**1. Introduction**

Endometriosis is a progressive and debilitating gynecologic disease whereby endometriallike tissue grows outside the uterine cavity, invading adjacent organs, such as the ovaries, bladder, colon, or pelvic peritoneum [1–3]. Endometriosis is often accompanied by chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia and can cause infertility [4,5]. The prevalence of endometriosis ranges from 5 to 15% of reproductive age women depending on the method of disease confirmation [3,6], affecting approximately 190 million women worldwide and 5 million women and adolescent girls in the United States [2].

Diagnosing endometriosis is exceptionally challenging since it shares non-specific symptoms, such as pelvic pain, with other conditions. The first-line imaging modality is typically pelvic ultrasound as it can allow for the diagnosis of other conditions that cause pelvic pain. However, the sensitivity and specificity of ultrasound are dependent on endometriosis lesion type and location. For example, transvaginal ultrasonography has high sensitivity and high specificity for ovarian endometriomas [7]. However, the diagnosis of deep infiltrating endometriosis lesions by ultrasound is related to operator expertise [7,8]. Surgical visual inspection by laparoscopy with histologic confirmation is currently the only way to diagnose pathology-proven endometriosis [5]. Surgery involves the risk of surgical complications, adhesion formation, and the need for future surgeries [9]. Because there is no gold standard for noninvasive diagnosis, there is often a significant delay in

**Citation:** Wang, X.; Parodi, L.; Hawkins, S.M. Translational Applications of Linear and Circular Long Noncoding RNAs in Endometriosis. *Int. J. Mol. Sci.* **2021**, *22*, 10626. https://doi.org/10.3390/ ijms221910626

Academic Editor: Antonio Simone Laganà

Received: 1 September 2021 Accepted: 28 September 2021 Published: 30 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

diagnosis [5]. The median time is seven years from the onset of symptoms with pain or infertility to endometriosis diagnosis [10]. Better diagnostic strategies must be developed.

Unfortunately, there is no cure for endometriosis. Non-steroidal anti-inflammatory medications are routinely used, but they are not more effective than a placebo [11]. Hormonal therapies, including gonadotropin-releasing hormone agonists and newer antagonists, can be prescribed only for a short time because of undesirable side effects, including irregular menstrual bleeding, the development of menopausal symptoms, and the detrimental impact on bone density [7,9,12]. Moreover, both medical and surgical therapies fail to prevent recurrence [2] as 20–50% of endometriosis recurs within five years of treatment [13]. The economic burden of endometriosis in the United States is estimated at \$78 billion per year, including direct healthcare costs and indirect costs to patients [14]. Better treatment options are warranted.

Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), encompass large segments of the transcriptome that do not have apparent protein-coding roles [15]. ncRNAs are divided into two subclasses based on size: short ncRNAs and long ncRNAs. LncRNAs are commonly defined as transcripts longer than 200 nucleotides. Short ncRNAs, including the ~22 nucleotide long miRNAs, have emerged as critical post-transcriptional regulators of gene expression that are fundamental for many disease processes [16]. Although numerous studies have investigated the potential roles of miRNAs as diagnostic biomarkers, no particular miRNA has been translated from bench to clinic for diagnostic purposes [17]. The role of miRNAs in endometriosis has been recently reviewed [18] and will not be included again here.

Similar to messenger RNAs, most lncRNAs are transcribed by RNA polymerase II, and then they undergo post-transcription processes, leading to a 50 cap, alternative splicing, and 30 poly(A) tail [19]. Some lncRNAs have been re-defined as protein-encoding genes by closer inspection of the transcriptome and proteome with next-generation sequencing and mass spectrometry [20]. lncRNAs represent the largest class of ncRNAs as over 60,000 lncRNAs have been identified [21]. Many lncRNAs have substantial roles in several biological processes, including endometriosis [22]. As a unique subset of lncRNAs, circR-NAs contain a circular secondary structure, characterized by a covalently closed continuous loop structure without 50 -30 polarity or a poly(A) tail [23]. CircRNAs are involved in the pathogenesis of many diseases [24]. This review will discuss the fundamental roles of both linear and circular long noncoding RNAs in the molecular features of endometriosis and their relevance to current clinical practice. We will also discuss how these preclinical insights into ncRNA biology could develop into diagnostics and therapies in endometriosis.
