PEG10 Promoter–Driven Expression of Reporter Genes Enables Molecular Imaging of Lethal Prostate Cancer

Abstract

The retrotransposon-derived paternally expressed gene 10 (PEG10) protein is ordinarily expressed at high levels in the placenta. Recently, it was discovered that PEG10 isoforms promote the progression of prostate cancer to a highly lethal androgen receptor (AR)-negative phenotype. The presence of PEG10 in other subtypes of prostate cancer has not been explored and a utility for PEG10 overexpression has not been developed. Here, we found that in addition to AR-null disease, PEG10 was also expressed in prostate cancer with constitutively active AR-splice variants. A molecular genetic imaging strategy for noninvasive imaging of AR-splice variant prostate cancer was developed by utilizing the cancer specificity of the PEG10 promoter to drive the expression of reporter genes. Plasmid insertion of a PEG10 promoter sequence optimized for enhanced output upstream of a reporter gene allowed detection of prostate cancer by near-infrared and positron emission tomography imaging after systemic administration of the plasmid in vivo. PEG10 expressing subcutaneous xenograft and intratibial tumor models were imaged by both modalities using this molecular genetic imaging strategy. This study demonstrates a preclinical proof-of-concept that the PEG10 promoter is a powerful and specific tool that can be utilized for noninvasive detection of aggressive prostate cancer subtypes.Significance: PEG10 is expressed by prostate cancer with constitutively active AR-splice variants that can be exploited for noninvasive molecular imaging of this aggressive prostate cancer subytpe.

IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression

“…Paternally imprinted genes are expressed in a variety of human cancers and are regarded as oncogenes 17 . PEG10 overexpression has been associated with several malignancies, such as liver cancer, pancreatic cancer and breast cancer 24 - 26 . In this study, we found that PEG10 is also highly expressed in EC and is directly related to patient survival.…”

“…In this study, we found that PEG10 is also highly expressed in EC and is directly related to patient survival. A large number of studies have focused on PEG10 gene transcription and promoter methylation to investigate the relationship between PEG10 and tumor progression 26 - 27 . However, we have provided a new perspective for understanding PEG10 expression regulation by demonstrating that IGF2BP1 is an m6A-dependent post-transcriptional regulator of PEG10 expression.…”

Cellular architecture of human brain metastases

“…Among the genes specifically upregulated in cycling cells were members of the core spliceosome and MYC targets (Table S5). Of note, two known imprinted genes were identified among the top hits: MEST (Mesoderm-Specific Transcript) and PEG10 (Paternally Expressed Gene 10), both previously implicated in poor prognosis in multiple cancer types (Ishii et al, 2017;Li et al, 2016;Pedersen et al, 1999;Shapovalova et al, 2019;Vidal et al, 2014) (Figure 6C). We confirmed these patterns by immunostaining for PEG10 and S100A6 in cycling (Ki67+) MTCs (Figure 6D).…”

Single-cell RNA-seq highlights a specific carcinoembryonic cluster in ovarian cancer

“…PEG10 was strongly expressed in the placenta, ovary, and testis. However, PEG10 dysregulation was reported in multiple tumours, such as metastasis prostate tumours [ 29 ], hepatocellular carcinoma [ 33 ], and endometrial cancer [ 34 ]. PEG10 was also closely related to the poor prognosis of cancers [ 29 , 33 , 34 ].…”

“…However, PEG10 dysregulation was reported in multiple tumours, such as metastasis prostate tumours [ 29 ], hepatocellular carcinoma [ 33 ], and endometrial cancer [ 34 ]. PEG10 was also closely related to the poor prognosis of cancers [ 29 , 33 , 34 ]. In our study, PEG10 was highly expressed in embryo and tumour and associated with poor survival in OC.…”