According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains a leading cause of death from cancer in the United States. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from colorectal cancer, but adverse side effects resulting from cyclooxygenase (COX) inhibition and suppression of physiologically important prostaglandins limit their long-term use for chemoprevention. The NSAID, sulindac has been reported to be highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and has shown promising anticancer activity in preclinical animal models. Our preliminary data show that the sulfide metabolite of sulindac (SS) can potently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism appears to involve the inhibition of the transcription factor, NF-kB to suppress an oncogenic microRNA (miRNA) cluster, miR-17- 92, and induce a tumor suppressor protein, quaking (QKI) that plays an important role in regulating tumor cell adhesion and metastasis. Our results suggest that this mechanism might not require COX inhibition because a non-COX inhibitory derivative, sulindac sulfide amide (SSA) can apparently induce QKI and inhibit colon tumor cell invasion. SSA is appreciably more potent than SS as it has good oral bioavailability with a unique tissue distribution pattern to achieve high concentrations in lung and liver, two main sites of metastasis from colorectal cancer. We hypothesize that the mechanism by which sulindac inhibits tumor invasion is unrelated to its COX inhibitory activity;and the miR-17-92/QKI axis accounts or is partially responsible for this action. The proposed aims are to: 1) study the role of the miR-17-92/QKI axis in mediating anti-invasive activity of slindac in vitro;and 2) study the role of the miR-17-92/QKI axis in mediating anti-metastatic activity of sulindac in vivo. This application is being submitted in response to PA-12-214 and will address two research objectives: """"""""determine the molecular pathways targeted by non-coding RNAs (ncRNAs) that predispose to cancer initiation or progression"""""""" and """"""""determine whether interfering with oncogenic ncRNAs processing, target selection, or associated pathways prevent cancer progression"""""""". The proposed studies have the potential to impact human health by: 1) supporting the use of an FDA approved generic drug, sulindac, for the prevention of metastatic progression in patients with colorectal cancer;2) evaluating a novel non-COX inhibitory of sulindac to accelerate its preclinical development;and 3) providing insight into ncRNA targets for the discovery of new biomarkers for clinical trials.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from colorectal cancer, but their long-term use for chemoprevention is not recommended because of potentially fatal toxicities associated with cyclooxygenase inhibition. Our preliminary results show that the NSAID, sulindac, inhibits colon tumor cell invasion by a cyclooxygenase-independent mechanism involving the microRNA cluster, miR-17-92. We propose in vitro and in vivo studies to determine if miR-17-92 and a target gene that encodes for the tumor suppressor protein, quaking (QKI), are responsible for the anti- invasive/metastatic activities of sulindac with the goals of repurposing this drugs for the prevention of metastatic colorectal cancer in high risk patients and accelerating the development of experimental derivatives with potential for improved efficacy and reduced toxicity.
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