Analysis of lncRNA-Mediated ceRNA Crosstalk and Identification of Prognostic Signature in Head and Neck Squamous Cell Carcinoma

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Abstract

Long non-coding RNA (lncRNA) can act as ceRNA to regulate the expression of target genes by sponging miRNAs, and therefore plays an essential role in tumor initiation and progression. However, functional roles and regulatory mechanisms of lncRNAs as ceRNAs in head and neck squamous cell carcinoma (HNSCC) remain to be determined. We downloaded RNA sequence profiles from The Cancer Genome Atlas (TCGA) database, and identified the differential RNAs by bioinformatics. Then we analyzed the biological processes of differential expressed RNAs (DER), and established their interaction networks and pathway analysis to find out potential biological effects of these DERs. Besides, we also explored the relationship between the DERs and prognosis of HNSCC patients. We obtained 525 tumor samples and 44 paracancerous controls, and there were 1081 DElncRNAs, 1889 DEmRNAs, and 145 DEmiRNAs. GO and KEGG pathways analysis of these DEmRNAs were mainly involved in “Protein digestion and absorption,” “Calcium signaling pathway,” and “ECM-receptor interaction.” The analysis of the ceRNA network identified 61 DElncRNAs as functional ceRNAs whose dysregulated expression may affect the expression of oncogenes/tumor suppressor genes. Furthermore, univariate and multivariate Cox regression analysis revealed that 4 DElncRNAs, 3 EDmiRNAs, and 6 DEmRNAs can predict survival with high accuracy. Survival analysis found that 4 lncRNAs was related to prognostic, including overexpressed RP11-366H4.1, HOTTIP, RP11-865I6.2, and RP11-275N1.1 patients had a worse survival. In conclusion, through constructing the ceRNA network in HNSCC patients, we identified key lncRNA-miRNA-mRNA network in HNSCC. All the DERs might participate in varieties of pathways in the initiation, progression, and invasion of HNSCC. Furthermore, some miRNAs (hsa-mir-99a, hsa-mir-337, and hsa-mir-137) and mRNAs (NOSTRIN, TIMP4, GRB14, HOXB9, CELSR3, and ADGRD2) may be the prognostic genes of HNSCC. This study provided a new target and theoretical basis for further research on molecular mechanisms and biomarkers.

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Head and neck cancer.

Athanassios Argiris, Michalis V. Karamouzis, David Raben … (2008)

Most head and neck cancers are squamous cell carcinomas that develop in the upper aerodigestive epithelium after exposure to carcinogens such as tobacco and alcohol. Human papillomavirus has also been strongly implicated as a causative agent in a subset of these cancers. The complex anatomy and vital physiological role of the tumour-involved structures dictate that the goals of treatment are not only to improve survival outcomes but also to preserve organ function. Major improvements have been accomplished in surgical techniques and radiotherapy delivery. Moreover, systemic therapy including chemotherapy and molecularly targeted agents--namely, the epidermal growth factor receptor inhibitors--has been successfully integrated into potentially curative treatment of locally advanced squamous-cell carcinoma of the head and neck. In deciding which treatment strategy would be suitable for an individual patient, important considerations include expected functional outcomes, ability to tolerate treatment, and comorbid illnesses. The collaboration of many specialties is the key for optimum assessment and decision making. We review the epidemiology, molecular pathogenesis, diagnosis and staging, and the latest multimodal management of squamous cell carcinoma of the head and neck.

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Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood

Silvana Konermann, Feng Zhang, Eric S. Lander … (2017)

Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.

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Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.

Rolando Herrero, Xavier Castellsagué, Michael Pawlita … (2003)

Human papillomavirus (HPV), the causal agent of cervical cancer, appears to be involved in the etiology of cancer of the oral cavity and oropharynx. To investigate these associations, we conducted a multicenter case-control study of cancer of the oral cavity and oropharynx in nine countries. We recruited 1670 case patients (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 control subjects and obtained an interview, oral exfoliated cells, and blood from all participants and fresh biopsy specimens from case patients. HPV DNA was detected by polymerase chain reaction (PCR). Antibodies against HPV16 L1, E6, and E7 proteins in plasma were detected with enzyme-linked immunosorbent assays. Multivariable models were used for case-control and case-case comparisons. HPV DNA was detected in biopsy specimens of 3.9% (95% confidence interval [CI] = 2.5% to 5.3%) of 766 cancers of the oral cavity with valid PCR results and 18.3% (95% CI = 12.0% to 24.7%) of 142 cancers of the oropharynx (oropharynx and tonsil combined) with valid PCR results. HPV DNA in cancer biopsy specimens was detected less frequently among tobacco smokers and paan chewers and more frequently among subjects who reported more than one sexual partner or who practiced oral sex. HPV16 DNA was found in 94.7% of HPV DNA-positive case patients. HPV DNA in exfoliated cells was not associated with cancer risk or with HPV DNA detection in biopsy specimens. Antibodies against HPV16 L1 were associated with risk for cancers of the oral cavity (odds ratio [OR] = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2, 95% CI = 4.8 to 17.7). HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation.

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Author and article information

Contributors

Yunbao Pan: URI : http://loop.frontiersin.org/people/155958/overview

Guohong Liu: URI : http://loop.frontiersin.org/people/527911/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 04 March 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 150

Affiliations

[1] ¹Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan, China

[2] ²Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University , Wuhan, China

[3] ³Department of Clinical Pathology, Houjie Hospital of Dongguan, The Affiliated Houjie Hospital of Guangdong Medical University , Dongguan, China

Author notes

Edited by: Francois X. Claret, The University of Texas MD Anderson Cancer Center, United States

Reviewed by: Valerio Costa, Italian National Research Council (CNR), Italy; Dingbo Shi, Sun Yat-sen University, China

*Correspondence: Guohong Liu, liuguoh@ 123456outlook.com Yirong Li, liyirong838@ 123456163.com

This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Pharmacology

Article

DOI: 10.3389/fphar.2019.00150

PMC ID: 6409312

SO-VID: cd7bafce-24d1-497d-b558-13142cf3c426

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 10 July 2018

Date accepted : 08 February 2019

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Figures: 12, Tables: 1, Equations: 0, References: 38, Pages: 12, Words: 0

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Analysis of lncRNA-Mediated ceRNA Crosstalk and Identification of Prognostic Signature in Head and Neck Squamous Cell Carcinoma

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RNA drug delivery

Most cited references 27

Head and neck cancer.

Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood

Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.

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Cited by 19

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