Cui Hengmi, Liu Yuan, Jiang Jingrui, Liu Yangyang, Yang Zhe, Wu Shaogen, Cao Wangsen, Cui Isabelle H, Yu Chenggong
Institute of Epigenetics and Epigenomics, Institute of Comparative Medicine and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu, China.
Laboratory of Epigenetics & Epigenomics, Medical School, Nanjing University, Nanjing, China.
Oncotarget. 2016 Jul 26;7(30):48456-48466. doi: 10.18632/oncotarget.10309.
Emerging evidence indicates that IGF2 plays an important role in various human malignancies, including colorectal cancer (CRC). Hsa-miR-483 is located within intron 7 of the IGF2 locus. However, the mechanism by which increased IGF2 induces carcinogenesis remains largely elusive. DLC-1 has been identified as a candidate tumor suppressor. In this study, we aimed at investigating whether miR-483 transcription is IGF2-dependent, identifying the functional target of miR-483, and evaluating whether tissue and serum miR-483-3p or miR-483-5p levels are associated with CRC. Our results showed that sequences upstream miR-483 had undetectable promoter activity and levels of IGF2, miR-483-3p, and miR-483-5p were synchronously increased in CRC tissues. Positive correlations between IGF2 and miR-483-3p (r=0.4984, ***p<0.0001), and between IGF2 and miR-483-5p (r=0.6659, ***p<0.0001) expression were found. In addition, patients with CRC had a significantly higher serum miR-483-5p level (*p<0.05) compared to normal controls. DLC-1 expression was decreased in colorectal cancer tissues and diminished through transient transfection with miR-483-3p. Our results suggest that IGF2 may exert its oncofunction, at least partly, through its parasitic miR-483 which suppressed DLC-1 in CRC cells. Thus, miR-483 might serve as a new target for therapy and a potential biomarker for the detection of colorectal cancer.
新出现的证据表明，胰岛素样生长因子2（IGF2）在包括结直肠癌（CRC）在内的多种人类恶性肿瘤中发挥重要作用。人miR-483位于IGF2基因座的第7内含子内。然而，IGF2增加诱导致癌作用的机制在很大程度上仍不清楚。DLC-1已被确定为候选肿瘤抑制因子。在本研究中，我们旨在研究miR-483转录是否依赖于IGF2，确定miR-483的功能靶点，并评估组织和血清中miR-483-3p或miR-483-5p水平是否与结直肠癌相关。我们的结果表明，miR-483上游序列的启动子活性检测不到，结直肠癌组织中IGF2、miR-483-3p和miR-483-5p水平同步升高。发现IGF2与miR-483-3p表达之间呈正相关（r=0.4984，***p<0.0001），IGF2与miR-483-5p表达之间呈正相关（r=0.6659，***p<0.0001）。此外，与正常对照组相比，结直肠癌患者血清miR-483-5p水平显著升高（*p<0.05）。结直肠癌组织中DLC-1表达降低，并通过用miR-483-3p瞬时转染而减少。我们的结果表明，IGF2可能至少部分地通过其寄生性miR-483发挥其致癌功能，miR-483在结直肠癌细胞中抑制DLC-1。因此，miR-483可能成为治疗的新靶点和结直肠癌检测的潜在生物标志物。
