MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9

Abstract

Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

miRNA‐215‐5p suppresses the aggressiveness of breast cancer cells by targeting Sox9

“…As revealed by our findings, miR-215-5p substantially suppressed not just the growth but also the migration and invasion of breast cancer cells. These findings were consistent with the previous report, in which miR-215-5p inhibits the progression of colon cancer by modulating epidermal growth factor receptor ligand and Homeobox protein Hox-B9 [20]. In contrast, miR-215-5p had the potential of inhibiting the mRNA and the protein expression of Protocadherin-9 in glioma cells through regulating its promoter and 3'-UTR [21].…”

“…The investigation of the fundamental function of miR‐215 in the progression of malignant tumors has been carried out in preclinical research . Herein, we discovered that miR‐215‐5p was significantly downregulated in breast cancer compared with noncancerous tissue.…”

miR-147a suppresses the metastasis of non-small-cell lung cancer by targeting CCL5

“…miRNAs are closely correlated with several tumors, including breast, gastric, ovarian, and colon cancers. [28][29][30][31] Previous investigations suggested that miR-147a plays a vital role in various cancers. 32,33 Nevertheless, the role of miR-147a in the growth and metastasis of NSCLC requires further investigation.…”

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication

“…Liu et al overexpressed miR‐15 in CRC cell lines by transfection and observed an increased chemo‐sensitivity of CRC cells to oxaliplatin and 5‐Fu . The tumors that were induced by miR‐215‐5p, miR‐152, miR‐124, and miR‐506 transfected cells grow significantly slower than control group in vivo models and cancer stem cells that express hsa‐miR‐140‐5p continuously failed to form tumors . In addition, lentivirus‐miR‐490‐3p transfected CRC cells that overexpress at stable rates of miR‐490‐3p demonstrated a decreased proliferation, migration, and motility in vitro and suppressed tumor growth in vivo .…”

“…There is increasing evidence that miRNAs are a novel CRC therapeutic candidate, although their use in decreasing the growth of cancer cells is based on in vitro and in vivo studies, it is hoped that miRNAs will become a tool for than control group in vivo models [92][93][94] and cancer stem cells that express hsa-miR-140-5p continuously failed to form tumors. 95 In addition, lentivirus-miR-490-3p transfected CRC cells that overexpress at stable rates of miR-490-3p demonstrated a decreased proliferation, migration, and motility in vitro and suppressed tumor growth in vivo.…”