Long noncoding RNA HAS2‐AS1 mediates hypoxia‐induced invasiveness of oral squamous cell carcinoma

Abstract

A hypoxic microenvironment plays important roles in the progression of solid tumors, including oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. However, it is not clear whether lncRNAs can regulate hypoxia adaptation of OSCC or which lncRNAs participate in this process. Using a lncRNA microarray, we analyzed the aberrant lncRNA expression profiles in OSCC tissues compared with paired normal oral mucosa and in hypoxic OSCC cells compared with normoxic OSCC cells. The top 10 lncRNAs that had more than threefold increase with P‐value <0.01 in both microarray data were validated by qRT‐PCR. Among the top 10 lncRNAs, hyaluronan synthase 2 antisense 1 (HAS2‐AS1) was the only one that has a hypoxia‐responsive element (HRE) on its promoter region and has been validated to increase in OSCC tissues and in cells cultured under hypoxia. Tumor HAS2‐AS1 levels were closely associated with lymph node metastasis and hypoxic tumor status in patients with OSCC. Moreover, the hypoxia‐induced HAS2‐AS1 expression is dependent on HIF‐1α which directly binds to and activates the transcription of HAS2‐AS1. In addition, HAS2‐AS1 mediates hypoxia‐induced epithelial mesenchymal transition of OSCC cells via stabilizing HAS2. In conclusion, our results suggest that hypoxia would induce an overexpression of HAS2‐AS1 in an HIF‐1α dependent manner. The increase of HAS2‐AS1 plays important roles mediating the hypoxia‐regulated EMT and invasiveness of OSCC.

World Workshop on Oral Medicine VII: Clinical evidence of differential expression of lncRNAs in oral squamous cell carcinoma: A scoping review

“…Most studies addressing TNM stage compared lesions with stage I‐II versus lesions with stage III‐IV disease. When both TNM staging and nodal involvement were assessed, a few transcripts (CCAT2, EGFR, HOTTIP, PTENp1) appeared to be associated with tumour size rather than with nodal involvement (Gao et al., ; Ma et al., ; Sun, Tang, & Zhang, ; Zhang, Zhao et al., ), while others seemed related to nodal involvement but not to tumour size (CEBPA‐AS1, HAS2‐AS1, MBL2‐4:3, TUG1, UCA1) (Fang et al., ; Gao, Chan, & Wong, ; Guo et al., ; Liang, Zhang, et al., ; Yang et al., ; Zhu et al., ).…”

Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC

“…Alterations in primary structure, secondary structure or expression levels of lncRNAs underlie diseases ranging from neurodegeneration to cancer . Thus, lncRNA‐based measurements have the potential for broad applications across diverse areas of human health, including disease diagnosis, prognosis and therapeutic selection . Importantly, lncRNAs, as master regulators for gene expression, play crucial roles in tumorigenesis .…”

“…37 Thus, lncRNA-based measurements have the potential for broad applications across diverse areas of human health, including disease diagnosis, prognosis and therapeutic selection. 38,39 Importantly, lncRNAs, as master regulators for gene expression, play crucial roles in tumorigenesis. 40,41 In the present study, hepatic cells were exposed to low dose irradiation and the endogenous expression of HULC was elevated.…”

LncRNA HOTAIR promotes the invasion and metastasis of oral squamous cell carcinoma through metastasis‐associated gene 2

“…Oral squamous cell carcinoma (OSCC) is an increasingly serious problem around the world and is characterized by progressive local invasion and high regional lymph node metastasis, leading to high mortality and an unfavorable prognosis. 1,2 In spite of recent advancements in anticancer therapy, few overall survival improvements are observed among OSCC patients, and regional lymph node metastasis remains the most important prognostic indicator for OSCC. 3 Thus, it is of great urgency to identify a vital molecular marker and understand the potential molecular mechanism underlying the progression and metastasis of OSCC.…”