Long Non-Coding RNAs as Functional Codes for Oral Cancer: Translational Potential, Progress and Promises

Abstract

Oral cancer is one of the leading malignant tumors worldwide. Despite the advent of multidisciplinary approaches, the overall prognosis of patients with oral cancer is poor, mainly due to late diagnosis. There is an urgent need to develop valid biomarkers for early detection and effective therapies. Long non-coding RNAs (lncRNAs) are recognized as key elements of gene regulation, with pivotal roles in various physiological and pathological processes, including cancer. Over the past few years, an exponentially growing number of lncRNAs have been identified and linked to tumorigenesis and prognosis outcomes in oral cancer, illustrating their emerging roles in oral cancer progression and the associated signaling pathways. Herein, we aim to summarize the most recent advances made concerning oral cancer-associated lncRNA, and their expression, involvement, and potential clinical impact, reported to date, with a specific focus on the lncRNA-mediated molecular regulation in oncogenic signaling cascades and oral malignant progression, while exploring their potential, and challenges, for clinical applications as biomarkers or therapeutic targets for oral cancer.

Keywords: cancer progression; long non-coding RNA; metastasis; oral cancer; tumorigenesis.

Figure 1

The potential actionmechanisms of lncRNAs in oral cancer. (a) Chromatin remodeling. LncRNA HOTAIR has been recognized as a scaffold interacting with chromatin modifying complexes PRC2 and LSD1 to epigenetically regulate gene expression. In OSCC, HOTAIR knockdown decreased the enrichment of EZH2 (the component of PRC2 complex) and H3K27me3 deposition within the E-cadherin promoter, suggesting HOTAIR could modify chromatin accessibility through recruiting chromatin modifying complex at the transcribed genomic locus. (b) Promoter regulation. Nuclear lncRNA lnc-p23154 has been demonstrated to suppress miR-378a-3p transcription by interacting with its promoter region, thereby upregulating the expression of the miR-378a-3p targeted gene, GLUT1, and promoting Glut1-mediated OSCC metastasis. (c) Intra-chromosomal interactions. Through dimerization, transcription factor CTCF could mediate chromatin looping between its binding sites and thereby modulate transcription. LncRNA LINC00941 could activate the expression of its nearby gene CAPRIN2 through CTCF-mediated DNA looping of the specific region between the two genes. (d) miRNA sponge/ceRNA. LncRNA RC3H2 could function as a miRNA sponge by physically binding miR-101-3p, whose target is EZH2 mRNA. The upregulated EZH2 subsequently suppresses the expression of the downstream gene CDKN2A, facilitating the malignant behavior of OSCC cells. (e) mRNA stability. LncRNA-SNHG3 is able to increase NFYC mRNA stability through interacting with RNA-binding protein ELAVL1, also known as HuR, thereby increasing NFYC protein levels.

Figure 2

LncRNAs involved in the relevant signaling pathways implicated in oral cancer progression. (a) Wnt/β-catenin signaling. LncRNAs, such as AC007271.3, MALAT1, PLAC2, SNHG3, TUG1, and UCA1, could activate Wnt/β-catenin signaling mainly through inducing β-catenin accumulation. The increased β-catenin would further translocate into the nucleus and bind to LEF/TCF transcription factors to activate the downstream effectors, promoting the malignant behavior of oral cancer cells. In addition, lncRNA LINC00941 could induce the expression of Caprin-2, which further promotes the phosphorylation of the Wnt co-receptor LRP6, and thereby activating Wnt/β-catenin signaling. (b) PI3K/AKT/mTOR signaling. Several lncRNAs are able to target the different components of the PI3K/AKT/mTOR pathway to affect oral cancer progression. Overexpression of lncRNA MALAT1 could increase the phosphorylation of PI3K to induce PI3K/AKT/mTOR signaling, thereby promoting the EMT and cisplatin resistance of OSCC. Another lncRNA GAS5 could suppress the malignant behavior of OSCC by serving as ceRNA to sequester miR-21 and thereby reverting the miR-21-mediated repression of PTEN, a negative regulator of PI3K signaling. In addition, lncRNA CASC9 could enhance cell proliferation by inhibiting autophage-mediated cell apoptosis via inducing AKT phosphorylation and the subsequent activation of the AKT/mTOR pathway in OSCC.