A novel antisense lncRNA, LPCRL, functions as a molecular scaffold for the USP15/MIB1 complex to promote primary cisplatin resistance and tumor progression in lung squamous cell carcinoma.

Background: Platinum-based chemotherapy remains the first-line treatment for advanced lung squamous cell carcinoma (LUSC), but its efficacy is often hindered by the development of chemoresistance. Although long noncoding RNAs (lncRNAs) are recognized as regulators of tumor progression and drug resistance, the functional contribution of natural antisense transcripts (NATs), a major subclass of lncRNAs involved in cisplatin resistance in LUSC, remains poorly understood.

Methods: Patient-derived xenograft (PDX) models of LUSC were established and treated with cisplatin to identify cisplatin-resistant and cisplatin-sensitive tumor tissues. LncRNA microarray profiling was used to identify transcripts associated with cisplatin resistance. The functional role of a candidate lncRNA, termed LPCRL (LUSC primary cisplatin resistance-associated LncRNA), was assessed in vitro via MTT, flow cytometry, colony formation, and Transwell migration assays. Its effects on tumor growth and metastasis were further validated in vivo. Mechanistic insights were gained through RNA pull-down, silver staining, RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), and Western blot analyses. Finally, the therapeutic potential of LPCRL-targeting siRNA was assessed in a LUSC PDX model.

Results: We found that LPCRL was significantly upregulated in primary cisplatin-resistant PDX tissues. Functionally, LPCRL promoted primary cisplatin resistance and enhanced the proliferation and migration of LUSC cells both in vitro and in vivo. Mechanistically, LPCRL functions as a molecular scaffold to facilitate the interaction between MIB1 and USP15. This complex enables USP15 to deubiquitinate MIB1, thereby increasing MIB1 stability and promoting its nuclear export. The subsequent cytoplasmic accumulation of MIB1 enhances the ubiquitination of DLL4, leading to Notch pathway activation and upregulation of the downstream effector HES1. Importantly, intratumoral administration of LPCRL-targeting siRNA in PDX models suppressed tumor growth and sensitized tumors to cisplatin in vivo.

Conclusions: Our study revealed that LPCRL promotes LUSC malignancy and cisplatin resistance via the USP15/MIB1/Notch axis, highlighting LPCRL as a promising therapeutic target.