Pseudogene lncRNAs regulate cancer stem cell behavior and signaling

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.