Musashi-1陽性結腸直腸癌幹細胞譜系中非典型途徑誘導耐藥性

Abstract

Musashi-1 (Msi-1) 是一種核酸結合蛋白，並被視為一種致癌的蛋白因子，最近許多研究指出Msi-1與結腸直腸癌(CRC)的發展，有很大的關聯性，但是Msi-1造成腫瘤生成的潛在機制，尚未明確的被探討。 癌症幹細胞譜系(CSCs) ，如CD44、CD133˗ 和 Lgr5被指出會促進CRC的轉型，其中Msi-1促使增加CD44結腸直腸癌譜系的表現，然而CSCs是造成抗藥性的主因，並且是操控腫瘤惡化與復發的主要調控者。本篇研究主要是探討是否在CRC發展中，Msi-1蛋白扮演主要的因子去調控CSCs的進程。而數篇報導顯示，在高壓的環境下，細胞產生應激顆粒(SGs) ，用以增強細胞存活並最小化細胞損失，且在CSCs 的演化上，SGs是關鍵因子，使細胞適應於高壓環境以及促進抗治療性干預。本篇研究顯示，在化療藥物5-Flouracil (5FU)作用下，Msi-1蛋白造成SGs的聚集，另外TUNEL數據顯示，Msi-1陽性細胞與其他細胞相比，具有較少的DNA片段化，表明Msi-1具有抗凋亡活性。由5FU誘導的Msi-1應激顆粒，通過Msi-1介導的SGs聚集，活化非規範信號轉導，以逃避化療作用，以及在5FU的治療下，增加β-catenin以及在鹼基ser 9/ser 21磷酸化的GSK3β。統整所有的研究結果，我們提出在CRC中，Msi-1作用於幹細胞性的基因，並通過SGs介導的CSCs演化，來增強癌症惡性腫瘤，且非規範信號轉導途徑介導的GSK3β磷酸化，可能作為將來臨床上，耐藥性CRC治療的觀察指標。

Musashi-1 (Msi-1), a RNA-binding protein, have emerged as an oncogenic protein, recent increasing evidence suggests that this protein correlated with colorectal cancer (CRC) progression. However, the underlying mechanism of Msi-1 mediated tumorigenesis is poorly understand. CD44, CD133˗ and Lgr5, cancer stem cell (CSCs) lineages are shown to promote CRC transformation, whereas Msi-1 promotes CD44+ CSC lineage. CSCs conduct the evil axis of drug resistance, malignancy and relapse of tumor. Our studies aim to prove whether Msi-1 plays a critical role to establish CSCs properties in CRC. In the stress condition, cell generate the formation of stress granule (SGs) to enhance cell survival and minimalize cell loss. Accumulating reports support that SGs are critical for cell adaptation to environmental stress and enhanced anti-therapeutic intervention by CSCs evolution. Our results show Msi-1 forms SGs assemble under chemotherapeutic drug, 5-Flouracil (5FU). TUNEL data showed that Msi-1 positive cell has less DNA fragmentation compared to other cell, indicating an anti-apoptotic activity of Msi-1. Msi-1 SGs induced by 5FU activates non-canonical signal transduction by Msi-1 associated SGs formation to evade chemotherapeutic effect. Treatment with 5FU increased β-catenin and phosphorylation of GSK3β at ser 9/ser 21 residues. All these findings taken together, we propose Msi-1 in CRC works as stemness gene and enhances cancer malignancy by SGs mediated CSCs evolution. And the non-canonical signaling transduction pathway mediated GSK3β phosphorylation may provide clinical insight for drug-resistant CRC treatment in the future.