A basal‐enriched microRNA is required for prostate tumorigenesis in a Pten knockout mouse model

Abstract

MicroRNAs (miRNAs) play important roles in prostate cancer development. However, it remains unclear how individual miRNAs contribute to the initiation and progression of prostate cancer. Here we show that a basal layer‐enriched miRNA is required for prostate tumorigenesis. We identify miR‐205 as the most highly expressed miRNA and enriched in the basal cells of the prostate. Although miR‐205 is not required for normal prostate development and homeostasis, genetic deletion of miR‐205 in a Pten null tumor model significantly compromises tumor progression and does not promote metastasis. In Pten null basal cells, loss of miR‐205 attenuates pAkt levels and promotes cellular senescence. Furthermore, although overexpression of miR‐205 in prostate cancer cells with luminal phenotypes inhibits cell growth in both human and mouse, miR‐205 has a minimal effect on the growth of a normal human prostate cell line. Taken together, we have provided genetic evidence for a requirement of miR‐205 in the progression of Pten null‐induced prostate cancer.

MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?

“…This results in underrepresentation of basal cell-associated markers and genes (e.g., KRT5 or p63), including miRNAs in prostate cancer compared to normal prostate. However, this does not necessarily mean that basal cell miRNAs, such as miR-205, are tumor suppressors in prostate cancer [22] and are actually essential for mouse prostate tumorigenesis [23]. Alternatively, some reports indicate that miR-205 may be not entirely be restricted to basal cells and is also expressed in luminal cells and in prostate cancer cells [24].…”

“…Alternatively, some reports indicate that miR-205 may be not entirely be restricted to basal cells and is also expressed in luminal cells and in prostate cancer cells [24]. Whether luminal miR-205 levels are relevant is unclear, but the stark differences in miR-205 levels between luminal and basal cells suggest that miR-205 may actually be a suppressor of the luminal cell phenotype [23] in line with the idea that miRNAs can suppress leaky transcripts that may interfere with correct differentiation and cell fate decision processes. Nevertheless, one of the major obstacles in prostate miRNA biology has been the lack of data on the miRNA expression pattern in luminal, basal, and non-epithelial cells; essentially, the lack of in situ hybridization (ISH) data or data of sorted cells.…”

“…Nevertheless, one of the major obstacles in prostate miRNA biology has been the lack of data on the miRNA expression pattern in luminal, basal, and non-epithelial cells; essentially, the lack of in situ hybridization (ISH) data or data of sorted cells. However, a steady stream of reliable ISH data and data on sorted cells will eventually clarify the cellular sources of individual miRNAs [23][24][25][26].…”

“…This concept can also be applied to the prostate. One of the most abundant miRNAs in basal cells of the prostate, miR-205, can be eliminated in mouse prostates without any consequences [23]. However, challenging the tissue in the absence of miR-205, e.g., by promoting prostate carcinogenesis, will produce a profound phenotype of cancer suppression [23].…”

“…Therefore, miR-375 may be called the keeper of the epithelial phenotype in prostate cancer especially luminal epithelial cell features. miR-375 is one of the few luminally enriched miRNAs (at least 10-fold) in the dataset by Fan et al [23]. MiR-375 may function as a gatekeeper and it stands before the transition to more aggressive and more mesenchymal forms of prostate cancer (PCa).…”