(P 136) TARGETING MIR-138-5P TO TREAT DEDIFFERENTIATED LIPOSARCOMA

Objective: Dedifferentiated liposarcoma (ddLPS) is an aggressive cancer originating from fat cells with a five-year survival rate of only 15-20%. Despite surgical interventions, the recurrence and systemic therapy failure rates remain high. This underscores the urgent need for innovative biomarkers and therapeutic strategies. In this context, microRNAs (miRNAs) emerge as pivotal regulators of gene expression with significant implications in cancer biology. Among them, miR-138-5p, traditionally recognized as a tumor suppressor in various cancers, displays an intriguingly contradictory role in ddLPS. We have identified upregulation of miR-138-5p in ddLPS tissue, positing a potential oncogenic function contrary to its known suppressive effects in other malignancies. Notably, miR-138-5p expression in ddLPS correlates with worse overall survival, suggesting its potential as a prognostic biomarker and therapeutic target in this malignancy.

Methods: We sequenced small RNAs from 12 ddLPS samples and 9 normal fat tissues. After scaling raw counts to reads per million and log2-transforming, differential expression was analyzed using the Limma R package. Dysregulated sncRNAs were identified with |Log2FC| > 0.58 and adjusted P.val < 0.05. The survival R package carried out survival analysis on the ddLPS of the internal cohort (n=24) and external cohort retrieved from TCGA (n=58). Functional inhibition of miR-138-5p was performed in ddLPS Lipo863 and Lipo815 cell lines, followed by colony formation, transwell migration, and cell cycle assays. To identify the miR-138-5p mRNA target, we will utilize the miR-eClip sequencing approach.

Results: Compared to normal adjacent fat, we identified dysregulation of sncRNAs in ddLPS, including pronounced upregulation of miR-138-5p. Notably, there was a significant association between high expression of miR-138-5p (over the median) and poorer overall survival both in the internal (P val=0.076) and external cohort (P.val=0.0014). Inhibition of miR-138-5p significantly decreased colony formation and migration in these cells. Slight changes in the cell cycle were observed after miR-138-5p inhibition.

Conclusion: Our research highlights the critical role of miR-138-5p, in ddLPS biology. Validated findings from internal and external cohorts emphasize miR-138-5p's potential as a prognostic biomarker and therapeutic target in ddLPS. Inhibition experiments demonstrated the therapeutic promise of targeting miR-138-5p to attenuate ddLPS growth. Our findings offer new avenues for effective therapeutic interventions and improved patient outcomes in ddLPS.