Background:

MicroRNA (miRNA)-503 is known to be down-regulated in several types of cancer, including oral, hepatocellular, gastric, and endometrial, suggesting that it plays a tumor-suppressor role in carcinogenesis. In contrast, other recent reports have demonstrated up-regulation of miR-503 in adrenocortical carcinoma, parathyroid carcinoma, and retinoblastoma, compared with adjacent normal tissues. Collectively, miR-503 shows tissue- or disease-specific expression patterns. However, to the best of our knowledge, miR-503 expression pattern, its clinical significance and molecular mechanism in colorectal cancer (CRC) have not been investigated.

Materials and Methods:

We analyzed miR-503 expression in a subset of 69 tissue samples from normal colonic mucosa (n = 20), adenoma (n = 29) and CRC (n = 20). Next, we further quantified miR-503 expression in a larger, independent cohort, which included CRC tissues from 181 patients, and investigated the clinical significance of miR-503 in CRC. In addition, CRC cell lines were transfected with anti-miR against miR-503 for the assessment of its function.

Results:

MiR-503 expression stepwise increased according to adenoma-carcinoma sequence, and its expression in adenoma and CRC was significantly higher than that in normal colonic mucosa, respectively (adenoma: p = 0.001, CRC: p<0.0001). MiR-503 expression gradually increased according to TNM stage. High expression in CRC were significantly associated with large tumor size (>40mm), high grade of T stage (T3/4), lymphatic and venous invasion positive and lymph node metastasis. In addition, Kaplan Meier survival curves revealed that the CRC patients with high miR-503 expression were significantly poorer disease free survival (DFS) and overall survival (OS) than that with low expression, respectively (DFS: p = 0.01, OS: p = 0.003). Our in vitro study demonstrated that attenuated miR-503 expression resulted in inhibition of proliferation, invasion and migration capacity of CRC cell lines and acquiring capacity of anoikis.

Conclusions:

We, for the first time, demonstrated that miR-503 in CRC acts as onco-miRNAs that is supported by several evidences from our in vitro analysis and clinical data. MiR-503 is significantly associated with malignant potential of CRC and can be biomarkers for predicting early recurrence and poor prognosis in patients with CRC.

Citation Format: Yuji Toiyama, Takahito Kitajima, Hiroki Imaoka, Mikio Kawamura, Hiroyuki Fujikawa, Junichiro Hiro, Susumu Saigusa, Minako Kobayashi, Toshimitsu Araki, Masaki Ohi, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Masato Kusunoki. MicroRNA-503 promotes tumor progression and acts as a novel biomarkers for early recurrence and poor prognosis in human colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3411. doi:10.1158/1538-7445.AM2015-3411