Key Takeaways & Executive Findings
- •• • UCA1 is upregulated in DDP-resistant cervical cancer tissues and HeLa cells; its knockdown suppresses proliferation, migration, and invasion while increasing apoptosis, establishing UCA1 as a functional driver of the resistant phenotype. • • UCA1 acts as a ceRNA for miR-195-5p, targeting IKBKB; this axis upregulates p-p65 and BNIP3Δex2 and downregulates BNIP3, linking lncRNA-mediated NF-κB activation to apoptotic evasion. • • In subcutaneous xenografts, UCA1 silencing inhibits tumor growth, enhances apoptosis, and upregulates IKBKB, BNIP3Δex2, and p-p65 while downregulating BNIP3, confirming in vivo target engagement. • • The study was supported by the National Natural Science Foundation of China (No. 82160351) and Guizhou provincial grants, with no conflicts of interest declared, supporting translational credibility.
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Abstract
Cisplatin (DDP) resistance remains a principal determinant of poor prognosis in cervical cancer, with five-year survival at 16.5% for recurrent or advanced metastatic disease. The long noncoding RNA UCA1 is upregulated in DDP-resistant cervical cancer tissues and HeLa cells. Mechanistically, UCA1 functions as a competing endogenous RNA for miR-195-5p, thereby derepressing IKBKB. UCA1 knockdown suppresses proliferation, migration, and invasion while increasing apoptosis in DDP-resistant HeLa cells through the miR-195-5p/IKBKB axis. UCA1 upregulates BNIP3Δex2 and p-p65 and downregulates BNIP3 in DDP-resistant HeLa cells; forced changes in BNIP3Δex2 and BNIP3 expression significantly alter malignant progression of HeLa/DDP cells. In subcutaneous xenografts in nude mice, UCA1 silencing inhibits tumor growth, enhances apoptosis, and upregulates IKBKB, BNIP3Δex2, and p-p65 while downregulating BNIP3 via miR-195-5p targeting. These findings identify UCA1 as a promising therapeutic target for DDP-resistant cervical cancer.
1. Introduction
Cervical cancer remains the fourth most common malignancy among women, with 604,127 new cases and 341,831 deaths reported in 2020. Chemotherapy, particularly cisplatin (DDP), is the mainstay for advanced disease, yet acquired resistance severely limits efficacy and drives recurrence or metastasis. The five-year survival rate for patients with recurrent or advanced metastatic cervical cancer is only 16.5%, underscoring an urgent clinical need to define the molecular circuitry of DDP resistance.
Long noncoding RNAs (lncRNAs) regulate proliferation, metastasis, and apoptosis, and UCA1 is overexpressed in gastric, colorectal, and breast cancers, where it enhances DDP resistance. UCA1 also accelerates cervical cancer progression via SMARCD3 or miR-145, but its role in DDP-resistant cervical cancer was undefined. Bioinformatics predicted that miR-195-5p binds both UCA1 and IKBKB, and IKBKB overexpression activates NF-κB (p65) and modulates apoptosis-related genes. This study tests whether UCA1 drives DDP resistance through the miR-195-5p/IKBKB axis, providing a mechanistic basis for targeting UCA1 in chemoresistant cervical cancer.
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WANG Bi, LI Ling, WU Zhengyu, QIAN Xuanzhen, YU Wenfeng, HUANG Zhi (2025). Long noncoding RNA UCA1 knockdown inhibits cisplatin-resistant cervical cancer tumorigenesis via the miR-195-5p/IKBKB axis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025032
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Frequently Asked Questions
What is the direct molecular mechanism by which UCA1 confers cisplatin resistance in cervical cancer?
UCA1 acts as a competing endogenous RNA for miR-195-5p, reducing its availability and thereby increasing IKBKB expression. Elevated IKBKB activates NF-κB (p65), upregulates BNIP3Δex2, and downregulates BNIP3, shifting the balance toward proliferation, migration, invasion, and apoptosis resistance in DDP-resistant HeLa cells.
Does UCA1 knockdown alter tumor growth and apoptosis in vivo?
Yes. In subcutaneous xenografts in nude mice, UCA1 silencing inhibited tumor growth, enhanced apoptosis, and upregulated IKBKB, BNIP3Δex2, and p-p65 while downregulating BNIP3, confirming that the miR-195-5p/IKBKB axis is operative in vivo.
What is the clinical significance of the 16.5% five-year survival rate cited for recurrent or advanced metastatic cervical cancer?
It quantifies the poor prognosis of patients who develop DDP resistance and establishes the therapeutic unmet need. The study identifies UCA1 as a candidate target whose inhibition reverses the resistant phenotype, offering a potential strategy to improve outcomes in this high-risk group.
Which signaling components downstream of IKBKB are modulated by UCA1?
UCA1 upregulates BNIP3Δex2 and p-p65 and downregulates BNIP3 in DDP-resistant HeLa cells. Abnormal expression of BNIP3Δex2 and BNIP3 significantly alters malignant progression, indicating that these apoptosis-related effectors mediate the downstream consequences of UCA1-driven IKBKB activation.
What funding and conflict-of-interest disclosures support the credibility of this study?
The work was supported by the National Natural Science Foundation of China (No. 82160351), Guizhou Provincial Science and Technology Department Project (Guizhou Science Foundation-ZK(2021) General 458), Guizhou Science and Technology Plan Project “14th Batch of Outstanding Young Scientific and Technological Talents Program” Qian Ke He Platform Talents-YQK[2023]032, Guizhou Medical University Affiliated Hospital “2023 Outstanding Backup Talent in Discipline” gyfyxkrc-2023-06, and the Doctoral Start-up Fund of Guizhou Medical University gyfybsky-2021-27. The authors declare no conflict of interest.
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