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A study of the role of microRNAs in gastric cancer: the effect of miR-140-5p dysregulation in the expression of MDM2 in p53-dependent gastric cancer subtypes

Meng, Xie 2019. A study of the role of microRNAs in gastric cancer: the effect of miR-140-5p dysregulation in the expression of MDM2 in p53-dependent gastric cancer subtypes. MD Thesis, Cardiff University.
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Abstract

Gastric cancer is one of the leading causes of cancer-related death worldwide. Since advanced gastric carcinoma often demonstrates marked architectural and cytological heterogeneity, chemotherapyor targeted agents are seldom effective across all gastric cancer patients. Therefore, there is an urgent need to developeffective biomarkers for identifying patients with highlyinvasive diseaseand planindividual treatment decisions for each gastric cancer patient. In this study, in Silicodata analysis from TCGA was employed to discover miRNAs which had value in predicting patients’outcome. Among them, miR-140-5p and-3pwerechosen to confirm their expression pattern in two independent cohorts with and without neoadjuvant chemotherapy. miR-140-5p, rather thanmiR-140-3p, was the dominant miRNA in both gastric tumoursand adjacent normal tissues. Reduced expression of miR-140-5p and -3p were found in most gastrictumourscompared to matched normal tissues without chemotherapy through online data analysis and qPCR detection. Intestinal-typegastric cancer patients with lower expression of miR-140-5p suffered worse survival. Gastriccancer patients treated with 5-fluorouracil(5FU)based neoadjuvant treatment, both in online data and in independent cohort examination,showed increasedexpression of miR-140-5pand -3p. Patients without upregulation of neither miR-140-5p nor -3p exhibited the worst survival. In this study, weexploreda new potential target of miR-140-5p, mouse double minute 2 homolog (MDM2), which is the principle p53antagonist in unstressed cells. We also provide evidence,via several functional assays,that enforcedmiR-140-5p expression inhibits malignant phenotypic characteristics, such as growth, spreading and attachment of gastric cancer cells lines with wild-typep53.However enforced miR-140-5p expression increased the 5FUresistance in these cells, probably due to upregulated p21 and a relativelylow proliferation rate. miR-140-5p expression may reflect the activity of p53-dependent apoptosis whentumourcells aretreated with 5FU.In this condition, elevated miR-140-5p correlated with higher BAX expression andindicated a highly activated cell apoptosis signaling. The results presented in this study collectively suggest that miR-140-5p and miR-140-3p are involved in controlling the behaviorof gastric cancer cells,buttheir subtype- specificexpression pattern may reflect distinct cell conditions or responses. Several molecular signalingpathways regulated by miR-140-5p or miR-140-3p that may be responsible for these changes. This study found thatthe expression of miR-140-5p, in particular,could be used as a biomarker for identification of gastric cancer patients with higher malignant potential and for selection of gastric cancer patients who can benefit from the 5FUbased treatment, and also may be used for monitoring patients’ chemotherapy response.

Item Type: Thesis (MD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 13 September 2019
Last Modified: 13 Sep 2019 10:04
URI: http://orca-mwe.cf.ac.uk/id/eprint/125426

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