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Background: We describe the first studies investigating a role for opiorphin genes ( PROL1, SMR3A and SMR3B) in prostate cancer (PrCa). Materials & methods: Databases and PrCa tissue arrays were screened for opiorphin expression. Xenografted tumor growth of human PrCa cells overexpressing PROL1 was compared with controls in nude mice. Modulated gene expression by overexpression of PROL1 was determined by RNA sequencing. Results: PrCa is associated with overexpression of opiorphin genes. Xenografted androgen-sensitive PrCa cells overexpressing PROL1 developed into tumors in castrated male mice (in contrast to parental cells). PROL1 overexpression modulates expression of genes in angiogenesis, steroid and hypoxic response pathways. Conclusions: Opiorphins promote the development of androgen-insensitive PrCa and activate pathways that potentially overcome the hypoxic barrier generated during tumor growth.

Background The opiorphin family of genes (represented in humans by ProL1, hSMR3A and hSMR3B) encode peptides which act as potent neutral endopeptidase (NEP) inhibitors. Because modulated NEP activity is associated with cancer development it has been suggested that dysregulated opiorphin expression may be involved in oncogenesis and recent reports have associated upregulated opiorphin gene expression with breast and oropharyngeal cancer. These observations prompted the present studies to determine if opiorphin genes play a role in prostate cancer (PrCa).Methods Publicly available data bases were screened for evidence associating opiorphin gene expression with PrCa and the findings confirmed using PrCa tissue arrays. Androgen-insensitive (PC3) and -sensitive (LNCaP) PrCa cells were engineered to overexpress ProL1, referred to as LNCaP-ProL1+ and PC3-ProL1+, respectively. Xenografted tumor growth of ProL1-overexpressing and parental cell-lines were compared in male, castrated-male and female nude mice. Changes in global gene expression resulting from overexpression of ProL1 in these cell-lines was determined by RNA-Seq.Results Publicly available datasets supported an association between overexpression of opiorphin genes and PrCa, which was confirmed using tissue arrays. Xenografted tumors derived from PC3-ProL1+ had an initial growth advantage over parent cell-lines in male mice, although at later time points there was no difference. Xenografted tumors derived from LNCaP-ProL1+ were able to grow in castrated male mice (in contrast to the parent cell-lines), and had impaired growth in female mice. Global gene expression analysis demonstrated that overexpression of ProL1 causes modulated expression of genes involved in signaling, angiogenesis and steroid response pathways.Conclusions This is the first report associating upregulated opiorphin gene expression and PrCa. Xengrafted tumors derived from the androgen-sensitive LNCaP cell-line engineered to overexpress ProL1 exhibit a more androgen-insensitive phenotype. Previous reports demonstrate opiorphins act as master regulators of the hypoxic response in smooth muscle cells. RNAseq data not only supports a similar role for ProL1 in PrCa (regulating genes involved in angiogenesis), but in addition, regulating genes involved in steroid response. Therefore, opiorphins may play a role in PrCa development by activating pathways that overcome the hypoxic environment of the developing tumor and promote the development of androgen-insensitivity.