Autophagy suppresses colorectal cancer cell LEF-1 expression through FOXO1 mediated upregulation of miR-449a

  • 王 瑋禎

Student thesis: Master's Thesis


Autophagy maintains cellular homeostasis through recruitment and degradation of accumulated and dysfunctional materials in the cell Aberrant autophagy can cause diseases including tumorigenesis MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression MiRNAs play a key role in cancer progression and control cell proliferation cell cycle differentiation metastasis et al to affect tumor growth Recent studies focus on miRNA in regulation of autophagy processes However few studies focus on autophagy regulation of miRNAs especially in tumorigenesis We previously showed that miR-449a is the most up-regulated miRNA under autophagy induced conditions and the expression of miR-449a was inversely correlated with recurrence and metastasis of the colorectal cancers (CRC) Furthermore amiodarone (an antiarrhythmic drug) induced autophagy up-regulates miR-449a to suppress the cell migration invasion proliferation colony formation and tumor formation of CRC cells SW480 Above data indicate that reduced autophagy and miRNA contribute to the tumorigenesis of CRC This study intends to the underlying mechanism of autophagy regulation of miR-449a In 72 paired CRC patient specimens the autophagy activity and miR-449a were lower in the tumor part In addition the target gene of miR-449a LEF-1 was up-regulated in CRC To clarify the relationship between autophagy and miR-449a and their effects on tumorigenesis amiodarone an antianginal and antiarrhythmic drug was used to induce autophagy and miR-449a expression was induced in colon cancer SW480 cells Furthermore we reveal that autophagy up-regulates miR-449a through FOXO1 at the transcription level and further down-regulates its target gene Fukamizu et al reported that p300-mediated acetylation of FOXO1 reduces its DNA-binding affinity and transcription activity and overexpression p300 correlates with poor prognosis of colorectal cancer Here we demonstrated that autophagy may down-regulate the expression of p300 through a degradation pathway indicating that miR-449a down expression in CRC may be regulated by overexpression of p300 which further acetylates FOXO1 In summary our findings indicate that autophagy regulates miRNA expression through promoting its transcription and further affects its target gene in CRC
Date of Award2016 Feb 1
Original languageEnglish
SupervisorHsiao-Sheng Liu (Supervisor)

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