HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer
Introduction
Head and neck squamous cell carcinoma (HNSCC) affects over 550,000 patients worldwide each year [1]. Tobacco and alcohol consumption, together with human papillomavirus (HPV) infection are the main etiological factors [2], [3], [4]. Many studies have found that patients with HPV-positive HNSCC have a better prognosis, with increased survival and less chance of recurrence [5], [6], [7]. However, there have been contradictory reports showing either no or poor associations with outcome. Nevertheless, the growing proportion of HPV-positive cases poses an urgent need for prognostic biomarkers that guide patient management according to HPV status [3], [6], [8], [9].
Small RNAs, particularly microRNAs (miRNAs), have proven to be promising prognostic tools in HNSCC patients [10], [11]. Piwi-interacting RNAs (piRNAs), an abundant class of small non-coding RNA that regulate genome stability [12], [13], [14], are emerging as a valuable addition to the category of small RNA biomarkers. Recently, piRNA expression patterns have been shown to be deregulated in a variety of cancer types, including head and neck tumors [15], [16], [17], [18], [19], [20], [21], [22]; however, the relationship between piRNA expression and clinicopathological features in HNSCCs is yet to be elucidated. Interestingly, we have reported an association between piRNA expression and nodal metastasis in HNSCC [16].
Here, we describe the expression pattern of piRNAs in HNSCC using a custom pipeline to generate piRNA transcriptomes for more than 20,000 human piRNAs. We have analyzed piRNA expression from 498 non-malignant and tumor tissues from HNSCC patients, and investigate their association with HPV infection status and patient survival. Our results reveal that specific piRNA expression patterns are associated with HPV status and virus type. Importantly, a piRNA expression signature was able to stratify patients based on overall survival, suggesting the potential utility of piRNA in assessing HNSCC patient prognosis.
Section snippets
Sample acquisition
A total of 498 HNSCC small RNA sequencing libraries (455 tumors and 43 matched non-malignant tissue) generated by The Cancer Genome Atlas (TCGA) consortium were acquired from the Cancer Genomics Hub (cgHUB) Data Repository (dbgap Project ID: 6208). The demographics and clinical data of these cases were obtained from the TCGA data portal and the USCS Cancer browser (Supplementary Table S1).
Assembly of piRNA transcriptome
A custom sequence analysis pipeline was developed to deduce piRNA expression from raw sequencing data
piRNAs are differentially expressed in head and neck non-malignant and tumor tissue
To identify piRNAs that might delineate tumor and non-malignant tissues, we analyzed piRNA expression in 43 non-malignant and 455 HNSCC samples. While the number of piRNAs expressed in either types of somatic tissue is small relative to the total number of piRNAs in the genome, we found intriguing patterns of differential expression between HNSCC tumors and their non-malignant counterparts. A total of 305 piRNAs were robustly expressed in both non-malignant and tumor tissue (Fig. 1,
Discussion
Considerable advances have been made in the detection and chemoprevention of head and neck cancer [4], [31]; however, major challenges still remain regarding the improvement of patient management once the disease is diagnosed. Additionally, the interaction between biological risk agents, such as HPV, and cellular mechanisms are not completely understood. In this proof of principle study, we show that another important component of the small RNA transcriptome, piRNA, is likely to play a role in
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by Grants from the National Institutes of Health – United States (NIH-NIDCR R01 DE015965), Canadian Institutes for Health Research (CIHR, FDN143345) and the Canadian Cancer Society (CCSRI), and CIHR Frederick Banting and Charles Best Canada Graduate Scholarships to K.S.S.E. and D.A.R. K.L.B. is a Michael Smith Foundation for Health Research Biomedical Research Scholar.
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2022, Pharmacology and TherapeuticsCitation Excerpt :In addition, the role of PIWI-interacting RNAs has also attracted the attention of scholars in recent years. One analysis revealed 41 differentially expressed piRNAs based on HPV infection status, among them, 30 piRNAs were overmodulated in HPV positive samples and 11 piRNAs were overmodulated in HPV negatives samples (Firmino et al., 2016). Moreover, a comprehensive miRNA profiling indicated that miR-106b, miR-20a, miR-93, miR-25, miR-27a, miR-142-3, miR-155, miR-16, miR-21, let-7i and miR-423 were upregulated whilst miR-375, miR-10a and miR-125b were downregulated in three HNSCCs cells (Hui et al., 2010).
Emerging roles of PIWI-interacting RNAs (piRNAs) and PIWI proteins in head and neck cancer and their potential clinical implications
2022, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Furthermore, the most aberrantly expressed piRNA, FR140858, showed 100% sequence complementarity with a region of chromosome 7 corresponding to a gene, minichromosome maintenance complex component 7 (mcm7), whose expression showed correlation with that of HPV viral oncogene E7 (Fig. 9). Thus, silencing of this piRNA could potentially increase mcm7 expression, and with further validation, it could emerge as a potential prognostic biomarker [213]. Weg M Ongkeko also conducted a similar study in which, in addition to identifying HPV-associated piRNAs in HNSCCs, a correlation between expression of HPV-related piRNAs and retrotransposons as well as retrotransposon-like genes was determined to identify potential targets for these piRNAs [214].
A 5’-tiRNA fragment that inhibits proliferation and migration of laryngeal squamous cell carcinoma by targeting PIK3CD
2022, GenomicsCitation Excerpt :Therefore, it is essential to thoroughly explore the pathological mechanisms and search for novel diagnostic biomarkers and therapeutic targets for LSCC. For decades, non-coding RNAs (ncRNAs) such as microRNA (miRNAs), long non-coding RNAs, circular RNAs, and piwi-interacting RNAs are aberrantly expressed in several tumors [3–6]. With the rapid advancement of sequencing technology, a novel type of ncRNA, tRNA-derived small RNAs (tsRNAs), were found to participate in many biological processes [7–10].
PIWI-interacting RNAs in human cancer
2021, Seminars in Cancer BiologyCitation Excerpt :Also lacking are studies on the upstream causes of aberrant piRNA activities in cancer. Besides genetic or epigenetic alterations that affect piRNA source loci, transcription factors (e.g., cyclin D1 and estrogen receptor β) [108,172] and exogenous cancer risk factors (e.g., smoking, viral infection and hormones) [173–177] may also affect the expression of some but not all piRNAs. A recent study found piRNA expression levels positively correlated with vitamin D concentration in benign prostate epithelium of participants in a clinical trial on vitamin D supplementation [88].
The Biogenesis and Functions of piRNAs in Human Diseases
2020, Molecular Therapy Nucleic AcidsCitation Excerpt :It is well known that virus infection and tobacco and alcohol consumption increase the risk of development of HNSCC.112 In HPV16/18-associated HNSCC tissues, the loss of the piRNA FR140858 could potentially promote the expression of minichromosomal maintenance complex component 7 (Mcm7), which controls the initiation and elongation steps of eukaryotic DNA replication.113 In smoking-related HNSCC tissues, four upregulated piRNAs (NONHSAT015828, NONHSAT081250, NONHSAT113708, and NONHSAT123636) are connected with advanced tumor stage and metastasis, and the downregulated NONHSAT067200 was related to longer patient survival.114
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These authors contributed equally to this work.