Long non-coding RNA LOC101926915-encoded micropeptide carboplatin-induced upregulation factor confers carboplatin resistance in ovarian cancer.

OBJECTIVE

While carboplatin remains a cornerstone chemotherapeutic agent for ovarian carcinoma, the emergence of resistance constitutes a major contributor to therapeutic failure and compromised clinical outcomes. This study elucidates molecular mechanisms driving carboplatin resistance and identifies novel therapeutic targets for carboplatin-refractory malignancies through characterization of a long non-coding RNA (lncRNA)-encoded micropeptide.

MATERIAL AND

METHODS

Ribosome profiling analysis delineated translational alterations induced by carboplatin in ovarian cancer models. Mechanistic validation was achieved through the integration of gain- and loss-of-function methodologies, nuclear localization assays, and quantitative assessment of deoxyribonucleic acid (DNA) damage through enumeration of gamma-H2AX (phosphorylated histone H2AX at serine 139) foci, supplemented by alkaline comet analysis. The therapeutic significance was corroborated using subcutaneous xenograft models derived from patient-derived ovarian cancer cells.

RESULTS

The micropeptide carboplatin-induced upregulation factor (CARUF), derived from lncRNA LOC101926915, was markedly upregulated in response to carboplatin treatment, with ribosome profiling showing significant enrichment of ribosome-associated LOC101926915 transcripts (adjusted P < 0.01 and log2FC >1). In clinical specimens, elevated CARUF expression was positively correlated with platinum resistance (r = 0.425, P < 0.001). Functional analyses showed that CARUF overexpression promoted DNA damage repair (P < 0.001) and enhanced carboplatin resistance both in vitro and in vivo (P < 0.001). In contrast, CARUF inhibition impaired DNA damage repair (P < 0.001) and restored carboplatin sensitivity (P < 0.001), resulting in reduced cell viability in vitro (P < 0.001) and suppressed tumor growth in vivo (P < 0.001). Mechanistically, carboplatin-induced DNA lesions activated ataxia-telangiectasia mutated and Rad3-related (ATR) kinase, which phosphorylated CARUF, facilitated its localization to DNA lesion sites, and enhanced DNA repair capacity.

CONCLUSION

Our findings identify CARUF as a critical mediator of aberrant DNA damage response signaling in carboplatin-resistant ovarian cancer, indicating its potential as a druggable target for overcoming carboplatin resistance.