探討內皮細胞特異分子在攝護腺癌進程之角色

Abstract

雖然Wnt/β-catenin訊息傳遞路徑的活化常見於晚期攝護腺癌中，然而其訊息傳遞路徑上的相關基因突變在攝護腺癌中卻十分少見，因此這條訊息傳遞路徑在攝護腺癌中可能存在未知的調控機轉。在此篇研究中，我們發現一種分泌型多醣蛋白Endothelial cell-specific molecule 1 (ESM1)的表現量與攝護腺癌的進程及轉移具高度相關性，且ESM1表現較高的病人其總體存活率較低。ESM1可透過活化Wnt/β-catenin訊息傳遞路徑調控癌細胞的幹性以促進攝護腺癌的進程。此外我們也發現ESM1在侵犯程度較高的攝護腺癌細胞核內高度表現，而這群在核內的ESM1相較於其原始的分泌狀態更可支持攝護腺癌幹性。透過與β-catenin的armadillo (ARM) repeat domain結合，ESM1可幫助穩定β-catenin及其cofactor T-cell factor 4 (TCF4)的聚合體，進而促進Wnt/β-catenin訊息傳遞路徑持續地活化。同時，活化的β-catenin也會幫助ESM1進入細胞核內，進一步促使ESM1/β-catenin/TCF4聚合體於核內停留並活化下游調控分子。我們的研究證實了核內的ESM1在攝護腺癌轉移過程的關鍵調控角色，可望成為一新穎的預後生物標記及藥物標靶。

Wnt/β-catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/β-catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here we report that the expression of endothelial cell-specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated with prostate cancer stemness and progression by promoting Wnt/β-catenin signaling. Elevated ESM1 expression correlates with poor overall survival and metastasis. Accumulation of nuclear ESM1, instead of cytosolic or secretory ESM1, supports prostate cancer stemness by interacting with the ARM domain of β-catenin to stabilize β-catenin-TCF4 complex and facilitate the transactivation of Wnt/β-catenin signaling targets. Accordingly, activated β-catenin in turns mediates the nuclear entry of ESM1. Our results establish the significance of mislocalized ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β-catenin pathway, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.