Cervical Cancer Treatment Resistance: The Role of Long Noncoding RNAs and Their Potential as Targets
Hidden Drivers of Treatment Resistance
Long noncoding RNAs (lncRNAs) in cervical cancer can increase either treatment resistance or treatment sensitivity, depending on the type. A review published in Frontiers in Cell and Developmental Biology summarizes the regulatory mechanisms of lncRNAs associated with resistance to anticancer drugs, radiation, and immunotherapy, as well as their potential as therapeutic targets. It synthesizes existing research rather than demonstrating new treatment efficacy in experiments or clinical trials.
How lncRNAs Regulate Resistance
Some lncRNAs act as competing endogenous RNAs (ceRNAs), binding microRNAs (miRNAs) with tumor-suppressive functions. This can weaken the miRNAs’ ability to suppress the expression of their target genes. The review explains that this regulation and changes in signaling pathways such as PI3K/Akt and Wnt/β-catenin are linked to cancer-cell survival and treatment resistance.
Not all lncRNAs increase resistance. MEG3 and CASC2, discussed in the review, increased expression of the tumor suppressor PTEN through interactions with miR-21, acting to increase cervical cancer cells’ sensitivity to cisplatin. Candidate targets therefore need to be selected with attention to each lncRNA’s function and direction of action.
DNA repair also contributes to radiation resistance. In cell research cited by the review, LINP1 was reported to bind key proteins in the non-homologous end joining (NHEJ) pathway, helping repair DNA double-strand breaks and reducing radiosensitivity. This does not mean that the efficacy of LINP1-targeted treatment has been validated in patients.
New Treatment Strategies and Challenges for Clinical Use
The review discusses strategies to inhibit lncRNAs or regulate their expression using antisense oligonucleotides (ASOs) and CRISPR-based tools. It also considers the potential use of lncRNAs detectable in patients’ serum or plasma as noninvasive diagnostic or prognostic biomarkers. However, detectability must be distinguished from clinical usefulness as a test. Assays and interpretation criteria still need to be standardized, and reproducibility must be verified across diverse patient groups.
lncRNA-targeted therapies also remain research-stage approaches requiring evaluation of delivery to tumor tissue, off-target effects, and long-term safety. Immunogenicity is another challenge identified for CRISPR-based strategies. This review cannot establish how much such approaches would reduce treatment resistance or patient relapse rates. The authors propose large prospective studies to assess the clinical utility of biomarkers and the safety and efficacy of targeted interventions.
Source: Full review available in Europe PMC
Despite significant advances in preventive and early-detection strategies, cervical cancer (CC) continues to pose a substantial clinical burden, especially when confronting the challenge of therapy-resistant or recurrent disease. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the development and progression of CC, particularly in mediating resistance to conventional and emerging therapies, including chemotherapy, radiotherapy, and immunotherapy. This review summarizes how specific lncRNAs drive therapeutic resistance through diverse mechanisms such as acting as competitive endogenous RNAs (ceRNAs) to sponge tumor-suppressive microRNAs, and by modulating key signaling pathways like PI3K/Akt and Wnt/β-catenin. Furthermore, we discuss the significant potential of lncRNAs as non-invasive diagnostic and prognostic biomarkers, detectable in liquid biopsies from patient serum or plasma, and as novel therapeutic targets. Advances in targeted strategies have primarily focused on the implementation of precise degradation or interference through antisense oligonucleotides (ASOs) and CRISPR-based systems, highlighting the translational potential of lncRNAs in overcoming refractory therapeutic resistance. Collectively, this review aims to provide a comprehensive overview of the multifaceted roles of lncRNAs in CC therapeutic resistance, offering critical insights that may accelerate the translation of lncRNA-based strategies into clinically actionable interventions to improve patient outcomes in therapy-resistant CC.
This review can help researchers studying cervical cancer treatment resistance distinguish which lncRNAs to inhibit and which lncRNAs’ functions to restore. For biomarker development, prospective studies could use repeated blood sampling during treatment to track changes in lncRNAs and their association with actual treatment response. A marker that helps diagnose cancer should not be assumed to predict treatment response as well. Assays and interpretation criteria need to be standardized, and predictive performance must be assessed across diverse patient groups. The available evidence supports these research directions, but does not establish that changing treatment based on test results improves patient outcomes.