Molecular Signature of Long Non-Coding RNA Associated with Areca Nut-Induced Head and Neck Cancer

Hung-Han Huang; Guo-Rung You; Shang-Ju Tang; Joseph T Chang; Ann-Joy Cheng

doi:10.3390/cells12060873

Molecular Signature of Long Non-Coding RNA Associated with Areca Nut-Induced Head and Neck Cancer

Cells. 2023 Mar 11;12(6):873. doi: 10.3390/cells12060873.

Authors

Hung-Han Huang^{1

2}, Guo-Rung You², Shang-Ju Tang², Joseph T Chang^{3

4}, Ann-Joy Cheng^{1

2

3}

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
² Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
³ Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan.
⁴ School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

Abstract

The areca nut is a high-risk carcinogen for head and neck cancer (HNC) patients in Southeast Asia. The underlying molecular mechanism of areca nut-induced HNC remains unclear, especially regarding the role of long non-coding RNA (lncRNA). This study employed a systemic strategy to identify lncRNA signatures related to areca nut-induced HNC. In total, 84 cancer-related lncRNAs were identified. Using a PCR array method, 28 lncRNAs were identified as being dysregulated in HNC cells treated with areca nut (17 upregulated and 11 downregulated). Using bioinformatics analysis of The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset, 45 lncRNAs were differentially expressed in tumor tissues from HNC patients (39 over- and 6 under-expressions). The integrated evaluation showed 10 lncRNAs dysregulated by the areca nut and altered expression in patients, suggesting that these panel molecules participate in areca nut-induced HNC. Five oncogenic (LUCAT1, MIR31HG, UCA1, HIF1A-AS2, and SUMO1P3) and tumor-suppressive (LINC00312) lncRNAs were independently validated, and three key molecules were further examined. Pathway prediction revealed that LUCAT1, UCA1, and MIR31HG modulate multiple oncogenic mechanisms, including stress response and cellular motility. Clinical assessment showed that these lncRNAs exhibited biomarker potentials in diagnosis (area under the curve = 0.815 for LUCAT1) and a worse prognosis (both p < 0.05, survival analysis). Cellular studies further demonstrated that MIR31HG facilitates areca nut-induced cancer progression, as silencing this molecule attenuated arecoline-induced invasion ability in HNC cells. This study identified lncRNA signatures that play a role in areca nut-induced HNC. These molecules may be further applied in risk assessment, diagnosis, prognosis, and therapeutics for areca nut-associated malignancies.

Keywords: LUCAT1; MIR31HG; UCA1; areca nut; cell invasion; clinical significance; head and neck cancer (HNC); long non-coding RNA (lncRNA).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Areca / adverse effects
Areca / genetics
Head and Neck Neoplasms* / genetics
Humans
Nuts
RNA, Long Noncoding* / genetics
Squamous Cell Carcinoma of Head and Neck / genetics

Substances

RNA, Long Noncoding

Grants and funding

This research was funded by Chang Gung Memorial Hospital-Linkou Medical Center, grant number CMRPD1M0191~2, and National Science and Technology Council, grant number MOST-111-2320-B-182-024-MY3.