Urine miRNA signature as a potential non-invasive diagnostic and prognostic biomarker in cervical cancer

Mehreen Aftab,Sachin Kumar,Simran Tandon,Bhudev C Das,Vaishnavi Seshan,Satish S Poojary,Pallavi Agarwal,Vijay Zutshi

doi:10.1038/s41598-021-89388-w

Abstract

MicroRNAs as cancer biomarkers in serum, plasma, and other body fluids are often used but analysis of miRNA in urine is limited. We investigated the expression of selected miRNAs in the paired urine, serum, cervical scrape, and tumor tissue specimens from the women with cervical precancer and cancer with a view to identify if urine miRNAs could be used as reliable non-invasive biomarkers for an early diagnosis and prognosis of cervical cancer. Expression of three oncomiRs (miR-21, miR-199a, and miR-155-5p) and three tumor suppressors (miR-34a, miR-145, and miR-218) as selected by database search in cervical pre-cancer, cancer, and normal controls including cervical cancer cell lines were analyzed using qRT-PCR. The expression of miRNAs was correlated with various clinicopathological parameters, including HPV infection and survival outcome. We observed a significant overexpression of the oncomiRs and the downregulation of tumor suppressor miRNAs. A combination of miR-145-5p, miR-218-5p, and miR-34a-5p in urine yielded 100% sensitivity and 92.8% specificity in distinguishing precancer and cancer patients from healthy controls and it well correlates with those of serum and tumor tissues. The expression of miR-34a-5p and miR-218-5p were found to be independent prognostic factors for the overall survival of cervical cancer patients. We conclude that the evaluation of the above specific miRNA expression in non-invasive urine samples may serve as a reliable biomarker for early detection and prognosis of cervical cancer.

Highlights

MicroRNAs as cancer biomarkers in serum, plasma, and other body fluids are often used but analysis of miRNA in urine is limited
A noninvasive urine sampling has been utilized to establish if urine can serve as an alternative clinical material for reliable detection of human papillomaviruses (HPVs) and other sensitive biomarkers such as miRNA expression for early detection of cervical cancer
HPV infection was detected in the cervical scrape of 35/50 (70%) of precancer lesions with 14% of low grade squamous intraepithelial lesion (LSIL) and 56% of HSIL found to be HPV positive

Summary

Introduction

MicroRNAs as cancer biomarkers in serum, plasma, and other body fluids are often used but analysis of miRNA in urine is limited. Available evidence suggests that there is a long gap between HPV infection and development of low-grade lesions that progress to invasive c ancer[7,8] This window period provides a unique opportunity for understanding molecular pathogenic pathways involved in cervical tumorigenesis and identification of cancer biomarker(s) for early diagnosis and prognosis which may result in the better management and control of cervical cancer. Differential expression of oncogenic and tumor suppressor miRNAs has been proposed as a candidate biomarker in many c ancers[9,10] Apart from their detection in tumor tissues, several studies have delineated the role of miRNAs derived from liquid biopsy samples, including blood plasma and serum, in cervical cancer[11,12,13,14]. After a comprehensive literature survey and complete search of databases on these miRNA targets related to cervical cancer, we shortlisted a panel of six miRNAs—three oncomiRs (miR199a-5p, miR-21-5p, miR-155-5p) and three tumor suppressors (miR-145-5p, miR-34a-5p, and miR-218-5p) to evaluate their functional role in HPV-induced cervical cancer

Methods

Results

Discussion

Conclusion