 (NcGP4; n=13). ACSM1, GRIN3A, PCDHB2 , and REG4 were identified as differentially expressed, and validation was performed using real-time reverse transcription polymerase chain reaction (n=99; 321 RNA samples) and RNA in situ hybridization on tissue microarrays (n=479; 2047 tissue cores). GRIN3A was significantly higher expressed in cribriform pattern vs. NcGP4, when assessed within the same patient (n=27; p=0.005) and between different patients (n=83; p=0.001). Tissue cores with IDC more often expressed GRIN3A compared to ICC, NcGP4, and benign tissue (52 % vs. ≤ 32 %). When IDC and NcGP4 was compared within the same patient (173 pairs of tissue cores; 54 patients), 38 (22 %) of the tissue microarray core pairs had GRIN3A expression in only IDC, 33 (19 %) had expression in both IDC and NcGP4, 14 (8 %) in only NcGP4 and 88 (51 %) were negative in both entities (p=0.001). GRIN3A was as well associated with biochemical recurrence (log-rank, p=0.002). In conclusion, ectopic GRIN3A expression is an RNA-based biomarker for the presence of cribriform prostate cancer, particularly for IDC. [ABSTRACT FROM AUTHOR]