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Research Article: LncRNA GAS8-AS1 is downregulated, correlates with early-stage disease and lymph node metastasis, and its knockdown promotes proliferation, migration, and invasion in differentiated thyroid cancer

Date Published: 2026-06-08

Abstract:
LncRNAs emerge as critical regulators of gene expression and epigenetic modulation in human cancer. However, the biological and clinical significance of the lncRNA GAS8-AS1 in differentiated thyroid cancers (DTCs) remains poorly understood. GAS8-AS1 expression in normal tissues was evaluated using LncExpDB. Quantitative RT-PCR was performed on 21 DTCs with matched adjacent normal tissues. RNA-seq data from TCGA (507 DTCs) were analyzed to assess GAS8-AS1 expression and clinicopathological associations. Independent validation was conducted using ENCORI (510 thyroid cancer, 58 normal) and TNMplot datasets. Expression profiles of GAS8-AS1 -associated genes were analyzed in TCGA and were corroborated with ENCORI dataset. Co-expression analyses were performed to identify regulatory relationships. Functional characterization was conducted using siRNA-mediated knockdown of GAS8-AS1 in HEK293T and BCPAP cells, and overexpression studies in papillary thyroid cancer cell lines (K1 and BCPAP). Cell proliferation, migration, and invasion assays were performed. Pathway enrichment analyses were used to identify GAS8-AS1 -mediated biological processes. GAS8-AS1 expression was significantly downregulated in DTCs compared with matched normal tissues ( p < 0.0001). TCGA analysis confirmed lower GAS8-AS1 expression, which was markedly associated with early-stage disease ( p = 0.03) and lymph node metastasis ( p = 0.03). GAS8-AS1 downregulation was remarkably consistent in thyroid cancer (ENCORI, p = 0.004). A dramatic downregulation of GAS8-AS1 was also observed across pan-cancer, including thyroid cancer (TNMplot, p = 2.01 × 10 -128 ). Expression analysis of GAS8-AS1 -associated genes revealed frequent deregulation in DTCs (24%), including downregulation of ATF2, ATG5, ATG7 , and BECN1 , and upregulation of NEAT1 and UCA1 . Co-expression analysis revealed that GAS8-AS1 and ATG5 expression levels were positively correlated with ATF2 , whereas NEAT1 showed a negative association, suggesting ATF2 -dependent transcriptional regulation of GAS8-AS1 , ATG5 , and NEAT1 . Functional characterizations demonstrated that GAS8-AS1 knockdown significantly increased proliferation, migration, and invasion, whereas GAS8-AS1 overexpression markedly suppressed tumor cell proliferation. Pathway enrichment analyses implicated GAS8-AS1 -related genes in autophagy, apoptosis, proliferation, invasion, and metastasis. These findings demonstrate that GAS8-AS1 may function as a tumor suppressor in DTCs, with its downregulation associated with disease progression and metastasis. The consistent loss of GAS8-AS1 expression and its functional impact on tumor progression suggest that it may serve as a valuable diagnostic and prognostic biomarker in DTCs.

Introduction:
LncRNAs emerge as critical regulators of gene expression and epigenetic modulation in human cancer. However, the biological and clinical significance of the lncRNA GAS8-AS1 in differentiated thyroid cancers (DTCs) remains poorly understood.

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