The aim of the project proposed by prof. Jażdżewski and his team is to elucidate the role of microRNA sequence variations in response to cancer treatment. MicroRNAs are short, non-coding RNAs that regulate the expression of protein-coding genes binding to complementary sequences in their transcripts and inhibiting further steps of protein synthesis. Changes in the levels of microRNAs lead therefore to deregulation of numerous genes, disrupting the physiological course of important cellular processes. Expression of microRNAs is highly tissue-specific and its alterations are observed in numerous pathologies. Numerous studies have revealed a great potential of microRNAs as prognostic and diagnostic tools in cancer, resulting from highly informative status of their expression profiles. In addition, changes in microRNA levels occur in early stages of carcinogenesis, allowing for detection of cancer during its initiation.
Studies on the role of microRNAs in pathogenesis of human cancers have been mainly focused on quantitative differences, i.e. on a search for differences in microRNA expression profiles between cancerous and normal, non-cancerous tissue. However, recent studies revealed that changes in the nucleotide sequence and length of microRNAs could be of no lesser importance in determination of their role in both predisposition to cancers and in the pathogenesis of carcinogenic process. Prof. Jażdżewski was among the first scientists to show that a single nucleotide polymorphism in a gene coding for a microRNA results in production of two alternative mature microRNAs that exhibit different expression levels and regulate distinct sets of target genes, thus their biological roles differ significantly. Subsequent association study showed that the discovered polymorphism predisposes to papillary thyroid carcinoma (PTC), which is the most common malignancy of the thyroid gland. Although approximately half of all the PTC cases are associated with RET/PTC rearrangements, resulting in aberrant RET/PTC-RAS/BRAF signalling, detailed molecular mechanisms underlying initiation and progression of thyroid carcinogenesis remain to be elucidated.
As can be therefore concluded, the proper understanding of the role of microRNAs in initiation and progression of cancer requires comprehensive information on the levels and nucleotide sequence of all the microRNAs present in a particular tissue type and aberrant in cancer. To achieve this, the team will employ next-generation deep sequencing to analyze the whole transcriptome of normal thyroid and papillary thyroid carcinoma. Next-generation sequencing is an innovative method allowing for simultaneous analysis of the sequence and expression levels of genes. In the first stage of the project dr Jażdżewski team will determine and quantitate all the microRNAs that are expressed in the thyroid tissue, including isoforms of already known microRNAs as well as novel, previously unknown microRNA molecules. By running a comparison between normal and PTC tissue expression profiles the team will identify microRNAs whose expression is aberrant in cancer. For all such microRNAs the team will determine putative target genes, and their direct interactions will be confirmed experimentally. The completion of this part of the project will result in elucidation of the role of microRNAs in pathogenesis of papillary thyroid carcinoma and identification of microRNA expression signatures, specific for this cancer.
The next stage of the project will be focused on the search of correlation between microRNA expression profiles and genetic changes occurring in PTC patients with clinical outcome of the disease, what will result in elucidation of each patient’s genetic background. This information will serve as an important step towards personalized medicine, in which the knowledge of the molecular background of a disease allows for estimation of chances of successful treatment and for the design of specific therapies, tailored to the needs of a particular patient.