The long non-coding RNA LINC02159 promotes non-small cell lung cancer progression through ALYREF/YAP1 signaling, according to the results of a recent cell culture study.
Lung cancer is the leading cause of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have recently emerged as key regulators in cancer development and progression, including non-small cell lung cancer (NSCLC), and show biomarker potential for cancer diagnosis and prognosis.
A study published in Molecular Cancer identified a new lncRNA, LINC02159, in NSCLC patients and evaluated its role in NSCLC progression.
Study Population
A total of 50 paired tumor and adjacent non-tumor tissues and 44 serum samples were collected from NSCLC patients. Additionally, 33 serum samples were obtained from pneumonia patients and 44 serum samples were obtained from healthy donors. None of the patients received chemotherapy, radiotherapy, immunotherapy, or other adjuvant therapy before surgery.
LINC02159: A Novel LncRNA Upregulated in NSCLC Tumor Tissues
RNA sequencing revealed 84 upregulated and 89 downregulated lncRNAs in tumor tissues compared to adjacent non-tumor tissues in NSCLC patients. LINC02159 was selected from the top ten upregulated lncRNAs for further study, as it had not previously been studied in cancer. Quantitative real-time PCR demonstrated higher LINC02159 expression levels in 72% of tumor tissues compared to adjacent non-tumor tissues. LINC02159 was predominantly located in the nucleus of NSCLC cells.
Diagnostic and Prognostic Significance of LINC02159 in NSCLC
A significant upregulation of LINC02159 expression was noted in the serum of NSCLC patients versus pneumonia patients (area under the receiver operating characteristic curve (AUC): 0.907, sensitivity: 78.72%, specificity: 90.91%) and NSCLC patients versus healthy donors (AUC: 0.879, sensitivity: 76.6%, specificity: 91.49%). NSCLC patients with higher LINC02159 levels demonstrated shorter overall survival. These results highlight the potential of LINC02159 as a diagnostic and prognostic biomarker for NSCLC.
LINC02159 Exerts Oncogenic Roles in the Progression of NSCLC
LINC02159 knockdown significantly inhibited NSCLC cell proliferation and induced apoptosis and cell cycle arrest. LINC02159 knockdown also suppressed NSCLC cell migration and invasion, upregulated E-cadherin, downregulated N-cadherin, vimentin, and epithelial–mesenchymal transition factors, and increased the sensitivity of NSCLC cells to chemotherapy. In vivo mouse models confirmed the inhibitory effects of LINC02159 knockdown on tumor growth. LINC02159 overexpression promoted NSCLC cell proliferation, migration, and invasion while inhibiting apoptosis.
LINC02159-ALYREF Interaction Promotes NSCLC Progression
A tagged RNA affinity purification assay identified several LINC02159-interacting proteins, with Aly/REF export factor (ALYREF) exhibiting the highest fold change. Another assay confirmed the binding of LINC02159 and ALYREF. Immunofluorescent staining demonstrated co-localization of LINC02159 with ALYREF in the nucleus of NSCLC cells. LINC02159 knockdown inhibited ALYREF expression and led to the protein’s relocalization from the nucleus to the cytoplasm.
ALYREF Expression in NSCLC Tissues
NSCLC patients demonstrated a high expression of ALYREF in 93% of tumor tissues with simultaneously elevated LINC02159 levels compared to non-tumor tissues (AUC: 0.882). Survival analyses linked high ALYREF levels to worse overall NSCLC prognosis. ALYREF knockdown reduced NSCLC cell proliferation, migration, and invasion and induced apoptosis and cell cycle arrest. Moreover, ALYREF knockdown upregulated E-cadherin, downregulated N-cadherin, vimentin, and epithelial–mesenchymal transition factors, and enhanced the sensitivity of NSCLC cells to chemotherapy.
LINC02159 Impact on Cancer Pathways
LINC02159 knockdown in NSCLC cells upregulated 409 and downregulated 583 genes and affected multiple cancer-related pathways, including Hippo, JAK-STAT3, and MAPK signaling. LINC02159 and ALYREF knockdown particularly decreased, and LINC02159 overexpression increased YAP1 gene and protein expression in NSCLC cells. NSCLC cells demonstrated YAP1 mRNA enrichment in the ALYREF-immunoprecipitated complex. LINC02159 knockdown decreased ALYREF’s binding to YAP1 mRNA and the 5-methylcytosine level of YAP1 3’-UTR.
LINC02159/ALYREF Impact on Wnt/β-Catenin Pathway
LINC02159/ALYREF knockdown also weakened the stability of YAP1 mRNA. YAP1 is a known regulator of the Wnt/β-catenin signaling pathway. LINC02159/ALYREF knockdown significantly decreased the expression of β-catenin, c-Myc, and cyclin-D1. LINC02159 knockdown distinctly inhibited YAP1 expression and the growth, migration, and invasion of NSCLC cells, but this effect was reversible with YAP1 overexpression.
Source:
Yang, Q., Wang, M., Xu, J., Yu, D., Li, Y., Chen, Y., Zhang, X., Zhang, J., Gu, J., & Zhang, X. (2023). LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling. Molecular Cancer, 22(1). https://doi.org/10.1186/s12943-023-01814-x
