Musashi-1蛋白在大腸癌細胞中調控CD44/CD44v6陽性癌症幹細胞線性轉型與抗藥性

Abstract

大腸直腸癌在台灣為發生率最高的癌症，並成為國人健康的重要議題，在國際間備受重視。瞭解大腸直腸癌，是為了近一步提供更好的方法與治療契機。癌症幹細胞(CSCs)在癌症轉型，發展，與惡化被認為扮演重要的角色。然而，多樣的基因損傷與環境引導癌症幹細胞造成大腸直腸腫瘤增生。但是癌症幹細胞在維持與造成腫瘤的關係尚未明朗。近期研究發現，大腸癌細胞(CRCCs)表現表面受體CD44或CD44v6造成臨床上治療與治療後的困難。在此，我們報導RNA鍵結蛋白Musashi-1—神經細胞與大腸上皮細胞幹性標記，提升CD44或CD44v6陽性表現族群。此外Musashi-1引發大腸直腸癌癌症幹細胞惡性與抗藥性。以上結果指出Musashi-1蛋白調控腫瘤惡化。進一步暸解細胞株過度表現Musashi-1並在抗癌藥物5-FU的誘導下形成壓力顆粒，其中Musashi-1 C-terminal domain與壓力顆粒形成有重要關係。Musashi-1可能在大腸癌癌症中以提升抗藥性與增加抗細胞凋亡特性，在惡性轉型中扮演重要角色。此外，Musashi-1蛋白在大腸直腸癌病人檢體表現率與實驗吻合呈正向關。綜合這些發現，我們展現Musashi-1，幹性基因，不只為一重要癌症幹細胞調控子，並提升癌症幹細胞惡性。除此之外，我們的結果也發現Musashi-1的新機制，與了解Musashi-1與壓力顆粒可能是造成癌症治療困難的原因之一。

Colorectal cancer has the highest incidence among all cancer types in Taiwan and it has become a critical national-wide health issue of Taiwanese residues or even global- wide health issues. To have better understanding of CR will provide better chances or maneuver for prevention or aggressive CRs treatments. Cancer stem cells (CSCs) lineages maintaining are critical for tumor transformation, progression and malignant advancing. Whereas, orchestrated multiple environmental and genetic hits eventually lead to CSCs driven CR tumorigenesis. However, how CSC lineages are maintained and generated are largely unknown. Recent findings showed that colorectal cancer cells (CRCCs) with CD44 or CD44v6 surface marker expressions and those CSCs contribute clinical difficulties and poor prognosis. Here, we reported RNA-binding protein Musashi-1, a stemness marker for neuronal cells and colorectal epithelial cells, enhance the population of CD44- and CD44v6-positive CSCs. Furthermore, Musashi-1 triggers CRCCs metastatic properties and drug resistance. Indicating a CSCs lineage specific induction of tumor malignancies are controlled by Musashi-1. Furthermore, Musashi-1 forms stress granules upon 5-FU inductions in CRC cell lines and the C-terminal domain of Musashi-1 is critical for recruiting Musashi-1 into stress granules. Musashi- 1 might exerts critical role in tumor malignancies transformations for CRCs by promoting drug resistance properties by increasing anti-apoptosis activities. Furthermore, analysis the Musashi-1 expression of clinical CRCs samples indicate Musashi-1 expression is correlated with pathological CRC progressions. Those findings combined, we demonstrated Musashi-1, a stemness gene, as a critical modulator not only in promoting CSCs populations and also enhancing CRCs malignancies. Besides, our results also suggest a novel mechanism of Musashi-1 and the formations of Musashi-1 associating stress granules might involve in clinical difficulties of CRCs treatments.