According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains the top three leading cancer types in the United States. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from colorectal cancer by as much as 40- 50%, but adverse side effects resulting from cyclooxygenase (COX) inhibition and suppression of physiologically important prostaglandins limit their long-term use for cancer chemoprevention in the general population. Certain prescription strength NSAIDs such as sulindac and indomethacin are also effective for the treatment of precancerous adenomas in high risk individuals and can extend survival of patients with malignant disease. Our preliminary data show that sulindac can potently inhibit the invasion of human colon tumor cells, which suggests that such drugs could prevent metastatic progression in high risk groups. The mechanism appears to involve the inhibition of the transcription factor, NF-?B to suppress an oncogenic microRNA cluster, miR-17-92, and in turn, induce a tumor suppressor gene quaking (QKI), which can regulate cell adhesion. We show here that sulindac can induce QKI at concentrations that inhibit invasion of COX-2 null colon tumor HCT116 cells. In addition, we found that a novel non-COX inhibitory sulindac benzylamine (SBA) derivative could induce QKI that may potently inhibit the invasion of colon tumor cells. The proposed aims are to: 1) study the role of the miR-17-92/QKI axis in mediating anti-invasive activity of sulindac and SBA in vitro; and 2) determine if sulindac and SBA can inhibit tumor metastasis and the involvement of the miR-17-92/QKI axis 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 strong potential to impact human health by: 1) supporting clinical trials of sulindac for the prevention of metastatic progression in patients wit colorectal cancer; 2) evaluating a novel non-COX inhibitory derivative of sulindac for preclinical development; and 3) providing insight into ncRNA targets for the discovery of new biomarkers for clinical trials.
The long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to significantly reduce the incidence and risk of death from colorectal cancer; although their 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. In this application; we propose in vitro and in vivo studies to determine how miR-17-92 and a target gene; QKI; a tumor suppressor protein; are involved in the anti-invasive/metastatic activities of sulindac for the prevention of metastatic progression in high risk groups.
