PRINS lncRNA Is a New Biomarker Candidate for HPV Infection and Prognosis of Head and Neck Squamous Cell Carcinomas

Numerous studies have shown that human papillomavirus (HPV) infection is one of the important risk factors for head and neck squamous cell carcinoma (HNSCC) progression and affects the expression of multiple genes, which might serve as new biomarkers. This study examines the effects of HPV infection on long non-coding RNA (lncRNA) expression and the immune system, particularly PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). The Cancer Genome Atlas (TCGA) expression data for lncRNA genes and clinical data were analyzed by GraphPad Prism 5/7. The expressions of PRINS, CDKN2B-AS1, TTTY14, TTTY15, MEG3, and H19 were significantly different in HPV-positive and HPV-negative patients. HPV-positive patients with high PRINS expression demonstrated significantly better overall survival (OS) and disease-free survival (DFS). HPV-positive patients with high PRINS expression showed changes in gene expression associated with immune and antiviral responses. A majority of HPV-positive patients with high PRINS expression demonstrated a high number of immune cells within tumors. PRINS expression was significantly associated with HPV-infection HNSCC tumors. Validation of these results using data set from Gene Expression Omnibus (GEO) indicated that PRINS is upregulated in HPV active infections and in “atypical 1 (IR)” HNSCC clusters, negatively influencing patients’ overall survival. Patients with high PRINS expression display different immunological profiles than those with low expression levels. For instance, they have active HPV infection status or are clustered in the “atypical 1 (IR)” subtype of HNSCC which influences both viral infection and patients’ survival. It is likely that PRINS could be used as a potential biomarker for HNSCC patients, but its role is dual. On the one hand, it stimulates patients’ immune response, while on the other it can be favorable in virus replication.

[1]  Lanlan Wei,et al.  Association of lnc‐IL17RA‐11 with increased radiation sensitivity and improved prognosis of HPV‐positive HNSCC , 2019, Journal of cellular biochemistry.

[2]  Daria A. Gaykalova,et al.  Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers , 2019, Nature Communications.

[3]  Daolin Xie,et al.  LncRNA PRINS is involved in the development of nephropathy in patients with diabetes via interaction with Smad7. , 2019, Experimental and therapeutic medicine.

[4]  K. Lamperska,et al.  Oncogenic Role of ZFAS1 lncRNA in Head and Neck Squamous Cell Carcinomas , 2019, Cells.

[5]  N. Issaeva,et al.  HPV-driven oropharyngeal cancer: current knowledge of molecular biology and mechanisms of carcinogenesis , 2018, Cancers of the Head & Neck.

[6]  K. Lamperska,et al.  lncRNA Expression after Irradiation and Chemoexposure of HNSCC Cell Lines , 2018, Non-coding RNA.

[7]  Zhihua Cui,et al.  PRINS Long Noncoding RNA Involved in IP-10-Mediated Allograft Rejection in Rat Kidney Transplant. , 2018, Transplantation proceedings.

[8]  Xiaohang Chen,et al.  Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis , 2018, Molecular immunology.

[9]  Scott M Langevin,et al.  Differential expression and prognostic value of long non‐coding RNA in HPV‐negative head and neck squamous cell carcinoma , 2018, Head & neck.

[10]  P. Boscolo-Rizzo,et al.  Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors , 2017, Clinical Epigenetics.

[11]  K. Lamperska,et al.  Biological role of long non-coding RNA in head and neck cancers. , 2017, Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology.

[12]  Chad J. Creighton,et al.  UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses , 2017, Neoplasia.

[13]  B. Erman,et al.  Long noncoding RNA (lincRNA), a new paradigm in gene expression control , 2016, Functional & Integrative Genomics.

[14]  Yaling Tang,et al.  LncRNAs as an intermediate in HPV16 promoting myeloid-derived suppressor cell recruitment of head and neck squamous cell carcinoma , 2017, Oncotarget.

[15]  J Silvio Gutkind,et al.  Unraveling the oral cancer lncRNAome: Identification of novel lncRNAs associated with malignant progression and HPV infection. , 2016, Oral oncology.

[16]  Maureen A. Sartor,et al.  Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures , 2016, Clinical Cancer Research.

[17]  Howard Y. Chang,et al.  Long Noncoding RNAs in Cancer Pathways. , 2016, Cancer cell.

[18]  M. B. Gillespie,et al.  Human papillomavirus status and gene expression profiles of oropharyngeal and oral cancers from European American and African American patients , 2016, Head & neck.

[19]  Farooq Rashid,et al.  Long Non-coding RNAs in the Cytoplasm , 2016, Genom. Proteom. Bioinform..

[20]  J. R. Plaça,et al.  Long Noncoding RNAs in HPV-Induced Oncogenesis , 2016 .

[21]  Chi-Yuan Li,et al.  RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1α and LncRNA PRINS , 2016, Scientific Reports.

[22]  M. Scholz,et al.  The role of HPV RNA transcription, immune response‐related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer , 2015, International journal of cancer.

[23]  M. von Knebel Doeberitz,et al.  p16INK4a/Ki‐67 co‐expression specifically identifies transformed cells in the head and neck region , 2015, International journal of cancer.

[24]  J. Kónya,et al.  Transcriptional regulation of genes involved in keratinocyte differentiation by human papillomavirus 16 oncoproteins , 2015, Archives of Virology.

[25]  C. Feschotte,et al.  Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implications. , 2014, Trends in genetics : TIG.

[26]  M. Hasegawa,et al.  A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma , 2014, International journal of oncology.

[27]  O. Peralta-Zaragoza,et al.  Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review) , 2014, Oncology reports.

[28]  Binyuan Jiang,et al.  The role of MALAT1 correlates with HPV in cervical cancer , 2014, Oncology letters.

[29]  S. Willems,et al.  Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma , 2014, Epigenetics.

[30]  P. Gariglio,et al.  Deregulation of the miRNAs Expression in Cervical Cancer: Human Papillomavirus Implications , 2013, BioMed research international.

[31]  M. Teixeira,et al.  Targeting CCL5 in inflammation , 2013, Expert opinion on therapeutic targets.

[32]  N. Grabe,et al.  Identification of oropharyngeal squamous cell carcinomas with active HPV16 involvement by immunohistochemical analysis of the retinoblastoma protein pathway , 2013, International journal of cancer.

[33]  Anushya Muruganujan,et al.  Large-scale gene function analysis with the PANTHER classification system , 2013, Nature Protocols.

[34]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[35]  Zhi-Ming Zheng,et al.  Regulation of cellular miRNA expression by human papillomaviruses. , 2011, Biochimica et biophysica acta.

[36]  Howard Y. Chang,et al.  Molecular mechanisms of long noncoding RNAs. , 2011, Molecular cell.

[37]  L. Kemény,et al.  The anti‐apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non‐coding RNA, PRINS , 2010, Experimental dermatology.

[38]  M. Tommasino,et al.  The biological properties of E6 and E7 oncoproteins from human papillomaviruses , 2010, Virus Genes.

[39]  A. Cmelak,et al.  Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. , 2008, Journal of the National Cancer Institute.

[40]  E. Sturgis,et al.  Trends in head and neck cancer incidence in relation to smoking prevalence , 2007, Cancer.

[41]  Carole Fakhry,et al.  Case-control study of human papillomavirus and oropharyngeal cancer. , 2007, The New England journal of medicine.

[42]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  L. Kemény,et al.  Identification and Characterization of a Novel, Psoriasis Susceptibility-related Noncoding RNA gene, PRINS* , 2005, Journal of Biological Chemistry.

[44]  K. Lamperska,et al.  EGOT lncRNA in head and neck squamous cell carcinomas. , 2018, Polish journal of pathology : official journal of the Polish Society of Pathologists.

[45]  Ruud H. Brakenhoff,et al.  The molecular biology of head and neck cancer , 2011, Nature Reviews Cancer.