Non-Canonical Pathways Induced Drug Resistance in Musashi-1 Positive Colorectal Cancer Stem Cell Lineages

• Main Authors: Nurul, Fadhilah, 方守諾
• Other Authors: Chiou, Guang-Yuh
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/9wqdtp

碩士 === 國立交通大學 === 分子醫學與生物工程研究所 === 105 === 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.