Hejazi Maryam, Jafari Tahmineh, Yari AmirHossein, Heshmat Ramin, Larijani Bagher, Ahvaz Samaneh, Pourbagherian Omid, Tavangar Seyed Mohammad, Shafiee Gita, Mokhtarzadeh Amir Ali
Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Med Oncol. 2025 Aug 26;42(10):448. doi: 10.1007/s12032-025-02987-9.
Among endocrine cancers, thyroid carcinoma (TC) is the most prevalent and ranks sixth in global mortality rates. Aberrant expression of long non-coding RNA (lncRNAs) is associated with the progression of various human cancers, including TC. The role of PICSAR lncRNA (LINC00162) has been validated in different human cancers. Therefore, this study aimed to assess the expression levels and functions of lncRNA PICSAR in thyroid cancer tumorigenesis. This comprehensive approach combined in silico and in vitro methods to explore the molecular mechanisms and clinical significance of PICSAR in thyroid cancer. This work assessed the expression of the long non-coding RNA LINC00162 and identified differentially expressed genes (DEGs) using the Cancer Genome Atlas (TCGA) database. Interactions among LINC00162, hsa-miR-320A, hsa-miR-485, and RAPGEFL1 were investigated using the LncACT and miRDB databases. Bioinformatics techniques were employed to conduct functional enrichment analysis to clarify the relevant molecular pathways. For the investigation of LINC00162 expression in TC samples, 50 matched samples of thyroid carcinoma and adjacent normal tissue were gathered. Real time PCR was used to objectively evaluate the expression levels of the targeted genes. Every tissue sample was examined pathologically. A specific siRNA was transfected into a thyroid cancer cell line to examine the functional role of LINC00162. The impact of LINC00162 silencing was then assessed by measuring the level of target genes expression following the transfection. Based on TCGA-THCA analysis and qRT-PCR on tissue samples, LINC00162 (PICSAR) was markedly overexpressed in thyroid cancer tissues compared to normal samples. However, no discernible correlation was found between LINC00162 expression and the pathological characteristics of thyroid cancer. Our bioinformatics predictions based on lncRNA-microRNA interactions demonstrate that LINC00162 acts as a molecular sponge for the downregulated microRNAs hsa-miR-320A and hsa-miR-485 in thyroid cancer. RAPGEFL1, a gene associated with the development of thyroid cancer, is upregulated in conjunction with this downregulation. The LINC00162-miRNA-RAPGEFL1 axis is involved in critical carcinogenic processes, including thiamine metabolism, cell cycle control, and folate biosynthesis, according to functional enrichment analysis. Additionally, a bioinformatics study revealed a negative association between PICSAR and the NUDT3 gene, while a positive correlation was found with the SNX18P14 gene. Thyroid cancer cells transfected with LINC00162-specific siRNA showed significant downregulation of LINC00162 and RAPGEFL1, alongside an increase in hsa-miR-320A and hsa-miR-485, ultimately inhibiting the growth of thyroid cancer. These findings suggest that targeting PICSAR may offer a treatment strategy for thyroid cancer by altering important biological processes. In conclusion, LINC00162, which is overexpressed in thyroid cancer, acts as a molecular sponge for hsa-miR-320A and hsa-miR-485, regulating key oncogenic pathways and leading to the upregulation of RAPGEFL1. These effects are reversed upon siRNA-mediated silencing of LINC00162, indicating its potential as a promising therapeutic target for thyroid cancer. RAPGEFL1 regulates the Rap signaling pathway, controlling adhesion, migration, polarity, and metabolism to maintain cellular and tissue homeostasis. Its dysregulation is linked to various diseases, highlighting its potential as a therapeutic target.
在内分泌癌中，甲状腺癌（TC）最为常见，在全球死亡率中排名第六。长链非编码RNA（lncRNAs）的异常表达与包括TC在内的各种人类癌症的进展相关。PICSAR lncRNA（LINC00162）在不同人类癌症中的作用已得到验证。因此，本研究旨在评估lncRNA PICSAR在甲状腺癌发生中的表达水平和功能。这种综合方法结合了计算机模拟和体外方法，以探索PICSAR在甲状腺癌中的分子机制和临床意义。这项工作评估了长链非编码RNA LINC00162的表达，并使用癌症基因组图谱（TCGA）数据库鉴定了差异表达基因（DEGs）。使用LncACT和miRDB数据库研究了LINC00162、hsa-miR-320A、hsa-miR-485和RAPGEFL1之间的相互作用。采用生物信息学技术进行功能富集分析，以阐明相关分子途径。为了研究TC样本中LINC00162的表达，收集了50对匹配的甲状腺癌和癌旁正常组织样本。使用实时PCR客观评估靶基因的表达水平。对每个组织样本进行病理检查。将特异性siRNA转染到甲状腺癌细胞系中，以研究LINC00162的功能作用。然后通过测量转染后靶基因表达水平来评估LINC00162沉默的影响。基于TCGA-THCA分析和组织样本的qRT-PCR，与正常样本相比，LINC00162（PICSAR）在甲状腺癌组织中明显过表达。然而，未发现LINC00162表达与甲状腺癌的病理特征之间存在明显相关性。我们基于lncRNA- microRNA相互作用的生物信息学预测表明，LINC00162在甲状腺癌中作为下调的microRNA hsa-miR-320A和hsa-miR-485的分子海绵。与之相关的甲状腺癌发展相关基因RAPGEFL1随着这种下调而上调。根据功能富集分析，LINC00162-miRNA-RAPGEFL1轴参与了关键的致癌过程，包括硫胺代谢、细胞周期控制和叶酸生物合成。此外，一项生物信息学研究揭示了PICSAR与NUDT3基因之间存在负相关，而与SNX18P14基因存在正相关。用LINC00162特异性siRNA转染的甲状腺癌细胞显示LINC00162和RAPGEFL1显著下调，同时hsa-miR-320A和hsa-miR-485增加，最终抑制了甲状腺癌的生长。这些发现表明，靶向PICSAR可能通过改变重要的生物学过程为甲状腺癌提供一种治疗策略。总之，在甲状腺癌中过表达的LINC00162作为hsa-miR-320A和hsa-miR-485的分子海绵，调节关键的致癌途径并导致RAPGEFL1上调。当通过siRNA介导沉默LINC00162时，这些效应会逆转，表明其作为甲状腺癌有前景的治疗靶点的潜力。RAPGEFL1调节Rap信号通路，控制黏附、迁移、极性和代谢以维持细胞和组织的稳态。其失调与多种疾病相关，突出了其作为治疗靶点的潜力。
Br J Dermatol. 2025-3-27
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