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Short and long transcripts variant of KRAS at 3'UTR region as genetic biomarkers in glioblastoma

Samantha Messina, Department of Human, Social and Health Sciences, University of Cassino and Southern Lazio, Italy.
Candida Zuchegna and Antonio Porcellini, Department of Structural and Functional Biology, "Federico II" University of Naples, Naples, Italy.

3'UTR shortening has been established as a key mechanism of oncogene activation and has demonstrated promising potential as a prognostic marker. Generally, rapidly proliferating cells preferentially express mRNAs with shortened 3′UTRs. As a general mechanism, the shortening of 3'UTRs enables key genes to escape microRNA repression, thus leading to higher expression and promoting proliferation. The KRAS gene is an important regulator of cellular proliferation and its 3'UTR region has recently attracted attention as genetic biomarkers predictive for prognosis, diagnosis and treatment of many cancers. mRNA transcripts of the KRAS gene differing in the lengths of their 3' untranslated regions (UTRs) are reported but their function is still largely unknown. In contrast to the well-studied SNP and MRE, the properties and dynamics of the emerging shortening 3’UTR remain elusive. Brain tumours are KRAS-driven cancer and the active involvement of KRAS in oncogenesis or resistance to therapies is now well documented. We investigated whether 3′UTR shortening can produce biologically relevant stratification of glioma cancers. Here, we report transcriptional analysis with specific primers for long and short transcripts of the KRAS gene at 3’UTR region. We measured differential expression of three transcript variants at 3'UTR respectively in size of 5.2 kb, 1.2 kb and 2.3 kb across a panel of primary and established cultures of human glioblastoma. Glioblastoma multiforme cases exhibited significantly higher KRAS mRNA levels compared to established cultures. Moreover, expression of long transcript variant correlates with reduced aggressiveness in primitive tumours and mitogenic stimulation induced preferentially this variant in almost all samples. Further analysis will determine its potential functional role as genetic biomarker in predicting glioblastoma outcome.

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