Abstract
Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.
Highlights
The primary cilium is a microtubule-based organelle that protrudes from the plasma membrane and acts much like an ‘antenna’ to sense extracellular signals
Primary cilia expression is decreased in preinvasive and invasive prostate cancer To characterize the frequency of primary cilia in different severities of human prostate cancer, primary cilia presence was determined for the different tissue types: cancer-free normal tissue, prostatic intraepithelial neoplasia (PIN), cancer and perineural invasion lesions
The hematoxylin and eosin (H&E) slide was used as a reference to find the tissue types of interest on the adjacent serial section, which was stained for acetylated tubulin (Ac-Tub) to visualize primary cilia and γtubulin (γ-Tub) to identify associated centrosomes (Figure 1A and 1B)
Summary
The primary cilium is a microtubule-based organelle that protrudes from the plasma membrane and acts much like an ‘antenna’ to sense extracellular signals. Primary cilia are usually immotile but can sense physical and chemical signals. At the base of the primary cilium is the basal body ( known as the mother centriole), which is anchored to the plasma membrane. Hundreds of proteins have been identified that make up the primary cilium [1]. Cilia act like antennae through sensing extracellular signals and help regulate cell signaling; for example, primary cilia are negative regulators of the Wnt pathway [2,3]. Primary cilia dampen the Wnt signaling response by compartmentalizing Wnt signaling proteins, such as the positive regulator Jouberin [3]. Cilia have a demonstrated role in developmental biology and human diseases known as ciliopathies (e.g. Joubert syndrome (JBTS), polycystic kidney disease (PKD), Bardet–Biedl syndrome (BBS), and nephronophthisis (NPHP)) [4]
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