Uterine microRNA signature and consequence of their dysregulation in uterine disorders.

Chegini N, Nasser Chegini
Animal reproduction · 2010 · vol. 7(3) , pp. 117–128 · PMID:22328907 · PMC3275910 · W2188295622
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This review highlights the biogenesis and regulatory functions of uterine microRNAs in normal physiological processes and disorders like endometriosis, dysfunctional uterine bleeding, and endometrial cancer.

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This paper reviews how uterine cyclic regeneration is regulated by ovarian steroid signaling through ER and PR pathways and how microRNAs (miRNAs) function as key post-transcriptional regulators within this process. It describes miRNA biogenesis (Drosha/DGCR8, Exportin-5, Dicer, RISC) and the broad potential for miRNAs to repress many target genes involved in cell-cycle control, differentiation, apoptosis, inflammation/immune responses, angiogenesis, and tissue remodeling, noting that dysregulated miRNA processing can lead to fibrosis and cancer. The authors highlight that menstrual-dependent miRNA expression and aberrant miRNA profiles in endometriosis and endometrial cancer have been reported, and that studies using steroid-treated endometrial cells support possible steroid–miRNA regulatory links, though the exact mechanisms remain unclear and many miRNA tissue-specific functions are not established. This paper does not explicitly present a single new experimental study but it is centrally about microRNA regulation in uterine biology, with explicit discussion of endometriosis and adenomyosis-related endometrial dysregulation.

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Abstract

MicroRNA (miRNA) has emerged as key post-transcriptional regulator and through this mechanism control many normal developmental and physiological processes. Conversely, aberrant expression of some miRNAs has been correlated with various disorders, more specifically, development and progression of malignancy. Endometrium is a dynamic tissue which undergoes extensive cyclic changes in preparation for embryo implantation during reproductive years, as well as changes that occur following menopause, and establishment of benign and malignant uterine disorders. These processes are highly regulated by ovarian steroids and locally expressed genes in response to steroid hormone receptor-mediated signaling and include genes related to inflammatory reaction, apoptosis, cell-cycle progression, angiogenesis and tissue remodeling. Here we present an overview of our current understanding of uterine miRNA biogenesis and highlights their potential regulatory functions in cellular processes relevant to normal uterine physiological and pathological disorders such as endometriosis, dysfunctional uterine bleeding and endometrial cancer. Understanding the expression, regulation and functional aspects of miRNAs in uterine environment under normal and various disorders may lead to their potential utilization as diagnostic as well as therapeutic tool.
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Intro

The endometrium is a dynamic tissue which undergoes highly organized cyclic structural changes in preparation for embryo implantation during the reproductive years. These overlapping and dynamic endometrial morphological and molecular changes are remarkably consistent during each cycle and, in many aspects, resemble the repair processes that occur during wound healing. Wound repair and cyclic endometrial regeneration are both initiated by an inflammatory reaction followed by a rapid cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. Although wound repair in response to inflammation and/or mechanical injuries is often associated with excess-tissue formation and scarring ( Chegini, 2002 ), cyclic endometrium undergoes near perfect regeneration. These processes are under the control of ovarian steroid actions and are essential for endometrial preparation for embryo implantation. The ovarian steroids actions are regulated by their specific receptors and by steroid metabolizing enzymes. In addition to estrogen and progesterone, evidence suggests that glucocorticoids and androgens may influence the above endometrial cellular activities (for review see ( King and Critchley, 2010 ). Estrogen and progesterone receptors (ERs and PRs) each consist of at least two isoforms, ERα and ERβ and PRA and PRB. The endometrial profile and cellular distribution of ERs and PRs have been well documented throughout the normal menstrual cycle, the post-menopausal period and pathological conditions; and knockout mice models implicated their fundamental biological and physiological roles in uterine and other steroid-sensitive tissues ( Conneely et al ., 2003 ; Zhao et al ., 2008a ; Critchley and Saunders, 2009 ; Ellmann et al ., 2009 ; Deroo and Buensuceso, 2010 ; King and Critchley, 2010 ). Upon ligand binding, ERs and PRs undergo conformational changes, bind to specific enhancer DNA elements of their target genes and through recruitment and interactions with co-regulators (co-activators and co-suppressors) modulate their transcription in a cell- and promoter-specific manner ( Conneely et al ., 2003 ; O’Malley and McKenna, 2008 ; Zhao et al ., 2008a ; Ellmann et al ., 2009 ). Considerable evidence exists regarding the endometrial expression of various autocrine/paracrine factors many of which are direct targets of ER and PR regulatory actions ( Girling and Rogers, 2005 ; Achache and Revel, 2006 ; Jabbour et al ., 2006 ; Makker and Singh, 2006 ; Du and Taylor, 2007 ; Horcajadas et al ., 2007 , 2008 ; Critchley and Saunders, 2009 ; Altmae et al ., 2010 ; King and Critchley, 2010 ). Transcriptional regulation of these mediators is considered to serve as downstream signal of ER and PR actions in the endometrium and other steroid-sensitive tissues. Any alteration in production of ovarian steroids, exposure to excess exogenous hormones, and changes in ERs and PRs expression, which results in differential regulation of these mediators, seems to be responsible for inappropriate tissue regeneration, embryo implantation failure and other abnormalities, including dysfunctional uterine bleeding, endometriosis and endometrial cancer ( Ferenczy, 2003 ; Abal et al ., 2006 ; Harada et al ., 2007 ; Prat et al ., 2007 ; Horcajadas et al ., 2008 ; Critchley and Saunders, 2009 ; Altmae et al ., 2010 ; King and Critchley, 2010 ).

Mirnas

In addition to Dicer, altered expression of DGCR8 and XPO-5 has been associated with deficiency in post-transcriptional and processing of miRNAs during tumorigenesis ( Murphy et al ., 2008 ; Bartel, 2009 ; Perron and Provost, 2009 ; Visone and Croce, 2009 ; Iorio et al ., 2010 ; et al ., 2010b; Siomi and Siomi, 2010 ). Aberrant expression of several miRNAs has been associated with a number of disorders, more specifically cancers ( Ambros and Chen, 2007 ; Cho, 2007 ; Huppi et al ., 2007 ; Ma and Weinberg, 2007 ; Lodish et al ., 2008 ; Crosby et al ., 2009 ; Chen et al ., 2010 ; Fabian et al ., 2010 ; Farajollahi and Maas, 2010 ; Iorio et al ., 2010 ). Among hundreds of genes predicted as target of these miRNAs are a number of oncogenes and tumor suppressor genes ( Chang et al ., 2008 ; Croce, 2008 ). In addition, miRNA genes are frequently located at fragile sites and regions of loss of heterozygosity or common breakpoint regions ( Calin and Croce, 2007 ; Croce, 2008 ). Common fragile sites are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells, including endometrial cancer cells ( McAvoy et al ., 2007 ). In addition to oncogenes and tumor suppressor genes, the expression of pro-inflammatory, angiogenic, cell cycle-related and adhesion molecules, which regulate various cellular activities critical to tumorigenesis, are targeted by many miRNAs. The expression of many of these oncogenes and tumor-suppressor genes, pro-inflammatory, angiogenic, cell-cycle related genes are expressed and associated with establishment and progression of endometrial cancer ( Abal et al ., 2006 ) and in pathogenesis of endometriosis and dysfunctional uterine bleeding. Although altered expression of a subsets of miRNAs has been identified in ectopic endometrium and endometrial cancer as compared to normal endometrium, and their regulatory function on specific genes expression awaits detailed investigation. However, the results suggest that ectopic endometrial tissues and endometrial cancer are programmed differently with respect to their gene expression regulation. Women with endometrial cancer, endometriosis and, more specifically, contraceptive users often experience dysfunctional endometrial bleeding, characterized by an increased inflammatory reaction and increased production of angiogenic mediators as well as excess production of proteolytic enzymes ( Rhoton-Vlasak et al ., 2005 ; Smith and Critchley, 2005 ; Jabbour et al ., 2006 ; Jones et al ., 2006 ). A detailed study involving miRNA expression profile during dysfunctional bleeding would allow for better understating of the disorder and its similarities to and differences from normal menstruation. Among the miRNA profiled, let7 family, which clusters with miR-99/miR-100 and miR-125 family, has been considered to serve as tumor suppressor ( Johnson et al ., 2007 ; Lee and Dutta, 2007 ; Tili et al ., 2007 ; Esquela-Kerscher et al ., 2008 ). Additionally, the expression of miR-15a and miR-16-1 inversely correlated with Bcl-2 expression ( Cimmino et al ., 2005 ). miR-15a and miR-16-1 cluster are located at 13q14.3, a region often rearranged in a number of disorders, and germline mutation in miR-16-1 precursor has been found to be associated with a low level of miR-16-1 expression in chronic lymphocytic leukemia ( Calin et al ., 2005 ). miR-15a and miR-16-1 as well as miR-17-92 which is a target of c-myc, are expressed in endometriosis and endometrial cancer tissues and are regulated by ovarian steroids ( Bircan et al ., 2005 ; Lu et al ., 2007 ; Rinaldi et al ., 2007 ). It has been suggested that miR-17-92 cluster in cooperation with increased c-myc expression results in accelerated tumor development ( Lu et al ., 2007 ; Rinaldi et al ., 2007 ). The transcription factor E2F1 which is associated with cell cycle progression is a target of the miR-17-92 cluster and miR-21 ( Woods et al ., 2007 ), while increased expression of miR-221 and miR-222 promotes cell growth by inhibiting p27 ( le Sage et al ., 2007 ). miR-27a suppresses cdc2/cyclin B inhibitor Myt-1 in MDA-MB-231 cells, promoting cell proliferation ( Mertens-Talcott et al ., 2007 ). Experimental evidence also indicates that overexpression of miR-206 promotes cellular differentiation in C2C12 myoblasts ( Kim et al ., 2006 ) and targets the expression of ERα in ER-positive breast cancer cells ( Adams et al ., 2007 ). Altered expression of ERα and ERβ has been associated with several uterine disorders, including endometrial cancer and endometriosis ( Gleeson et al ., 1993 ; Singh et al ., 2007 ; Bukulmez et al ., 2008 ), and miR-206 as well as miR-18 and miR-181 may potentially regulate their expression in these and other steroid target tissues ( Adams et al ., 2007 ; Pan and Chegini, 2008 ; Maillot et al ., 2009 ; Al-Nakhle et al ., 2010 ). Although evidence suggests that ovarian steroids either directly and/or indirectly may regulate the expression of miRNAs, resulting in reprogramming of their target genes expression, detailed studies are needed to ascertain the molecular mechanism that account for such regulation.

Expression

Since their discovery over a decade ago, our understanding of miRNA expression and regulatory function has increased exponentially ( Ambros and Chen, 2007 ; Cho, 2007 ; Huppi et al ., 2007 ; Ma and Weinberg, 2007 ; Lodish et al ., 2008 ; Crosby et al ., 2009 ; Chen et al ., 2010 ; Fabian et al ., 2010 ; Farajollahi and Maas, 2010 ; Iorio et al ., 2010 ). In reproductive tract tissues, expression profiling has also identified a large number of miRNAs in the ovarian, fallopian tube and uterine tissues in both normal and diseased states( Chakrabarty et al ., 2007 ; Boren et al ., 2008 ; Hong et al ., 2008 ; Hu et al ., 2008 ; Luo and Chegini, 2008 ; Merritt et al ., 2008 ; Nagaraja et al ., 2008 ; Pan and Chegini, 2008 ; Burney et al ., 2009 ; Chung et al ., 2009 ; Gonzalez and Behringer, 2009 ; Kobel et al ., 2009 ; Qian et al ., 2009 ; Creighton et al ., 2010 ; Filigheddu et al ., 2010 ; Kuokkanen et al ., 2010 ; Myatt et al ., 2010 ). The menstrual-dependent expression of some miRNAs imply their possible regulation by ovarian steroids, while their aberrant expression in endometriosis and endometrial cancer associates these miRNAs with endometrial disorders( Boren et al ., 2008 ; Pan and Chegini, 2008 ; Burney et al ., 2009 ; Qian et al ., 2009 ; Creighton et al ., 2010 ; Filigheddu et al ., 2010 ). Expression profiling of endometrial epithelial cells isolated from mid-luteal phase, or isolated endometrial cells treated with ovarian steroids provided support for potential regulatory functions of ovarian steroids on miRNA expression ( Pan and Chegini, 2008 ; Maillot et al ., 2009 ; Kuokkanen et al ., 2010 ). Functional regulatory interactions between ovarian steroids, their receptors and miRNAs expression have also been reported in other steroids-sensitive cells( Chakrabarty et al ., 2007 ; Kondo et al ., 2008 ; Zhao et al ., 2008b ; Bhat-Nakshatri et al ., 2009 ; Maillot et al ., 2009 ; Pandey and Picard, 2009 ; Wickramasinghe et al ., 2009 ; Yamagata et al ., 2009 ; Al-Nakhle et al ., 2010 ; Li et al ., 2010 ; Loven et al ., 2010 ; Zhao et al ., 2010 ). Although the molecular mechanisms to explain the regulatory action of ovarian steroids on miRNA expression remain unclear, recent reports suggested that inhibition of miRNA maturation at the level of processing of pri-miRNAs into pre-miRNAs and estrogen-dependent association with Drosha complex may account for ERα mediated actions on target gene expression ( Castellano et al ., 2009 ; Yamagata et al ., 2009 ). miRNAs such as miR-21, miR-18a, miR-181a, miR-206, miR-133 and miR-142-5p; predicted to target a large number of genes, including transforming growth factor beta (TGF-β), TGF-β receptor, ERs, and PRs ( Adams et al ., 2007 ; Maillot et al ., 2009 ; Kuokkanen et al ., 2010 ; Pan et al ., 2010 ) are expressed in the endometrium. The product of these genes plays a critical role in various endometrial activities. Functional analysis in other cells has also provided support for regulatory influence of these miRNAs on the expression of genes involved in cell-cycle progression, differentiation, apoptosis, inflammatory and immune response and angiogenesis ( Ambros and Chen, 2007 ; Cho, 2007 ; Huppi et al ., 2007 ; Ma and Weinberg, 2007 ; Lodish et al ., 2008 ; Crosby et al ., 2009 ; Chen et al ., 2010 ; Fabian et al ., 2010 ; Farajollahi and Maas, 2010 ; Iorio et al ., 2010 ). These cellular processes are integrated parts of the cyclic endometrial regeneration and pathogenesis of a number of disorders, including endometriosis and endometrial cancer. Although cell- and tissue-specific biological function of many miRNAs, including in the endometrium, remains to be established, conditional inactivation of Dicer has provided evidence for the pivotal function of miRNAs in ovarian as well as oviductal and uterine mesenchymal cellular development, female sterility and multiple reproductive defects ( Hong et al ., 2008 ; Hu et al ., 2008 ; Nagaraja et al ., 2008 ; Gonzalez and Behringer, 2009 ). Similar tubal morphological abnormalities seen as a result of Dicer conditional-inactivation are often observed in fallopian tubes of women with endometriosis (Chaudhri et al. , 2010). Fallopian tubes of women with endometriosis display an altered expression of miRNAs and mRNAs; personal communication). Although, alterations in peritoneal environment, endometrial receptivity, ovarian reserve, and oocyte quality often attend endometriosis-associated infertility, the contribution of an overt tubal disease may influence early embryonic development and be reflected in an altered expression of a number of miRNAs. Through expression profiling of a large number of miRNAs and mRNAs in fallopian tubes of women with and without endometriosis, we identified not only the expression of DGCR8, Dicer and Exportin-5, but also the expression of the same set of miRNAs that were altered in the oviduct of mice with Dicer conditional-inactivation in the fallopian tubes of women with endometriosis (Chaudhri et al ., 2010).

Conclusions

In recent years, an unprecedented advancement has been made into the understanding of the uterine molecular environment under normal and diseased conditions. More specifically, expression profiling of thousand of genes allowed identification of new genomic pathways with potential regulatory functions in development and homeostasis of uterine normal biological and physiological activities, as well as uterine disorders. Through these studies it has become more clear that the products of several of these genes, either alone, or through interactive mechanisms, function as regulators of inflammatory and immune responses, cell cycle progression, differentiation, apoptosis, and tissue remodeling. These events play key roles in normal development as well as establishment and progression of uterine disorders. Clearly, identifying the precise regulation of these genes at transcriptional and translational levels, the influence of epigenetic mechanism and genomic re-arrangement, is central to understanding of their functions in normal endometrial integrity and pathological outcomes. Expression profiling, cloning strategies and next generation sequencing have identified a large number of miRNAs, and functional analysis has implicated miRNAs as major component of post-transcriptional regulatory mechanism. Various experimental models have provided valuable information regarding the biological relevance of miRNAs in numerous cells and tissues under normal and diseased conditions. The expression profiling and, to a limited extent, functional analysis, also supports the biological relevance of miRNAs in normal endometrial developmental processes as well as disorders such as endometriosis and endometrial cancer. Moreover, evidence suggests that uterine miRNAs expression either directly or indirectly is regulated by ovarian steroids; however the manners by which ovarian steroids mediate their actions in unclear. This is of particular importance because ovarian steroids are central to uterine normal physiological function and the outcome of uterine pathogenesis and tissue and serum profiling of miRNAs appears to be more superior to mRNA expression profiling to differentiate normal from diseased conditions. If the expression pattern of a number of miRNAs differentiates the normal endometrium from diseased conditions, the result may have a significant impact on prognostics and on diagnostic approaches as tools for assessing response to various treatment strategies. Evidence generated in other cell and in vivo systems supports the experimental utilization of miRNA modulation for therapeutic and medical management of disorders such as lowering of plasma cholesterol (miR-122), cancer therapy (miR-21), cardiac hypertrophy (miR-21) and cardiac arrhythmia (miR-1; Esau et al ., 2006 ; Krichevsky and Gabriely, 2009 ; Jiang et al ., 2010b ). Moreover, genetic variations, single nucleotide polymorphisms and chromosomal rearrangements, which can impact the interaction between miRNAs and/or their target genes, have been associated with various aspects of cellular development, and serve as underlying cause of many human diseases and disorders, including reproductive tract tissues. Additionally, many new small RNA families and novel miRNAs are being discovered, further underscoring the biological regulatory importance of these RNAs and their interactions with their target genes. As such major challenges lie ahead in deciphering many functional aspects of miRNAs in uterine and other reproductive tract tissues. Since the biological relevance of a vast majority of the genes profiled in uterine and other reproductive tissues remains unknown, and the discovery of small RNAs, including miRNAs, added another layer of complexity, individual and combined collaborative efforts are required to enhance our understanding of their interactions and regulatory functions at cellular and tissue levels.

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