Abstract
Simple SummaryAlthough ovarian cancer (OC) is one of the most lethal gynecological cancers, its development and progression remain poorly understood. The piRNA pathway is important for transposon defense and genome stability. piRNA maturation and function involve a number of genes known as the piRNA pathway genes. These genes have recently been implicated in cancer development and progression but information about their role in OC is limited. Our work aimed to provide a better understanding of the roles of piRNA pathway genes in OC. Through analyzing changes in the abundance of 10 piRNA pathway genes, we discovered gene expression differences in benign vs. cancer, chemosensitive vs. chemoresistant and post hormone treatment in OC samples and cells. Furthermore, we observed the differential effects of these genes on patient survival and OC cell invasion. Overall, this work supports a role of the piRNA pathway genes in OC progression and encourages further study of their clinical relevance.Ovarian cancer (OC) is one of the most lethal gynecological malignancies, yet molecular mechanisms underlying its origin and progression remain poorly understood. With increasing reports of piRNA pathway deregulation in various cancers, we aimed to better understand its role in OC through a comprehensive analysis of key genes: PIWIL1-4, DDX4, HENMT1, MAEL, PLD6, TDRD1,9 and mutants of PIWIL1 (P1∆17) and PIWIL2 (PL2L60). High-throughput qRT-PCR (n = 45) and CSIOVDB (n = 3431) showed differential gene expression when comparing benign ovarian tumors, low grade OC and high grade serous OC (HGSOC). Significant correlation of disparate piRNA pathway gene expression levels with better progression free, post-progression free and overall survival suggests a complex role of this pathway in OC. We discovered PIWIL3 expression in chemosensitive but not chemoresistant primary HGSOC cells, providing a potential target against chemoresistant disease. As a first, we revealed that follicle stimulating hormone increased PIWIL2 expression in OV-90 cells. PIWIL1, P1∆17, PIWIL2, PL2L60 and MAEL overexpression in vitro and in vivo decreased motility and invasion of OVCAR-3 and OV-90 cells. Interestingly, P1∆17 and PL2L60, induced increased motility and invasion compared to PIWIL1 and PIWIL2. Our results in HGSOC highlight the intricate role piRNA pathway genes play in the development of malignant neoplasms.
Highlights
Ovarian cancer (OC) is one of the leading causes of death in women worldwide where184,799 deaths were projected in 2018
Following the differential expression observed in high grade serous OC (HGSOC) staging, we investigated if the piRNA pathway genes had distinct expression levels in low grade (G1) versus high grade (G2, G3) disease in OC (Figure 3)
We found that PIWIL1 and PIWIL2 had a similar expression pattern in chemosensitive and chemoresistant primary HGSOC cells (Figure 4a,b)
Summary
Ovarian cancer (OC) is one of the leading causes of death in women worldwide where. This was the second highest mortality among all gynecological cancers [1]. OC consists of epithelial ovarian cancers (EOC) (90%) which include subtypes serous, mucinous, clear cell and endometroid. Nonepithelial ovarian cancers (10%) include smallcell carcinomas and sarcomas and malignancies originating from germ or sex cord-stromal cells [8,9]. While mutations in tumor suppressor TP53 have been postulated as the driver of HGSOC, the etiology, subsequent progression and development of chemoresistance are poorly understood [15,16]. In the serous OC context, low grade (grade 1) and high grade (grades 2 and 3) are classified as two separate diseases with different underlying molecular pathology and clinical behavior [11,17,18]
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