Dysregulated LINC01133 expression in laryngeal carcinoma: Prognostic implications and predicted ceRNA interactome

Abstract

Long non-coding RNAs (lncRNAs) have recently emerged as critical regulators of oncogenic or tumor-suppressive pathways in human cancers. LINC01133 is a lncRNA that has exhibited dichotomous roles in various malignancies but to the best of our knowledge, the role of LINC01133 in laryngeal squamous cell carcinoma (LSCC) has not been previously investigated. This study aimed to investigate the expression, clinical significance, and potential functions of the LINC01133 in LSCC. Integrative bioinformatics analysis of sequencing data obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed LINC01133 as a differentially expressed lncRNA in head and neck/laryngeal cancers. Experimental validation via quantitative real-time PCR in 41 pairs of stage III and IV LSCC tissues and normal tissues adjacent to the tumor (NAT) demonstrated significant downregulation of LINC01133 in tumors (p<0.0001). Decreased LINC01133 expression associated with advanced tumor stage (p=0.0206) and lymph node metastasis (p=0.0203). The receiver operating characteristic analysis indicated potential diagnostic utility (AUC=0.7115, p=0.001). Bioinformatic predictions and literature mining suggested two potential competing endogenous RNA (ceRNA) mechanisms whereby LINC01133 may act as a tumor suppressor by sponging miR-205-5p to derepress the leucine-rich repeat kinase 2 (LRRK2) and androgen receptor, leading to dysregulation of cancer-related signaling cascades. This study provides initial evidence that loss of lncRNA LINC01133 expression may promote LSCC tumorigenesis, possibly by dysregulating microRNA interactions. Further verification of its regulatory mechanisms and diagnostic value is warranted.

Keywords: Androgen Receptor; Competing endogenous RNA; LINC01133LRRK2; Laryngeal Squamous cell carcinoma; Long non-coding RNA.

Figure 1

Venn diagrams of intersected deferentially expressed sequencing data. a. 1185 DE mRNAs (547 downregulated), b. 16 DElncRNAs (15 upregulated and one controversial LINC01133), and c. 4 DEmiRNAs. See also tables S1-S3.

Figure 2

LINC01133 expression in LSCC. A. Lower expression of LINC01133 (****p<0.0001) in LSCC tissues compared with adjacent non-cancerous tissues. B. The corresponding relationship of LINC01133 expression between each pair of LSCC tissues and adjacent non-tumor tissues (****p<0.0001). C. LINC01133 expression was obviously lower in stage IV than in stage III (*p=0.020). D. Expression of LINC01133 was significantly lower in patients with lymph node metastasis (LNM) (*p=0.020).

Figure 3

The receiver operating characteristic (ROC) curve of LINC01133 expression for discrimination of LSCC from adjacent tissues. AUC indicates area under the ROC curve.

Figure 4

Enrichment analysis according to Enrichr database and according to the p-value for 12 hub-genes.

Figure 5

Two potential networks for LINC01133 activity