Unraveling diverse roles of noncoding RNAs in various human papillomavirus negative cancers

Abstract

Human papillomavirus (HPV)-negative tumors distinguish from cancers associated with HPV infection. Due to its high rate of lymph node metastasis and difficulty in inchoate discover and diagnosis, the treatment efficacy of HPV-negative cancers is unsatisfactory. Epidemiological evidence suggests that HPV-negative tumor patients have a poor prognosis, and the mortality is higher than that of cancer patients caused by HPV infection. Evidence has demonstrated that noncoding RNAs (ncRNAs) play a crucial role in regulation of physiological and developmental processes. Therefore, dysregulated ncRNAs are involved in the occurrence of diversified diseases, including cancer. In cumulative studies, ncRNAs are concerned with pathogenetic mechanisms of HPV-negative tumors via regulating gene expression and signal transduction. It is important to decipher the functions of ncRNAs in HPV-negative cancers and identify the potential biomarkers, which will bring new treatment strategies for improving outcome of cancer therapy. In this review, we demonstrated the effects of ncRNAs via regulating the development and progression of HPV- negative tumors by directly or indirectly acting on target molecules, which provide a basis for future tumor targeted therapy by targeting ncRNAs for HPV-negative cancers.

Introduction

Since the late half of this century, the understanding of the correlation between cancer and pathogen infection has been deepen increasingly with the cancer prevention moving forward. Among these related infections, human papillomavirus (HPV), as a noteworthy risk factor, is considered to have a direct relationship with carcinogenesis (Dunne & Park, 2013). According to HPV infection status, tumors in these anatomical sites were divided into two broad categories, HPV-associated and HPV-independent tumors (Lechner, Liu, Masterson, & Fenton, 2022). Although the sensitivity of HPV screening techniques is improving gradually, people found that there is always a fraction of cancer samples that are negative for HPV (Negri, Rigo, Vittadello, Mian, & Egarter-Vigl, 2007; De Sanjose et al., 2010; Rodriguez-Carunchio et al., 2015). Due to popularization of the cytological screening, colposcopy and an increase of HPV vaccination rate, the HPV infection rate is declining (Chabeda et al., 2018). Therefore, the occurrence of HPV-negative tumors may increase relatively. Because of the great difference in molecular mechanisms of tumorigenesis between the two cancer types, the sensitivity to chemoradiotherapy and the survival outcomes of HPV negative cancer were distinct from HPV positive cancer clinically (Costa, Boroni, & Soares, 2018). In addition, a large number of surveys consistently showed that HPV negative tumor was more likely to relapse and distant metastasize, and thought to be connected with worse prognosis (Riou et al., 1990; Higgins et al., 1991; Rodriguez-Carunchio et al., 2015).

In recent years, the regulatory functions of noncoding RNAs (ncRNAs) in various cellular processes have caused people's attention (Anastasiadou, Jacob, & Slack, 2018), and gradually been recognized as the important regulatory factors in the occurrence of various cancers (Martens-Uzunova et al., 2014; Chen, Lin, Shu, He, & Gao, 2020). Currently, HPV negative tumor regarded as an independently classified tumor has no definitive studies on its pathogenic mechanism, whereas multiply researches indicated that ncRNAs have the special connection with HPV negative cancer. Thus, it is urgent for us to explore the specialness of ncRNAs in gene expression levels and downstream signaling pathway as well as to identify the prognostic biomarkers and therapeutic targets in HPV negative tumor. In this review, we summarized the abnormally expressed ncRNAs in HPV negative tumors and their mechanisms of tumorigenesis and progression.