P53‐induced miR‐30e‐5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1

• Published in: International journal of cancer 2017-11, Vol.141 (9), p.1879-1890
• Main Authors: Laudato, Sara, Patil, Nitin, Abba, Mohammed L., Leupold, Joerg H., Benner, Axel, Gaiser, Timo, Marx, Alexander, Allgayer, Heike
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell adhesion; Cell adhesion & migration; Cell cycle; Cell Cycle Checkpoints - genetics; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Colon; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Gene Expression Regulation, Neoplastic; Genomes; HCT116 Cells; Homeostasis; Humans; Immune checkpoint; Integrin alpha6 - genetics; Integrins; Intracellular Signaling Peptides and Proteins - genetics; Medical research; Membrane Proteins - genetics; Metastases; Metastasis; Mice; MicroRNAs; MicroRNAs - genetics; Migration; miRNA; miR‐30e; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Metastasis; P53; p53 Protein; Proteins; Tissues; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30854

The tumor suppressor P53 is a critical regulator of normal cellular homeostasis whose function is either distorted or lost in several cancer types including colorectal cancer (CRC). A small group of microRNAs have come to be recognized as essential mediators of P53 function. In a genome‐wide systematic approach, we explored miRNAs that are substantially altered by P53 loss and found miR‐30e to be the most significantly deregulated miRNA in P53‐knockout human CRC cells. We identified miR‐30e‐5p to be a novel direct transcriptional target of P53 with gain and loss of function experiments revealing miR‐30e‐5p to be a significant regulator of tumor cell migration, invasion and in vivo metastasis mediated in part by integrins alpha‐6 and beta‐1 as novel targets. MiR‐30e‐5p also significantly reduced tumor cell proliferation by causing G1/S cell cycle arrest, which was achieved by inducing P21 and P27 expression. Finally, we found miR‐30e‐5p to be lost in resected CRC tumors as compared to normal colon tissues. Taken together, miR‐30e‐5p is a novel effector of P53‐induced suppression of migration, invasion and metastasis. What's new? The P53 tumor suppressor plays a critical role in preventing tumor development. To carry out its functions, it is suspected of interacting with select microRNAs (miRNAs). Here, members of the miRNA‐30 family, notably miR‐30e‐5p, were found to be downregulated in P53 knockout human colorectal cancer cells. MiR‐30e‐5p bound directly to integrins alpha‐6 and beta‐1, suppressing cancer cell adhesion, migration, and invasion. Moreover, enhanced miR‐30e‐5p expression inhibited cell proliferation by upregulating cell cycle checkpoint inhibitor proteins P21 and P27, even in the absence of P53. The findings identify miR‐30e‐5p as a potential target for curbing metastatic spread in P53‐deficient tumors.