Expression and functional properties of selected miRNAs in human cancer tissue and cancer cell lines

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) involved in the regulation of gene expression, and they are often seen dysregulated in cancer. For this reason, it is of great scientific interest to study these ncRNAs to better understand their distribution in human tissues and their mode of function. Based on a comprehensive miRNA microarray from 108 breast cancers in the Norwegian Woman and Cancer Study and 44 healthy controls, this thesis sought to investigate tissue expression and functional properties of the miRNA cluster miR-143/145 in breast- and lung cancer tissues and cell lines, as well as miR-126 in breast cancer (BC) tissue and cell lines.

Our analysis found the miR-143/145 cluster to be downregulated in tumor samples from both breast and lung, as well as in their corresponding cancer cell lines. The transfection of miR-143 into a number of cancer cell lines from both breast and lung, promoted proliferation in some, whilst having opposite or no effect in others. In contrast, all cell lines suffered inhibition in both proliferation and migration when transfected to miR-145.

In BC tissue, expression of miR-143 and miR-145 was lower in malignant compared to benign breast tissue, and lower in the more aggressive tumors. Interestingly, miR-145 was mainly expressed in the myoepithelial cells of benign breast tissue, and at the subcellular level located to the nuclei. In lung cancer tissue, expression of the miR-143/145 cluster was found to correlate with expression of several sex steroid hormone receptors. Also, stromal expression of miR-143 was an independent positive prognostic factor in female patients, whereas stromal expression of miR-145 was associated with improved disease specific survival for male patients.

Both miR-126-3p and its passenger strand, miR-126-5p, was verified as downregulated in BCs as well as in all tested BC cell lines. The passenger strand had a strong proliferation promoting effect in the most aggressive BC cell line, whilst having the opposite effect in the other cell lines. The introduction of miR-126-3p resulted in decreased proliferation and invasion in all BC cell lines. In BC tissue, expression of miR-126-5p was significantly higher in high grade tumors, and both miR-126 strands were downregulated in lymph node positive BCs when compared to tumors with no nodal involvement.

This thesis depicts interesting findings, and ads new knowledge into function, expression and distribution of a selected few miRNAs in breast- and lung cancer. Their duplicitous properties described throughout this work, contributes new insight into their complex mode of action, and is likely to gain more attention in the future.