miR-18a-5p Is Involved in the Developmental Origin of Prostate Cancer in Maternally Malnourished Offspring Rats: A DOHaD Approach.

The Developmental Origins of Health and Disease (DOHaD) concept correlates early life exposure to stressor conditions with the increased incidence of non-communicable chronic diseases, including prostate cancer (PCa), throughout the life span. However, the molecular mechanisms involved in this process remain poorly understood. In this study, the deregulation of two miRNAs (rno-miR-18a-5p and rno-miR-345-3p) was described in the ventral prostate VP of old rats born to dams fed with a low protein diet (LPD) (6% protein in the diet) during gestational and lactational periods. Integrative analysis of the (VP) transcriptomic and proteomic data revealed changes in the expression profile of 14 identified predicted targets of these two DE miRNAs, which enriched terms related to post-translational protein modification, metabolism of proteins, protein processing in endoplasmic reticulum, phosphonate and phosphinate metabolism, the calnexin/calreticulin cycle, metabolic pathways, N-glycan trimming in the ER and the calnexin/calreticulin cycle, hedgehog ligand biogenesis, the ER-phagosome pathway, detoxification of reactive oxygen species, antigenprocessing-cross presentation, RAB geranylgeranylation, collagen formation, glutathione metabolism, the metabolism of xenobiotics by cytochrome P450, and platinum drug resistance. RT-qPCR validated the deregulation of the miR-18a-5p/P4HB (prolyl 4-hydroxylase subunit beta) network in the VP of older offspring as well as in the PNT-2 cells transfected with mimic miR-18a-5p. Functional in vitro studies revealed a potential modulation of estrogen receptor α (ESR1) by miR-18a-5p in PNT-2 cells, which was also confirmed in the VP of older offspring. An imbalance of the testosterone/estrogen ratio was also observed in the offspring rats born to dams fed with an LPD. In conclusion, deregulation of the miR-18a-5p/P4HB network can contribute to the developmental origins of prostate cancer in maternally malnourished offspring, highlighting the need for improving maternal healthcare during critical windows of vulnerability early in life.

Mucinous metaplasia in Pten conditional knockout mice and mucin family genes as prognostic markers for prostate cancer.

AIMS: This study evaluated the association of mucinous metaplasia (MM) with tumor cell proliferation, androgen receptor (AR) expression and invasiveness in Pten conditional knockout mice and the prognostic value of MM markers for patients with PCa. MAIN METHODS: Prostatic lobes samples from genetic engineered mouse model Ptenf/f and Pb-Cre4/Ptenf/f were submitted for histopathological analysis and tissue expression of AR, the proliferation marker Ki67, alpha-smooth muscle actin, and laminin. RNAseq data of prostatic lobes samples were analyzed searching for MM gene expression patterns. We also investigated gene and protein expression related to MM in human PCa public databases. KEY FINDINGS: All knockout animals analyzed showed at least one area of stroma-invading MM, which was absent in the control animals. The tumoral regions of MM showed a proliferative index 5 times higher than other tumoral areas and low expression of the AR (less than 20% of the cells were AR-positive). Disrupted basement membrane areas were observed in MM. The mouse and human PCa transcriptomes exhibited increased expression of the MM markers such as MUC1, MUC19, MUC4, MUC5AC, MUC5B, and TFF3. Gene expression profile was associated with castration-resistant prostate cancer (CRPC) and with a lower probability of freedom from biochemical recurrence. SIGNIFICANCE: The expression of goblet cell genes, such as MUC1, MUC5AC, MUC5B, and TFF3 have significant prognostic value for PCa patients and represent another class of potential therapeutic targets.

Identification of potential molecular pathways involved in prostate carcinogenesis in offspring exposed to maternal malnutrition.

The developmental origins of health and disease concept links adult diseases with early-life exposure to inappropriate environmental conditions. Intrauterine and postnatal malnutrition may lead to an increased incidence of type 2 diabetes, obesity, and cardiovascular diseases. Maternal malnutrition (MM) has also been associated with prostate carcinogenesis. However, the molecular mechanisms associated with this condition remain poorly understood. Using a proteomic analysis, we demonstrated that MM changed the levels of proteins associated with growth factors, estrogen signaling, detoxification, and energy metabolism in the prostate of both young and old rats. These animals also showed increased levels of molecular markers of endoplasmic reticulum function and histones. We further performed an in silico analysis that identified commonly deregulated proteins in the ventral prostate of old rats submitted to MM with a mouse model and patients with prostate cancer. In conclusion, our results demonstrated that estrogenic signaling pathways, endoplasmic reticulum functions, energy metabolism, and molecular sensors of protein folding and Ca2+ homeostasis, besides histone, and RAS-GTPase family appear to be involved in this process. Knowledge of these factors may raise discussions regarding the role of maternal dietary intervention as a public policy for the lifelong prevention of chronic diseases.