Cancer stem cells (CSCs), a critical subpopulation within tumors, drive cancer initiation, progression, metastasis, relapse, and resistance to therapy due to their innate capacity for self-renewal and differentiation. Although the molecular mechanisms controlling CSC biology are poorly understood, recent research highlights the pivotal regulatory role of non-coding RNAs—specifically long non-coding RNAs (lncRNAs)—in governing these processes.

Among these molecules, pseudogene-derived lncRNAs have garnered significant attention. Once dismissed as "genomic artifacts," these transcripts are now recognized as active regulators that structurally resemble conventional lncRNAs. In a recent Genes & Diseases review, researchers from Shahrekord University of Medical Sciences, Tehran University of Medical Sciences, and Babol University of Medical Sciences explore how these transcripts drive CSC dynamics across various cancers through miRNA sponging, antisense regulation, and protein interactions.
Pseudogene-derived lncRNAs can act through several mechanisms, predominantly as competitive endogenous RNAs (ceRNAs) that “sponge” microRNAs (miRNAs), preventing miRNAs from binding their target messenger RNAs and thereby influencing gene expression post-transcriptionally.

The review elucidates how these molecules hijack key signaling pathways—such as Wnt/β-catenin, PI3K/AKT, TGF-β, ERK, and JAK-STAT—that control CSC survival, proliferation, self-renewal, and differentiation to maintain the malignant phenotype. They can either promote or suppress these pathways via their ceRNA activity, altering the stemness characteristics of cancer cells.

The authors detail specific lncRNAs implicated in various malignancies. For example, CYP4Z2P and RPSAP52 enhance CSC traits in breast cancer and glioblastoma, respectively; notably, CYP4Z2P also promotes chemoresistance. In liver cancer, the RSU1P2/let-7a/Tex10 axis activates the Wnt/β-catenin pathway to drive CSC-related gene expression. Furthermore, PDIA3P1 interacts directly with the OCT4 protein in esophageal squamous cell carcinoma, preventing its degradation and establishing a positive feedback loop that sustains stemness.

In contrast, TPTEP1, GUSBP11, and AZGP1P2 suppress cancer stemness in glioma, triple-negative breast cancer, and prostate cancer, respectively. Other molecules, such as ZNF204P, promote stemness and are associated with poorer outcomes, while LPAL2 inhibits stemness in hepatocellular carcinoma.

Because the expression levels of these lncRNAs correlate with tumor grade and patient outcomes, they serve as high-value diagnostic and prognostic biomarkers. To investigate these roles, researchers employ an integrated pipeline of high-throughput RNA sequencing and bioinformatics, followed by validation via RT-qPCR and FISH. CRISPR/Cas9 or siRNA-mediated modulation is employed to define functional mechanisms, while biochemical assays—such as RIP and dual-luciferase reporters—map the molecular interactions and ceRNA activities that drive cancer stem cell properties.

In conclusion, this review provides a comprehensive synthesis of pseudogene-derived lncRNAs, discussing their biogenesis, associated signaling pathways, and their dual roles in modulating cancer stemness.

Reference

Title of the original paper: Emerging roles of pseudogene-derived lncRNAs in cancer stem cells: Non-coding clues and therapeutic targets in cancer medicine

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101793

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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