1. Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato (CA), Italy;
2. Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43-b, 07100 Sassari, Italy;
3. Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy;
4. CRS4, Science and Technology Park Polaris, Piscina Manna, 09010 Pula, CA, Italy;
5. Department of Pathology, AOU Sassari, Via Matteotti 60, 07100 Sassari, Italy;
6. Department of Prevention, Registro Tumori Provincia di Sassari, ASSL Sassari-ATS Sardegna, Via Rizzeddu 21, Sassari, Italy;
7. Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, Via Bazzoni-Sircana, 07026 Olbia, Italy.
*These two authors contributed equally to this work.
Colorectal cancer (CRC) is a leading cause of cancer death worldwide and about 20% is metastatic at diagnosis and untreatable. The anti-EGFR therapy in metastatic patients is led by the presence of KRAS-mutations in tumor tissue. KRAS-wild-type CRC patients showed a positive response rate of about 70% to cetuximab or panitumumab combined with chemotherapy. MiRNAs are promising markers in oncology and could improve our knowledge on pathogenesis and drug resistance in CRC patients. This class of molecules represents an opportunity for the development of miRNA-based strategies to overcome the ineffectiveness of anti-EGFR therapy.
We performed an integrative analysis of miRNA expression profile between KRAS-mutated CRC and KRAS-wildtype CRC and paired normal colic tissue (NCT). We revealed an overexpression of miR-425-5p in KRAS-mutated CRC compared to KRAS-wild type CRC and NCT and demonstrated that miR-425-5p exerts regulatory effects on target genes involved in cellular proliferation, migration, invasion, apoptosis molecular networks. These epigenetic mechanisms could be responsible of the strong aggressiveness of KRAS-mutated CRC compared to KRAS-wildtype CRC. We proved that some miR-425-5p targeted genes are involved in EGFR tyrosine kinase inhibitor resistance pathway, suggesting that therapies based on miR-425-5p may have strong potential in targeting KRAS-driven CRC. Moreover, we demonstrated a role in the oncogenesis of miR-31-5p, miR-625-5p and miR-579 by comparing CRC versus NCT.
Our results underlined that miR-425-5p might act as an oncogene to participate in the pathogenesis of KRAS-mutated CRC and contribute to increase the aggressiveness of this subcategory of CRC, controlling a complex molecular network.
Keywords: Colorectal carcinoma, KRAS mutation, miR-425-5p expression levels, DICER1 gene, TNFRSF10B gene, PTEN gene.