MiR-17 mediates sulindac anti-metastatic activity in human colorectal cancer

项目概要： 在美国，大约3%的癌症患者在退伍军人事务医疗中心接受治疗。 中心（VAMC），其中11%是结肠或直肠恶性肿瘤。结直肠癌（CRC）仍然存在 是美国癌症相关死亡的主要原因。尽管CRC患者的总生存率 在过去的几十年里，晚期疾病已经得到了显着改善，最近报道的5年 IV期CRC患者的存活率低于14%。到目前为止，只有少数药物被批准 用于治疗晚期CRC患者。沿着新的军事人员进入退伍军人事务部 系统，医生短缺，老年人的寿命延长，对VA医疗保健资源的需求是 变得重要。因此，开发更有效和更安全的治疗退伍军人患者的疗法， 可能是一个经济可行的战略，以抵消由于需求增加而对VAMC造成的压力 退伍军人医疗保险 非甾体类抗炎药（NSAID）已被证明可以显着降低发病率和风险 死于CRC和其他形式的癌症。特别是舒林酸， 用于通过减小尺寸来治疗家族性腺瘤性息肉病患者的癌前病变， 息肉的数量高达60- 70%。这些观察结果与许多临床前研究一致 这些研究表明舒林酸和其他非甾体抗炎药能够抑制各种实验动物的肿瘤发生 涉及早期或晚期疾病的模型。然而，与 环氧合酶/前列腺素（考克斯/PGE）抑制排除了长期使用NSAID治疗癌症 一般人群中的症状。我们的初步研究支持了一个新的观点，即低剂量的舒林酸 通过涉及选择的miRNA的非COX/PGE抑制机制抑制CRC细胞侵袭和转移。 令人感兴趣的是，首次发现外泌体miR-17- 5 p（ES-miR-17- 5 p）作为关键介质之一， 通过舒林酸靶向和调节以干预转移前的小生境形成。这些数据提供了一个 利用低剂量舒林酸预防和阻断CRC转移的潜力的创新见解 进展，尚未专门研究。我们假设ES-miR-17- 5 p与细胞凋亡密切相关。 参与低剂量舒林酸延迟和潜在阻断CRC远端的分子机制 转移提出了三个具体的目标，以追求我们的前提，以证明一个新的指示低 剂量舒林酸控制转移性CRC。在目的1中，我们将研究涉及ES-miR-17- 5 p的新机制 为了了解舒林酸在结直肠癌细胞运动中的抑制活性;在目标2中，我们将确定舒林酸在结直肠癌细胞运动中的作用。 利用动物模型，研究ES-miR-17- 5 p介导舒林酸体内抗转移活性;在目的3中，我们 将评估miR-17- 5 p在预测CRC标本样本的肿瘤进展中的临床效用。我们 我希望我们的研究能够支持一种有效和安全的选择，使患有晚期CRC的退伍军人受益， 最终改善VA医疗保健。

PROJECT SUMMARY: In the United States, approximately 3% of cancer patients are being treated in the Veterans Affairs Medical Centers (VAMCs) each year, of which 11% are colon or rectal malignancies. Colorectal cancer (CRC) remains a leading cause of cancer-related death in the United States. Although the overall survival for CRC patients with advanced disease has been dramatically improved over the past decades, the most recently reported 5-year survival rate for patients with stage IV CRC was lower than 14%. To date, there are only a few drugs approved by the FDA to treat CRC patients with advanced disease. Along with new military personnel entering the VA system, physician shortages, and extended lifespan of seniors, the demands on VA health care resources are becoming significant. Therefore, developing more efficacious and safer therapeutics for treating veteran patients could be an economical and feasible strategy to offset the pressure on the VAMCs due to the increasing needs for VA health care. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from CRC and other forms of cancer. Sulindac, in particular, has been shown to display strong efficacy for the treatment of precancerous lesions in patients with familial adenomatous polyposis by reducing the size and number of polyps as much as 60-70%. These observations are consistent with numerous preclinical studies that have shown the ability of sulindac and other NSAIDs to inhibit tumorigenesis in various experimental animal models involving either early or late-stage diseases. However, the cardiovascular toxicity associated with cyclooxygenase/prostaglandin (COX/PGE) inhibition precludes the long-term use of NSAIDs for cancer indications in the general population. Our preliminary studies support a novel notion that a low dose of sulindac inhibits CRC cell invasion and metastasis with non-COX/PGE inhibition mechanisms involving select miRNAs. Of interest, exosomal miR-17-5p (ES-miR-17-5p), for the first time, was found to act as one of the key mediators targeted and modulated by sulindac to intervene in pre-metastatic niche formation. These data provide an innovative insight into the potential of utilizing low dose sulindac to prevent and block CRC metastatic progression, which has not yet been studied exclusively. We hypothesize that ES-miR-17-5p is intimately involved in the molecular mechanism by which low dose sulindac can delay and potentially block CRC distant metastasis. Three specific aims are proposed in pursuit of our premise to demonstrate a new indication of low dose sulindac in control of metastatic CRC. In Aim 1, we will study a new mechanism involving ES-miR-17-5p in order to understand the inhibitory activity of sulindac in CRC cell motility; in Aim 2, we will determine the role of ES-miR-17-5p in mediating the in vivo anti-metastatic activity of sulindac utilizing animal models; in Aim 3, we will evaluate the clinical utility of miR-17-5p in predicting tumor progression with CRC specimen samples. We expect that our study can support an efficacious and safe option to benefit the veterans with advanced CRC and eventually improve the VA health care.