MiR-338-5p Promotes Metastasis of Colorectal Cancer by Inhibition of Phosphatidylinositol 3-Kinase, Catalytic Subunit Type 3-Mediated Autophagy Pathway

Abstract

Background: In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo. Methods: The potential clinical relevance of miR-338-5p and its target gene was analyzed on benign colorectal polyp and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis. Findings: PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumor staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/ PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumors. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumors. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration induced by miR-338-5p. Interpretation: MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients. Funding Statement: This work was supported by research grants [NCKUH-10704015] from National Cheng Kung University Hospital (Tainan, Taiwan) and [MOST-105-2320-B-006 -029 -MY3] from the Ministry of Science and Technology, TAIWAN. Declaration of Interests: The authors declare that they have no competing financial interests. Ethics Approval Statement: This study was approved by the NCKUH Institutional Review Board (B-ER-103-031). Informed consent was signed by all patients.