A PCA3 gene-based transcriptional amplification system targeting primary prostate cancer

Abstract

Targeting specifically primary prostate cancer (PCa) cells for immune therapy, gene therapy or molecular imaging is of high importance. The PCA3 long non-coding RNA is a unique PCa biomarker and oncogene that has been widely studied. This gene has been mainly exploited as an accurate diagnostic urine biomarker for PCa detection. In this study, the PCA3 promoter was introduced into a new transcriptional amplification system named the 3-Step Transcriptional Amplification System (PCA3-3STA) and cloned into type 5 adenovirus. PCA3-3STA activity was highly specific for PCa cells, ranging between 98.7- and 108.0-fold higher than that for benign primary prostate epithelial or non-PCa cells, respectively. In human PCa xenografts, PCA3-3STA displayed robust bioluminescent signals at levels that are sufficient to translate to positron emission tomography (PET)-based reporter imaging. Remarkably, when freshly isolated benign or cancerous prostate biopsies were infected with PCA3-3STA, the optical signal produced from primary PCa biopsies was significantly higher than from benign prostate biopsies (4.4-fold, p < 0.0001). PCA3-3STA therefore represents a PCa-specific expression system with the potential to target, with high accuracy, primary or metastatic PCa epithelial cells for imaging, vaccines, or gene therapy.

Retracted: Long noncoding RNA PCA3 regulates prostate cancer through sponging miR‐218‐5p and modulating high mobility group box 1

“…It demonstrated in mechanism that PCA3 promoted cell viability and mobility whereas lncRNA PCA3, which is typically overexpressed in cancer cells (de Kok et al, 2002), has been identified as a genetic marker with a high specificity for PCa (Schalken, Hessels, & Verhaegh, 2003). Considering multiple promising findings, PCA3 has been regarded as a screening tool (Birnbaum et al, 2015;De Luca et al, 2014) and an adjunct to serum PSA to determine the risk of PCa (Neveu et al, 2016;Ramos et al, 2013). Previous research revealed that miR-218-5p inhibited tumor growth by targeting BCAT1 in PCa (Zhu, Shao, & Peng, 2017).…”

Bioluminescence Microscopy as a Method to Measure Single Cell Androgen Receptor Activity Heterogeneous Responses to Antiandrogens

“…2d). Interestingly, when we used the PCa-specific and androgen-insensitive PCA3 -3STA 18 promoter system for cell imaging, the percentage of detected PCa cells reached that of the CMV -TSTA ( Fig. 1c ).…”

“…With the goal of imaging primary prostate cancer (PCa) single cell response to antiandrogens, we first had to develop conditions for an appropriate imaging system driven by a promoter containing the androgen response elements sequence (ARE), which could be delivered into PCa cells. Because of high infectivity and thorough characterization in primary PCa cells, type 5 adenovirus was chosen as our delivery method 18 . For the PCa cell imaging using bioluminescence microscopy, we constructed type 5-adenovirus-enabling firefly luciferase (fl) expression driven by either a strong ubiquitous promoter ( CMV ), a well-characterized ARE-bearing promoter ( PSEBC ) 19 20 , or a PCa-specific androgen-insensitive promoter ( PCA3 ) ( Fig.…”

“…For the PCa cell imaging using bioluminescence microscopy, we constructed type 5-adenovirus-enabling firefly luciferase (fl) expression driven by either a strong ubiquitous promoter ( CMV ), a well-characterized ARE-bearing promoter ( PSEBC ) 19 20 , or a PCa-specific androgen-insensitive promoter ( PCA3 ) ( Fig. 1a ) 18 …”

Long Non-Coding RNA as Potential Biomarker for Prostate Cancer: Is It Making a Difference?

“…Furthermore, Neveu et al [41] have introduced PCA3 promoter into a new transcriptional amplification system, namely the 3-Step Transcriptional Amplification System (PCA3-3STA), and cloned it to adenovirus, which provides a superior amplification of the PCA3 promoter activity, and has a higher specificity for PCa cells compared to benign primary prostate epithelial cells or non-PCa cells. Moreover, the bioluminescent signals generated by PCA3-3STA have shown to be sufficient to translate to positron emission tomography imaging.…”