In the relentless quest to unravel the molecular intricacies of cancer, a groundbreaking study has recently revealed an unexpected culprit in the progression of thyroid cancer: a previously obscure long non-coding RNA (lncRNA) named PICSAR. This novel RNA molecule has been implicated in enhancing tumor growth and aggressiveness by orchestrating a complex regulatory network involving microRNAs and a pivotal signaling protein. The findings, published in the latest issue of Medical Oncology, shed new light on the fundamental biology of thyroid malignancies and open the door to innovative therapeutic strategies targeting RNA-based molecular pathways.
Thyroid cancer, one of the most common endocrine malignancies worldwide, has demonstrated rising incidence rates over recent decades. Despite advances in diagnosis and treatment, challenges remain, particularly concerning aggressive and metastatic forms of the disease. Molecular studies have previously focused on protein-coding genes and genetic mutations; however, the non-coding portions of the genome, which constitute the majority of RNA transcripts in cells, are increasingly recognized for their regulatory roles in cancer development. Among these, long non-coding RNAs — transcripts longer than 200 nucleotides that do not encode proteins — have emerged as versatile modulators of gene expression and cellular function.
The team of researchers led by Hejazi et al. embarked on an in-depth molecular investigation to identify novel lncRNAs implicated in thyroid cancer progression. Utilizing high-throughput RNA sequencing and rigorous bioinformatics analysis, they isolated PICSAR as a significant player upregulated in thyroid tumor tissues relative to normal counterparts. PICSAR’s notoriety had been hinted at in other cancers, but its role in the thyroid had remained elusive — until now.
Further functional assays delineated the biological impact of PICSAR overexpression on thyroid cancer cells. These cells exhibited enhanced proliferation, migration, and invasion capabilities, hallmark traits of aggressive oncogenic behavior. Conversely, silencing PICSAR expression curtailed these malignant phenotypes, underscoring the lncRNA’s driving role in tumour pathophysiology. The mechanistic underpinnings of PICSAR’s influence necessitated further elucidation, prompting the exploration of its downstream molecular partners.
A hallmark discovery within this study was PICSAR’s modulation of the hsa-miR-320A and hsa-miR-485 microRNAs — small non-coding RNA molecules that typically suppress gene expression by binding messenger RNA transcripts. Intriguingly, PICSAR appears to function as a competitive endogenous RNA, effectively sponging these microRNAs and preventing them from targeting their usual mRNA substrates. This ceRNA (competing endogenous RNA) activity frees certain genes from microRNA-mediated repression, altering cellular signaling landscapes.
The key gene unlocked from microRNA suppression in this axis is RAPGEFL1, a guanine nucleotide exchange factor known to regulate intracellular signaling involved in cell adhesion, migration, and proliferation. Dysregulation of RAPGEFL1 has been implicated in various cancers, but its integration within a lncRNA/microRNA regulatory module represents a novel insight. By binding and sequestering hsa-miR-320A and hsa-miR-485, PICSAR indirectly elevates RAPGEFL1 expression, thereby fueling oncogenic signaling pathways that drive thyroid cancer progression.
At the molecular level, RAPGEFL1 activates downstream effectors in cell signaling cascades such as those mediated by Rho family GTPases, which govern cytoskeletal dynamics and cellular motility. The overactivation of these pathways often correlates with enhanced metastatic potential, offering a plausible explanation for the aggressive behaviors observed in PICSAR-overexpressing thyroid cancer cells. These molecular interplays highlight the multifaceted role of non-coding RNAs beyond mere transcriptional noise and emphasize their functional importance in cancer biology.
To validate their findings, the researchers employed in vivo models where modulation of PICSAR expression significantly influenced tumor growth rates and metastatic dissemination. These results confirmed the in vitro data and reinforced the potential of targeting the PICSAR/hsa-miR-320A/hsa-miR-485/RAPGEFL1 axis as a therapeutic avenue. Importantly, the study suggests that the inhibition of PICSAR or restoration of microRNA function could stymie thyroid cancer aggressiveness and improve patient outcomes.
The implications of this research are profound. Firstly, PICSAR could serve as a novel biomarker for thyroid cancer diagnosis or prognosis, enabling clinicians to identify high-risk patients who may benefit from more intensive treatment regimens. Secondly, pharmacological agents designed to disrupt lncRNA-microRNA interactions or mimic microRNA activity stand as promising therapeutic strategies in an era increasingly focused on precision medicine and RNA-based interventions.
Moreover, this study underscores the necessity of broadening our molecular investigations beyond the traditional protein-centric paradigms. Non-coding RNAs, once considered “junk” or transcriptional noise, are proving to be master regulators intricately woven into the cellular fabric. Their ability to coordinate complex regulatory networks provides cancer cells with versatile mechanisms to adapt, survive, and proliferate under diverse conditions.
The technological advancements that facilitated this discovery, including high-throughput sequencing, CRISPR interference, and advanced computational modeling, will undoubtedly accelerate the identification of similar regulatory axes in other cancers. As the catalog of functional lncRNAs expands, so too does the potential for exploiting these molecules as diagnostic and therapeutic targets, revolutionizing oncology practices across many tumor types.
Looking forward, it will be critical to elucidate whether PICSAR expression patterns correlate with clinical parameters such as tumor stage, metastasis, patient survival, and response to existing therapies. Integrating molecular profiling with clinical data could foster the development of predictive models and personalized treatment strategies. Additionally, evaluating the safety and efficacy of lncRNA-targeted interventions in preclinical and clinical trials remains a priority.
From a broader perspective, the discovery of the PICSAR axis adds an exciting chapter to the burgeoning field of RNA medicine. RNA molecules are uniquely positioned to act as both disease drivers and therapeutic tools, with modalities such as antisense oligonucleotides, small interfering RNAs, and RNA aptamers already making inroads in clinical applications. PICSAR, as part of this versatile family, may soon transition from a molecular curiosity to a clinical target.
In summary, the identification of PICSAR and its regulatory network underscores the complexity and elegance of cancer biology, revealing how lncRNAs orchestrate oncogenic pathways through intricate interactions with microRNAs and protein-coding genes. This multifaceted axis not only advances our fundamental understanding of thyroid cancer progression but also heralds new possibilities for diagnostics and therapeutics. Continued exploration of such molecular circuits promises to transform the landscape of cancer treatment, ultimately improving prognosis and quality of life for patients worldwide.
Subject of Research: The role of the long non-coding RNA PICSAR in promoting thyroid cancer progression via interaction with hsa-miR-320A, hsa-miR-485, and the RAPGEFL1 signaling axis.
Article Title: A novel long non-coding RNA, PICSAR, promotes thyroid cancer progression through the hsa-miR-320A/hsa-miR-485/RAPGEFL1 axis.
Article References:
Hejazi, M., Jafari, T., Yari, A. et al. A novel long non-coding RNA, PICSAR, promotes thyroid cancer progression through the hsa-miR-320A/hsa-miR-485/RAPGEFL1 axis.
Med Oncol 42, 448 (2025). https://doi.org/10.1007/s12032-025-02987-9
Image Credits: AI Generated
