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Mechanisms regulating the gene expression program at different hypoxia severity levels in patient tumors are not understood. We aimed to determine microRNA (miRNA) regulation of this program at defined hypoxia levels from moderate to severe in prostate cancer. Biopsies from 95 patients were used, where 83 patients received the hypoxia marker pimonidazole before prostatectomy. Forty hypoxia levels were extracted from pimonidazole‐stained histological sections and correlated with miRNA and gene expression profiles determined by RNA sequencing and Illumina bead arrays. This identified miRNAs associated with moderate (n = 7) and severe (n = 28) hypoxia and predicted their target genes. The scores of miRNAs or target genes showed prognostic significance, as validated in an external cohort of 417 patients. The target genes showed enrichment of gene sets for cell proliferation and MYC activation at all hypoxia levels and PTEN inactivation at severe hypoxia. This was confirmed by RT‐qPCR for MYC and PTEN, by Ki67 immunohistochemistry, and by gene set analysis in an external cohort. To assess whether miRNA regulation occurred within the predicted hypoxic regions, a method to quantify co‐localization of multiple histopathology parameters at defined hypoxia levels was applied. A high Ki67 proliferation index co‐localized significantly with hypoxia at all levels. The co‐localization index was strongly associated with poor prognosis. Absence of PTEN staining co‐localized significantly with severe hypoxia. The scores for miRNAs correlated with the co‐localization index for Ki67 staining and hypoxia, consistent with miRNA regulation within the overlapping regions. This was confirmed by showing miR‐210‐3p expression within severe hypoxia by in situ hybridization. Cell line experiments (22Rv1, PC3) were conducted to determine whether miRNAs and target genes were regulated directly by hypoxia. Most of them were hypoxia‐unresponsive, and probably regulated by other mechanisms such as MYC activation. In conclusion, in aggressive, hypoxic prostate tumors, cancer cells exhibit different proliferative gene expression programs that is regulated by miRNAs and depend on whether the cells reside in moderate or severe hypoxic regions. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Little is known about the transport mechanism of anti -3-18F-fluorocyclobutane-1-carboxylic acid (FACBC) into prostate tumors. Because of the structural similarity to natural amino acids, FACBC is anticipated to cross the cell membrane via amino acid transporters, and preclinical studies have suggested that ASCT2, LAT1 and SNAT2 are involved. In 16 patients with intermediate or high-risk prostate cancer we matched the FACBC uptake from clinical PET to the location of punch biopsies from resected prostatectomy specimens and compared maximum standardized uptake value (SUVmax) with the gene expression of 40 amino acid transporters. The study also included immunohistochemistry for the three amino acid transporters ASCT2, LAT1 and SNAT2. Furthermore, we performed global gene expression analysis of the biopsies to investigate biological processes associated with FACBC uptake. Several amino acid transporters had a higher gene expression level than the others, but we found no significant correlations between SUVmax and the gene expression levels of any of 40 different amino acid transporters. In the immunohistochemical analyses, ASCT2 and SNAT2 were highly expressed, but not correlated to SUVmax. LAT1 had low gene- and protein expression. Global gene expression analyses identified 153 unique genes that were positively correlated to SUVmax. These genes were found to be associated with gene sets reflecting intracellular transport and high metabolic activity. Based on the study findings we propose that the uptake mechanism of FACBC is more complex than mediated by a few amino acid transporters., Competing Interests: None., (AJNMMI Copyright © 2021.)

OBJECTIVE. The objective of our study was to investigate whether phosphatase and tensin homolog ( PTEN ) expression is associated with clinicopathologic features and multiparametric MRI findings in prostate cancer. MATERIALS AND METHODS. Forty-three patients with prostate cancer who underwent radical prostatectomy were included. Index tumor was identified on pretreatment MRI and delineated in the area that correlated best with histopathology results. The apparent diffusion coefficient (ADC) from DWI and pharmacokinetic parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) using the extended Tofts model (K trans , k ep , v e , and v p ) within the tumor were estimated. The following clinicopathologic parameters were assessed: pretreatment serum levels of prostate-specific antigen, disseminated tumor cell status, age, Gleason score, tumor size, extraprostatic extension (EPE), tumor location, and lymph node metastases. Gene expression profiles were acquired in biopsies from the tumor using bead arrays, and validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR) on a different part of the biopsy. RESULTS. Based on bead arrays ( p = 0.006) and RT-qPCR ( p = 0.03) data, a significantly lower ADC was found in tumors with low PTEN expression. Moreover, PTEN expression was negatively associated with lymph node metastases (bead arrays, p = 0.008; RT-qPCR, p < 0.001). A weak but significant association between PTEN expression, EPE ( p = 0.048), and Gleason score ( p = 0.028) was revealed on bead arrays. ADC was negatively correlated with Gleason score ( p = 0.001) and tumor size ( p = 0.023). No association among DCE parameters, PTEN expression, and clinicopathologic features was found. CONCLUSION. ADC derived from DWI may be useful in selecting patients with potentially aggressive tumor caused by PTEN deficiency.