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- W2980526515 abstract "In this study, the potential role of miR-34a as a tumor suppressor in mouse models of carcinogen-induced colorectal cancer and colitis-associated cancer was investigated.In the first part, I demonstrated that germline deletion of Mir34a promotes inflammation-induced colorectal carcinogenesis in mice. In a colitis-associated cancer model Mir34a-deficiency was associated with an increase in the frequency and size of colon tumors, and enhanced invasion into surrounding tissue. Mir34a-deficient colon tumors displayed IL6R/Stat3 pathway activation with elevated expression of EMT markers, such as Snail and Zeb1, which might explain the observed invasive characteristics of these colon tumors. Therefore, this study provided first in vivo proof for a tumor suppressive function of Mir34a in a genetic mouse model of CAC.It was previously shown that miR-34a is a down-stream target of tumor suppressor Tp53. Inactivation of both TP53 (by mutation) and MIR34A (by CpG methylation) occurs in late stages of colorectal carcinogenesis. In the second part of this study we found that TP53 and the MIR34A were inactivated in 50% of CRCs which developed distant metastases. To trace the consequences of this combined inactivation, I deleted these genes in a mouse model of colorectal cancer, and characterized the CRC initiation and progression. RNA expression profiling of colon tumors revealed the activation of key oncogenic factors and pathways, such as c-Myc, EMT, hypoxia, and an inflammatory response in Mir34aΔIECTp53ΔIEC mice. Treatment of Mir34aΔIECTp53ΔIEC mice with inhibitors of up-regulated Mir34a targets, as exemplarily demonstrated here for IL6R and Pai-1, reduced tumor progression and inhibited the lymph-node metastasis. Analysis of 628 colon cancer cases represented in online databases and 61 primary tissue samples obtained from patients demonstrated that the findings made in a preclinical mouse model can be transferred to humans. Taken together, the results obtained within this study improved the understanding of the role of miR-34a in colorectal cancer and underlined the therapeutic potential of miR-34a targets as an alternative approach for the treatment of colorectal cancer." @default.
- W2980526515 created "2019-10-25" @default.
- W2980526515 creator A5066105474 @default.
- W2980526515 date "2019-03-26" @default.
- W2980526515 modified "2023-09-27" @default.
- W2980526515 title "Genetic analysis of Mir34a in mouse models of colorectal cancer" @default.
- W2980526515 hasPublicationYear "2019" @default.
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