MicroRNAs in HPV-induced cervical cancer A multidimensional approach

Cervical cancer, driven by persistent high-risk HPV (hrHPV) infection and (epi)genetic alterations in host cells, is a significant public health burden. While miRNAs have emerged as key regulators in various cancers, their precise roles in cervical carcinogenesis and their influence on treatment sensitivity are not yet fully understood.
This thesis aims to comprehensively explore the role of miRNAs in cervical carcinogenesis and their potential clinical applications in enhancing cancer treatment and non-invasive biomarker discovery through urine sampling.
In Chapters 2 and 3, we investigated the roles of miR-193a/b-3p and miR-129-5p in regulating key oncogenic processes, specifically anchorage-independent growth, a hallmark of malignant transformation. Using computational and laboratory approaches, we identified and validated target genes regulated by these miRNAs.
In Chapter 4, we examined the therapeutic potential of miRNAs in sensitizing locally advanced cervical cancers to thermoradiotherapy. High-throughput screenings of 14 cancer cell lines, followed by functional analyses of six miRNAs, demonstrated their ability to enhance sensitivity to thermoradiotherapy by inhibiting DNA damage repair mechanisms, specifically downregulating key repair proteins such as ATM, DNA-PKcs, Ku70/80, and RAD51.
In Chapter 5, we evaluated urinary miRNAs as non-invasive biomarkers for cervical cancer detection. Through a systematic comparison of four miRNA isolation methods across different urine fractions, we identified the optimal approach using digital nanoplate PCR (dPCR). Small RNA sequencing (IsoSeek) revealed that cervical cancer patients had lower urinary concentrations of let-7a and let-7e compared to healthy controls. These findings were validated in an independent cohort using dPCR.