血浆miR-144作为肾癌早期诊断标志物的鉴定及其生物学功能和机制研究

Renal cell carcinoma (RCC) is a common malignant tumor of urologic system, of which about 80% is clear cell renal cell carcinoma (ccRCC).RCC is a highly malignant, easily diagnosis-missed and metastasis cancer. The key of clinical improvement of RCC lies on early diagnosis and treatment. However, RCC still lacks of simple, non-invasive biomarkers for early diagnosis and follow-up during therapy. The study of miRNAs opens a new window to seek tumor biomarkers. Our preliminary data have showed that preoperative plasma miR-144 of ccRCC patients is the only plasma miRNA whose level is significantly higher than miR-144 from its postoperative plasma , from benign renal tumor patients' and healthy people's plasma, and its plasma level will reduce to normal level postoperatively. Furtherfore, plasma miR-144 is the only miRNA highly expressed in both renal cancer tissue and preoperative ccRCC plasma. Based on our previous studies, we plan to further screen and verify ccRCC plasma miRNA biomarker candidates such as miR-144, and expect to set up miR-144 or other possible miRNA as RCC biomarker which can be easily used in RCC for early diagnosis, identification between benign and malignant tumors, and /or treatment follow-up. The study will help the clinical transiton of RCC biomarker such as plasma miR-144 and improving the level of RCC diagnosis and treatment in China.

肾细胞癌（RCC）是泌尿系常见恶性肿瘤，其中透明细胞癌（ccRCC）约占80%。RCC恶性程度高，容易漏诊和转移，提高RCC疗效的关键在于早期确诊和治疗。但是，迄今为止肾癌仍然缺乏简易、非侵袭性的早期诊断和治疗随访标志物。新近发现的miRNA为生物标志物的研究提供了一个新领域。我们前期的研究发现：血浆miR-144是ccRCC患者中唯一一个术前血浆水平显著高于术后、肾良性肿瘤和正常人水平的miRNA，其术后降至正常人水平；miR-144也是唯一一个在ccRCC组织与术前血浆中均高表达的miRNA。我们拟在此基础上，进一步筛选并验证血浆miR-144等miRNA成为RCC早期诊断、和/或鉴别肾脏良恶性肿瘤、治疗随访标志物的可能。为血浆miR-144作为RCC标志物的临床转化应用奠定基础，提高中国的肾癌诊治水平。

本课题旨在研究miR-144-3p、miR-224、miR-141在肾癌发生发展中的临床意义、生物学功能及其相应的分子机制。通过对不同患者血浆中miR-144-3p的检测，发现肾透明细胞癌(ccRCC)患者术前血浆miR-144-3p的含量显著高于术后; 此外，ccRCC患者术前血浆miR-144-3p含量也明显高于健康人血浆及泌尿系结石、错构瘤患者的术前血浆；肾透明细胞癌组织中的miR-144-3p含量也明显高于癌旁组织；而非透明细胞性肾细胞癌及肾错构瘤的组织miR-144-3p无此特异性。过表达miR-144-3p能显著增强肾癌细胞的增殖、侵袭、迁移能力；同时过表达miR-144-3p还能增强肾癌细胞对舒尼替尼的耐受性。另外，过表达miR-144-3p能明显下调肾癌细胞ARID1A的表达，且ARID1A在肾透明细胞癌组织中也普遍下调。我们检测到miR-224在肾透明细胞癌中明显上调，而miR-141在肾透明细胞癌中则下调显著。由miR-224 与miR-141相结合即miR-224/141，用于诊断ccRCC的准确性高至0.99，敏感性为97.06%，特异性提高为98.53%。因此，我们认为miR-224/141具有巨大的诊断ccRCC的潜能。