Computational methods reveal novel functionalities of PIWI-interacting RNAs in human papillomavirus-induced head and neck squamous cell carcinoma

Abstract

Human papillomavirus (HPV) infection is the fastest growing cause of head and neck squamous cell carcinoma (HNSCC) today, but its role in malignant transformation remains unclear. This study aimed to conduct a comprehensive investigation of PIWI-interacting RNA (piRNA) alterations and functionalities in HPV-induced HNSCC. Using 77 RNA-sequencing datasets from TCGA, we examined differential expression of piRNAs between HPV16(+) HNSCC and HPV(–) Normal samples, identifying a panel of 30 HPV-dysregulated piRNAs. We then computationally investigated the potential mechanistic significances of these transcripts in HPV-induced HNSCC, identifying our panel of piRNAs to associate with the protein PIWIL4 as well as the RTL family of retrotransposon-like genes, possibly through direct binding interactions. We also recognized several HPV-dysregulated transcripts for their correlations with well-documented mutations and copy number variations in HNSCC as well as HNSCC clinical variables, demonstrating the potential ability of our piRNAs to play important roles in large-scale modulation of HNSCC in addition to their direct, smaller-scale interactions in this malignancy. The differential expression of key piRNAs, including NONHSAT077364, NONHSAT102574, and NONHSAT128479, was verified in vitro by evaluating endogenous expression in HPV(+) cancer vs. HPV(–) normal cell lines. Overall, our novel study provides a rigorous investigation of piRNA dysregulation in HPV-related HNSCC, and lends critical insight into the idea that these small regulatory transcripts may play crucial and previously unidentified roles in tumor pathogenesis and progression.

Site-Specific Expression Pattern of PIWI-Interacting RNA in Skin and Oral Mucosal Wound Healing

“…Intriguingly the PIWI-piRNA system has been suggested to regulate essential cellular functions of relevance to the repair of somatic tissues, including cell proliferation, viability, cell invasion and migration [22]. However, most of the newly gained knowledge of the functional role of piRNA is based on cancer studies, including studies on skin cancers [23,24] and oral cancers [25][26][27][28]. It is tempting to hypothesize that piRNAs play a role in wound healing.…”

The disease-related biological functions of PIWI-interacting RNAs (piRNAs) and underlying molecular mechanisms

“…A total of 30 piRNAs were dysregulated in HPV16 (+) HNSCC with the protein PIWIL4 and RTL family of retrotransposon-like genes been their potential targets. Three differential expressed piRNAs were further validated in vitro [69]. It was also reported that a collection of 13 piRNAs was found in HNSCC related to smoking.…”

PIWI-interacting RNAs: Mitochondria-based biogenesis and functions in cancer

“…3 A). 20 , 55 , 78 , 79 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 Ectopically expressed piRNAs identified in numerous cancers are shown in Fig. 3 A and Table 1 .…”

“…4 C). 79 , 84 , 86 , 90 , 100 , 109 Typically, piRNAs target the 3′-untranslated region (3′-UTR) of an mRNA, which may be attributed to the fact that most human genomic piRNAs are derived from 3′-UTR ( Fig. 4 C).…”