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Long non-coding RNAs and endometrial cancer
Biomedicine & Pharmacotherapy 119 (2019) 109396
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Review
Long non-coding RNAs and endometrial cancer Hongyang Liu a b
a,⁎,1
b,1
, Junhu Wan
, Jie Chu
T
b
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Endometrial cancer Long non-coding RNAs Tumorigenesis Metastasis Biomarkers
Endometrial cancer (EC) is one of the most common gynecologic malignancies. In spite of the advance in chemotherapy, radiotherapy or surgical techniques for EC in recent years, the survival rate of advanced stage EC patients remains unsatisfactory. Long non-coding RNAs (lncRNAs) are known as transcripts longer than 200 nucleotides exhibiting no or limited protein-coding potential. Growing evidence suggested lncRNAs may be a critical class of pervasive genes involved in cancer progression. However, the function and biological relevance between lncRNAs and EC remain not yet fully understood. Accumulating evidence has indicated that lncRNAs are dysregulated in EC, and closely related to tumorigenesis, metastasis and chemoresistance. In this review, we summarize the known regulation and functional roles of lncRNAs in EC. Besides, we will discuss the potential of lncRNAs as diagnostic biomarkers and therapeutic targets in EC.
1. Introduction It has been well accepted that almost 90% of the human genome is transcribed into non-coding RNAs (ncRNAs), which leading the hotspots of scientific research from protein-coding genes to ncRNAs [1,2]. Although ncRNAs were once regarded as transcriptional “noise’’, because of no specific function described for it, many studies have shown that they can regulate protein-coding gene expression at different levels, such as epigenetic, transcriptional and posttranscriptional [3,4]. Besides, they also participate in multiple biological processes, including X chromosome inactivation, chromatin modification and genomic imprinting [5,6]. According to different size, ncRNAs can be divided into two groups: small ncRNAs (﹤200 nucleotides) and long ncRNAs [7,8]. Several kinds of small ncRNAs like transfer RNAs (tRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs) or PIWI-interacting RNAs (piRNAs) have been extensively studied, with significant regulatory roles in cancer and other diseases [9]. Long ncRNAs (lncRNAs) (﹥200 nucleotides) are poorly conserved and have received less attention [10]. LncRNAs are highly abundant expressed across all kingdoms, from prokaryotes to mammals and expressed in a tissue or disease with specific manner [11,12]. However, their functions and biological relevance remain not very clear. Endometrial cancer (EC) is one of the most common types of gynecological cancer. In spite of the advance in chemotherapy,
radiotherapy and surgical techniques for EC treatment, the survival rate of EC patients remains unsatisfactory [13]. The pathogenesis of EC is very complicated and poorly understood. Recent studies indicated that a number of lncRNAs are dysregulated in EC and their aberrant expressions are associated with tumorigenesis, metastasis, prognosis and diagnosis. In this review, we will briefly outline the known functions of lncRNAs, highlight the functional roles of several lncRNAs in EC and suggest reasonable strategies for future research. 2. Endometrial cancer Endometrial cancer is one of the most common gynecologic malignancies and the fourth most common cause of cancer in women [14]. In 2018, there was an estimated 63,230 new cases and 11,350 deaths of EC [15]. Women diagnosed with early EC stage usually have a good prognosis with overall survival (OS) rates of greater than 90% for 5 years. However, women with stage III or IV disease only have 5-year survival rates of 60% or 20%, respectively. Generally, EC has been segmented into type I and type II, according to Bokhman`s model [16]. Type I is also described as endometriod endometrial carcinoma (EEC) and comprised the most common endometrial carcinoma (approximately 80–85% cases), which is associated with anovulatory bleeding and infertility in the premenopausal state, obesity, and metabolic disturbances [17]. Furthermore, these tumors are commonly well differentiated and have a good prognosis. Type II, known as non-
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Corresponding author. E-mail address: [email protected] (H. Liu). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.biopha.2019.109396 Received 23 May 2019; Received in revised form 11 August 2019; Accepted 28 August 2019 0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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Fig. 1. Overview of five categories of lncRNAs: intergenic, intronic, bidirectional, sense and antisense lncRNA.
3.1. Signal lncRNA
endometrioid endometrial carcinoma (NEEC), is uncorrelated to circulating estrogen levels. In addition, type II EC presages a poor prognosis because they are often high-grade endometrioid adenocarcinomas with a worse differentiation and diagnosed at an advanced stage with a distant metastases.
These lncRNAs belonging to this prototype can serve as molecular signals that immediately regulate cellular processes. Signal lncRNA can regulate gene regulation in space and time, specifically by combining with signaling pathways or transcription factors or interacting with DNA directly.
3. Overview of lncRNAs 3.2. Decoy lncRNAs Long non-coding RNAs (LncRNAs) are RNA molecules with more than 200 nucleotides in length. LncRNAs can be divided into sense, antisense, bidirectional, intronic or intergenic according to their proximity to the nearest known protein-coding genes (Fig. 1). LncRNAs have no or limited protein coding potential owing to lacking open reading frames. The homologous expression of lncRNAs exists in mammals by cancer-specific manners, which support lncRNAs might be potential biomarkers and therapeutic targets [10,11]. Furthermore, growing evidences have indicated that lncRNAs play a crucial role in the occurrence and development of various diseases through several different mechanisms such as signaling, decoying, scaffolding and guidance [18–20] (Fig. 2).
LncRNAs of this archetype can negatively regulate their targets such as microRNAs, RNA-binding proteins or transcription factors to prevent their expression. The functions of these lncRNAs are called “competing endogenous RNAs”. The pseudogene lncRNA PVT1 is an example of a decoy lncRNA. It may function as competing endogenous RNAs by binding with miR-143 to regulate the expression of HK2 in gallbladder cancer [21]. 3.3. Scaffold lncRNAs The most complex archetype was scaffold lncRNAs, which have
Fig. 2. Overview of molecular functions of lncRNAs. A. signal. B. decoy. C. scaffold. D. guide. 2
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tissues compared to control. Moreover, FER1L4 could promote PTEN expression and inhibit Akt phosphorylation, to decrease EC cell proliferation and arrest cells at G0/G1 phase [33]. LncRNA NEAT1, transcribed from the familial tumor syndrome multiple endocrine neoplasia, was found up-regulated in both EC tissues and EC cell lines. Besides, the expression level was positively correlated with FIGO stage and lymph nodes metastasis [34]. Moreover, NEAT1 promoted HEC-1A cell proliferation, invasion and migration, by regulating Wnt/β-catenin pathway via miR-214-3p and miR-146b-5p [35–37]. LncRNA TDRG1 promoted EC cell viability, invasion and migratory ability, and inhibited apoptosis, by regulating VEGF-A, PI3K, Bcl-2, MMP2 and survivin [38]. LncRNA DLEU1 was found overexpressed in EC cells and tissues. DLEU1 knockdown significantly suppressed EC cell viability, promoted cell apoptosis, decreased BCL-2 expression and increased the expression of Bax and cleaved-caspase-3 [39]. Besides, DLEU1 inhibited EMT process by increasing the expression of E-cadherin and decreasing the expression of N-cadherin, snail and vimentin. Furthermore, DLEU1 could sponge microRNAs miR-490 and miR-490 to reverse the effects of DLEU1 in regulating the malignant behaviors of EC cells. LncRNAs PVT1 and PCGEM1 were also reported to promoting EC cell proliferation, migration by regulating miR-195-5p or miR-129-5p expression respectively [40,41].
different domains binding to different effector molecules. The scaffolding complexes could initiate the relevant biological functions through regulating chromosome rearrangement, RNA polymerase II activity or histone modifications. HOTAIR functioned as a molecular scaffold [22]. It could recruit the PRC2 complex to the targets, such as histone H3K27 trimethylation or the promoters of epigenetic silencing genes. 3.4. Guide lncRNAs A further archetype of lncRNAs can combine with target proteins to form a ribonucleoprotein complex and then guide them to specific locations. In addition, these lncRNAs can change the expression of neighboring (cis) or distantly located (trans) genes by activation or repression. Guide lncRNAs can lead to these changes in the targeted gene epigenome by regulating of information through DNA fragments. For instance, lncRNAs can function as guiding in cis including COLDAIR, CCND1, and HOTTIP. Moreover, these lncRNAs play a crucial role in trans genes including linc-p21, HOTAIR and Jpx [23]. 4. The functional roles of lncRNAs in endometrial cancer Endometrial cancer is considered to be a multi-factor and multistage process, with genetic alteration accumulated [13]. Given the diversity of function, lncRNAs behave like tumor suppressors or oncogenes, by impinging on miscellaneous cancer-related cellular processes, including cell growth, metastasis, differentiation and stem-ness [12]. Besides, the special functional significance of lncRNAs hint at the possibility of using them as promising biomarkers in clinical cancer therapy. In this section, we will systematically discuss the endometrial cancer-related lncRNAs reported in recent years and their roles in different cancer hallmarks (Fig. 3 and Table 1).
4.2. LncRNAs regulate tumor metastasis LncRNA H19 is one of the highest expressed genes during embryogenesis and placental development, and has been implicated in the pathogenesis of diverse human cancers [42]. H19 was found expressed significantly higher in EC tumor tissues than in normal tissues. Interestingly, Zhao et al indicated that H19 knockdown did not affect the EC cell growth rate, but significantly inhibited the cell migration and invasion [43]. Besides, downregulation H19 could reverse the epithelialmesenchymal transition (EMT), by decreasing snail level and increasing E-cadherin expression without affecting vimentin level. Another group investigated that H19 could enhance the expression of metastasis-promoting genes targeted by let-7, including Hmga2, c-Myc, Igf2bp3, and its expression level was regulated by anti-diabetic drug metformin via DNA methylation [44]. The expression level of LncRNA UCA1 in lymph node metastasis tissue was found higher than that in the proliferative endometrium and primary EC tissues. Besides, the UCA1 expression level was found to be closely correlated with lymph node metastasis, distant metastasis, tumor grade, advanced TNM stage and vessel invasive in EC tissues [45]. LncRNA, colon cancer-associated transcript 2 (CCAT2), was first discovered in colon cancer by promoting tumor growth, metastasis, and chromosomal instability [46]. After analyzing 30 pairs of EC and matched non-cancerous tissues by qRT-PCR, Xie et al found the expression level of CCAT2 was significantly higher in tumor tissues. Moreover, CCAT2 acted as an endogenous sponge by competing for miR-216b to regulate anti-apoptotic gene Bcl-2, thereby affected EC cells growth and metastasis process [47]. The lncRNA ABHD11-AS1 has been reported to be overexpressed in ovarian cancer and gastric cancer tissues [48,49]. In endometrial cancer, ABHD11-AS1 was also found significantly overexpressed. Besides, ABHD11-AS1 regulated EC cell proliferation, cycle, apoptosis and enhanced the invasive and metastatic process, by affecting the expression of CDK1, CDK2, CDK4, Bcl-xl, VEGFA, cyclin D1 and p16 [50,51]. ABHD11-AS1 bound directly to cyclin D1 in the RNA pull down assays, to regulate tumorigenicity in an in vivo model of EC in nude mice. LncRNA LINC00261 was reported to be downregulated in EC. Overexpression LINC00261 decreased these dissociative miRNAs, including miR-182, miR-183, miR-153, miR-27a, and miR-96, leading to increase of FOXO1, as a result of affecting EC cell proliferation, migration, and invasion [52]. LncRNA activated by TGF-β (ATB) has been found to regulate EC cell proliferation and metastasis process by tumor suppressive miRNA-related signals. The high expression level of ATB was correlated with high FIGO stage and poor EC tumor differentiation
4.1. LncRNAs affect tumor growth The lncRNA HOTAIR, transcribed from the antisense strand of chromosome 12 at the HOXC gene cluster, has been investigated in numerous solid tumors [12]. Using lentivirus-mediated siRNA expression system, Huang et al found knockdown of HOTAIR significantly reduced the proliferation and colony numbers of EC cell line HEC-1A [24]. Besides, down-regulation of HOTAIR induced cell cycle arrest at G0/G1 phase. Likewise, HOTAIR was reported interacted with miR-646 in the RNA pull-down assays, to regulate the viability, migration and invasion of EC cells [25]. LncRNA matastasis associated lung adenocarcinoma transcript 1 (MALAT1), was firstly discovered as a prognostic factor for lung cancer metastasis [26]. Overexpressed MALAT1 in EC cell line AN3CA and HEC-1-B enhanced cell proliferation. Furthermore, TUNEL assay showed that MALAT1 knockdown induced a striking increase in apoptotic cell population, compared with control treatment. The expression of MALAT1 is activated by Wnt/β-catenin signaling, and as a direct transcriptional target of Wnt/β-catenin in EC cells [27]. However, another study indicated that MALAT1 levels were lower in most EEC specimens than in non-tumor tissues, and miR-200 family member miR-200c binds to the 3`UTR of MALAT1 to form a MALAT1/miR-200c sponge to facilitate epithelial-to-mesenchymal transition (EMT) in EC cells [28]. Li et al identified long intergenic non-coding RNA lincRNANR_034037 overexpression enhanced EC cell proliferation using colony formation and CCK-8 assays [29]. Besides, xenografts with lincRNANR_034037 overexpressed cells resulted in significant tumor growth. LncRNA MEG3 obviously inhibited EC cell proliferation and tumor growth by inhibiting Notch and PI3K pathway [30,31]. LncRNA BANCR was shown to promote cell proliferation and inhibit apoptosis of EC cells by up-regulating Cyclin D1 and Bcl-2, with significantly increasing the percentage of EC cells in S phase [32]. The expression of lncRNA FER1L4 was significantly reduced in EC 3
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Fig. 3. Overview of the role of representative lncRNAs in EC.
4.3. LncRNAs are involved in maintain of cancer stem cells
[53,54]. Besides, inhibition of ATB in RL95 and HEC1A cells impaired the cell vitality, and increased caspase-3-related tumor apoptosis, by increasing the miR-126 level. Meanwhile, ATB also regulated EC cell migration and invasion by inhibiting Sox2 signals and TGF-β-induced epithelial-mesenchymal transition (EMT) process.
Cancer stem cells (CSCs) are considered as a subpopulation of tumor cells to initiate and sustain tumor growth, with self-renewal and differentiation potential [55]. LncRNA RoR was recently shown to maintain the pluripotency of human embryo stem cells (hESCs). The core
Table 1 LncRNAs implicated in EC. LncRNA
Expression level in EC
Biological function
Molecular function
Refs
MALAT1 lincRNA-NR_034037 HOTAIR
Downregulated Upregulated Upregulated
Signal and decoy Scaffold and guide Signal and decoy
[27,28] [29] [24,25,58,62]
H19 FER1L4 MEG3 BANCR NEAT1 UCA1 LINC00672 TUSC7 CCAT2 ABHD11-AS1 TDRG1 DLEU1 LINC00261 PVT1 PCGEM1 CDKN2B ATB
Upregulated Downregulated Downregulated Upregulated Upregulated Upregulated Downregulated Downregulated Upregulated Upregulated Upregulated Upregulated Downregulated Upregulated Upregulated Upregulated Upregulated
Regulate cell migration, invasion, polarization and proliferation Modulate cell growth Regulate cell proliferation, migration, invasion, EMT, cancer stem cells and cisplatininduced resistance Promote tumor cell migration and invasion Regulate cell proliferation and cell cycle Inhibit endometrial carcinoma tumorigenesis and progression Promote cell proliferation and invasion Promotes cell proliferation, invasion and migration Regulate cell migration and invasion Promote endometrial cancer chemosensitivity Advance chemotherapy sensitivity of endometrial carcinoma Regulate cell growth and metastasis Promote the development of endometrial carcinoma Enhance tumorigenicity in endometrial carcinoma Contribute to the development of endometrial cancer Inhibit endometrial carcinoma cell proliferation, migration and invasion Regulate cell proliferation, migration and invasion Promote the proliferation, migration and invasive Contribute to paclitaxel resistance Regulate cell migration and invasion
Signal Signal Signal and Signal Signal and Signal Scaffold Decoy Decoy Decoy Decoy Signal and Signal and Decoy Signal and Decoy Decoy
[43,44] [33] [30,31] [32] [34,35] [45] [63] [64] [47] [50] [38] [39] [52] [40] [41] [65] [53]
4
decoy decoy
decoy decoy decoy
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resistant HEC1A/CR cell line, which revealed that TUSC7 was involved in chemotherapy resistance. Besides, TUSC7 may act as a potential tumor suppressor to inhibit cell growth and advance chemotherapy sensitivity through targeted silencing of miR-23b. Subsequently, this group found the overexpression of lncRNA CDKN2B-AS was associated with the low sensitivity to paclitaxel of EC patients. CDKN2B-AS knockdown decreased IC50 of paclitaxel in Ishikawa/PA and HEC-1A/ PA cells. Besides, CDKN2B-AS promoted the paclitaxel induced cytotoxicity through miR-125a-5p-Bcl2/MRP4 pathway [65].
transcription factors (TFs), including Nanog, Oct4 and Sox2, were overexpressed in a variety of cancer and essential for maintaining the pluripotency of cancer stem cells (CSCs). Zhou et al found the expression of RoR and core TFs were obviously reduced in all differentiated EC stem cell tumor spheres, suggesting that RoR expression was positively correlated with the levels of undifferentiated tumor spheres [56]. Besides, RoR also acted as an endogenous miRNA sponge by inhibiting miR-145 mediating tumor sphere differentiation. More and more evidence indicates that EMT process induced stem cell activity [57]. HOTAIR was reported to regulate the methylation of multiple genes, which were associated with EMT and stem cell phenotype in colon and breast cancer cell lines. Łuczak et al revealed HOTAIR expression may serve as an independent prognostic factor in EC, but there were no correlations between HOTAIR expression level and EMT or CSC markers for the molecular subtypes of EC patients [58].
4.6. LncRNA and miRNA interaction Both lncRNAs and miRNAs are epigenetic regulators and dysregulated in EC. miRNAs are small (∼19-22 nucleotides), evolutionarily conserved and single-stranded ncRNAs. Braicu et al evaluated miRNA expression pattern in formalin-fixed paraffin-embedded samples from endometriosis and ovarian cancer patients using PCR-array technology [66]. They found higher number of altered miRNAs in endometriosis versus ovarian cancer tissue. miRNAs could regulate mRNA translation or stability by base-pairing with miRNA response elements in the 3`UTR of the target transcript within the RNA-induced silencing complex. Besides, lncRNAs could act as sponges for miRNAs, which are called ceRNAs, and decoys for proteins. Several lncRNAs bind to miRNAs by interfering with this mechanism, thus blocking their action on target mRNAs. For example, overexpression LINC00261 decreased these dissociative miRNAs, including miR-182, miR-183, miR-153, miR-27a, and miR-96, leading to increase of FOXO1, as a result of affecting EC cell proliferation, migration, and invasion [52].
4.4. LncRNAs act as molecular based classification of endometrial cancer Endometrial cancer is generally classified into two subtypes, endometrioid endometrial carcinoma (EEC, type I) and non‑endometrioid endometrial carcinoma (NEEC, type II), classificated by different patterns of pathogenesis, molecular alterations, and clinical outcome [16]. Besides, the studies about the etiology of EC using traditional immunohistochemistry and Sanger sequencing methods have identified the mutations of PTEN, KRAS and CTNNB1 genes [59]. Although several genetic alterations and mutations have been associated with increased risk and poor clinical outcomes of EC, new molecular classification markers need to be identified for early diagnosis and treatment purpose. Using next-generation sequencing methods, Ravo et al detected the differential expression level of lncRNAs between the EC patients’ tumor samples and six paired normal tissues. Besides, they compared and validated these results with different EC datasets of TCGA database. Totally, they identified 80 lncRNAs statistically distributed in five clusters, with a higher fold expression, reflecting tumor grade stratification and different survival trend [60]. Another group also reported the lncRNA subgroup classification of EC by unsupervised clustering and integrative analysis of EC primary tumors dataset [61]. They identified three lncRNAs subgroups, which were correlated with clinico-genomic tumor aberrations. The subgroups lncRNAs were named basal-like, luminal-like and CTNNB1-enriched subgroups. Basal-like subgroup was characterized by aggressive tumors with higher pathological grade, TNM stage and somatic mutations in trithorax-group genes (MLL, MLL2 and MLL3). In contrast to the basallike subgroup, progesterone (PGR) and estrogen receptor (ESR1) genes in luminal-like subgroup were highly up-regulated in the EC. CTNNB1enriched subgroup was similar to that of the CTNNB1-enriched liver cancer subgroup.
5. Future perspective LncRNA, as a relatively recent discovery in the RNA world, has become rapidly evident and plays a pivotal role in EC development and progression. However, the molecular mechanisms and functions of the vast majority of lncRNAs in EC remain uncharacterized. With the deepening understanding of lncRNAs function, lncRNAs are in the focus of intensive study. LncRNAs can regulate cellular biological processes through a variety of different molecular mechanisms [11,12]. LncRNAs not only act as miRNA sponges to regulate gene expression, but also bind to chromatin to promote epigenetic regulation function. Besides, they interact with RNA-binding proteins to monitor multiple cellular processes. LncRNAs also perform multifaceted functions in facilitating EC development by controlling tumor growth, invasion and chemoresistance. More and more experiments proved that lncRNAs could serve as crucial regulators in the initiation and development of EC. They also exhibit large potential to be developed as therapeutic targets and novel biomarkers for EC. Although studies on the relationship between EC and lncRNAs are still at preliminary stage. We believe that with the rapid advancements in technology and increasing knowledge on lncRNAs, elucidation of its roles in EC would further extend our understanding of the mechanisms underlying EC development, occurrence, diagnosis and treatment.
4.5. LncRNAs contributes to EC chemoresistance Cisplatin, one of the platinum drug, is regarded as the first choice for EC. However, due to the development of chemoresistance, it limits cisplatin efficacy in clinical chemotherapy. The expression level of LncRNA HOTAIR was found significantly decreased in cisplatin-resistant EC cell Ishikawa [62]. Besides, HOTAIR can reverse the chemoresistance of Ishikawa cells to cisplatin by regulation of autophagy process with influencing MDR, Beclin-1 and P-gp expression. Paclitaxel is regarded as the primary single chemotherapeutic agent for the treatment of advanced and recurrent EC. Overexpression of LncRNA LINC00672 was found to decrease the paclitaxel IC50 and promote the chemosensitivity of EC cells in vitro and in vivo, with no effect on another two chemotherapeutic drugs carboplatin and cisplatin [63]. Shang et al reported that the expression level of lncRNA TUSC7 was much lower in resistant patients to chemotherapy cisplatin (CDDP) and paclitaxel (Taxol) than that in sensitive patients [64]. TUSC7 overexpression enhanced the chemotherapy sensitivity of chemotherapy-
6. Conclusions In this review, we summarize the known functional roles of lncRNAs in EC. We believe that lncRNAs might act as diagnostic biomarkers and therapeutic targets of EC in the future. Funding This study was supported by grants from the National Natural Science Foundation of China grants (Grant No. 81702780). This work was also supported by the Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University. 5
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Declaration of Competing Interest The authors declared no conflict of interest.
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Acknowledgment [30]
We thank for the support from Academy of Medical Sciences of Zhengzhou University Translational Medicine platform.
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Review
Long non-coding RNAs and endometrial cancer Hongyang Liu a b
a,⁎,1
b,1
, Junhu Wan
, Jie Chu
T
b
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Endometrial cancer Long non-coding RNAs Tumorigenesis Metastasis Biomarkers
Endometrial cancer (EC) is one of the most common gynecologic malignancies. In spite of the advance in chemotherapy, radiotherapy or surgical techniques for EC in recent years, the survival rate of advanced stage EC patients remains unsatisfactory. Long non-coding RNAs (lncRNAs) are known as transcripts longer than 200 nucleotides exhibiting no or limited protein-coding potential. Growing evidence suggested lncRNAs may be a critical class of pervasive genes involved in cancer progression. However, the function and biological relevance between lncRNAs and EC remain not yet fully understood. Accumulating evidence has indicated that lncRNAs are dysregulated in EC, and closely related to tumorigenesis, metastasis and chemoresistance. In this review, we summarize the known regulation and functional roles of lncRNAs in EC. Besides, we will discuss the potential of lncRNAs as diagnostic biomarkers and therapeutic targets in EC.
1. Introduction It has been well accepted that almost 90% of the human genome is transcribed into non-coding RNAs (ncRNAs), which leading the hotspots of scientific research from protein-coding genes to ncRNAs [1,2]. Although ncRNAs were once regarded as transcriptional “noise’’, because of no specific function described for it, many studies have shown that they can regulate protein-coding gene expression at different levels, such as epigenetic, transcriptional and posttranscriptional [3,4]. Besides, they also participate in multiple biological processes, including X chromosome inactivation, chromatin modification and genomic imprinting [5,6]. According to different size, ncRNAs can be divided into two groups: small ncRNAs (﹤200 nucleotides) and long ncRNAs [7,8]. Several kinds of small ncRNAs like transfer RNAs (tRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs) or PIWI-interacting RNAs (piRNAs) have been extensively studied, with significant regulatory roles in cancer and other diseases [9]. Long ncRNAs (lncRNAs) (﹥200 nucleotides) are poorly conserved and have received less attention [10]. LncRNAs are highly abundant expressed across all kingdoms, from prokaryotes to mammals and expressed in a tissue or disease with specific manner [11,12]. However, their functions and biological relevance remain not very clear. Endometrial cancer (EC) is one of the most common types of gynecological cancer. In spite of the advance in chemotherapy,
radiotherapy and surgical techniques for EC treatment, the survival rate of EC patients remains unsatisfactory [13]. The pathogenesis of EC is very complicated and poorly understood. Recent studies indicated that a number of lncRNAs are dysregulated in EC and their aberrant expressions are associated with tumorigenesis, metastasis, prognosis and diagnosis. In this review, we will briefly outline the known functions of lncRNAs, highlight the functional roles of several lncRNAs in EC and suggest reasonable strategies for future research. 2. Endometrial cancer Endometrial cancer is one of the most common gynecologic malignancies and the fourth most common cause of cancer in women [14]. In 2018, there was an estimated 63,230 new cases and 11,350 deaths of EC [15]. Women diagnosed with early EC stage usually have a good prognosis with overall survival (OS) rates of greater than 90% for 5 years. However, women with stage III or IV disease only have 5-year survival rates of 60% or 20%, respectively. Generally, EC has been segmented into type I and type II, according to Bokhman`s model [16]. Type I is also described as endometriod endometrial carcinoma (EEC) and comprised the most common endometrial carcinoma (approximately 80–85% cases), which is associated with anovulatory bleeding and infertility in the premenopausal state, obesity, and metabolic disturbances [17]. Furthermore, these tumors are commonly well differentiated and have a good prognosis. Type II, known as non-
⁎
Corresponding author. E-mail address: [email protected] (H. Liu). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.biopha.2019.109396 Received 23 May 2019; Received in revised form 11 August 2019; Accepted 28 August 2019 0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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Fig. 1. Overview of five categories of lncRNAs: intergenic, intronic, bidirectional, sense and antisense lncRNA.
3.1. Signal lncRNA
endometrioid endometrial carcinoma (NEEC), is uncorrelated to circulating estrogen levels. In addition, type II EC presages a poor prognosis because they are often high-grade endometrioid adenocarcinomas with a worse differentiation and diagnosed at an advanced stage with a distant metastases.
These lncRNAs belonging to this prototype can serve as molecular signals that immediately regulate cellular processes. Signal lncRNA can regulate gene regulation in space and time, specifically by combining with signaling pathways or transcription factors or interacting with DNA directly.
3. Overview of lncRNAs 3.2. Decoy lncRNAs Long non-coding RNAs (LncRNAs) are RNA molecules with more than 200 nucleotides in length. LncRNAs can be divided into sense, antisense, bidirectional, intronic or intergenic according to their proximity to the nearest known protein-coding genes (Fig. 1). LncRNAs have no or limited protein coding potential owing to lacking open reading frames. The homologous expression of lncRNAs exists in mammals by cancer-specific manners, which support lncRNAs might be potential biomarkers and therapeutic targets [10,11]. Furthermore, growing evidences have indicated that lncRNAs play a crucial role in the occurrence and development of various diseases through several different mechanisms such as signaling, decoying, scaffolding and guidance [18–20] (Fig. 2).
LncRNAs of this archetype can negatively regulate their targets such as microRNAs, RNA-binding proteins or transcription factors to prevent their expression. The functions of these lncRNAs are called “competing endogenous RNAs”. The pseudogene lncRNA PVT1 is an example of a decoy lncRNA. It may function as competing endogenous RNAs by binding with miR-143 to regulate the expression of HK2 in gallbladder cancer [21]. 3.3. Scaffold lncRNAs The most complex archetype was scaffold lncRNAs, which have
Fig. 2. Overview of molecular functions of lncRNAs. A. signal. B. decoy. C. scaffold. D. guide. 2
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tissues compared to control. Moreover, FER1L4 could promote PTEN expression and inhibit Akt phosphorylation, to decrease EC cell proliferation and arrest cells at G0/G1 phase [33]. LncRNA NEAT1, transcribed from the familial tumor syndrome multiple endocrine neoplasia, was found up-regulated in both EC tissues and EC cell lines. Besides, the expression level was positively correlated with FIGO stage and lymph nodes metastasis [34]. Moreover, NEAT1 promoted HEC-1A cell proliferation, invasion and migration, by regulating Wnt/β-catenin pathway via miR-214-3p and miR-146b-5p [35–37]. LncRNA TDRG1 promoted EC cell viability, invasion and migratory ability, and inhibited apoptosis, by regulating VEGF-A, PI3K, Bcl-2, MMP2 and survivin [38]. LncRNA DLEU1 was found overexpressed in EC cells and tissues. DLEU1 knockdown significantly suppressed EC cell viability, promoted cell apoptosis, decreased BCL-2 expression and increased the expression of Bax and cleaved-caspase-3 [39]. Besides, DLEU1 inhibited EMT process by increasing the expression of E-cadherin and decreasing the expression of N-cadherin, snail and vimentin. Furthermore, DLEU1 could sponge microRNAs miR-490 and miR-490 to reverse the effects of DLEU1 in regulating the malignant behaviors of EC cells. LncRNAs PVT1 and PCGEM1 were also reported to promoting EC cell proliferation, migration by regulating miR-195-5p or miR-129-5p expression respectively [40,41].
different domains binding to different effector molecules. The scaffolding complexes could initiate the relevant biological functions through regulating chromosome rearrangement, RNA polymerase II activity or histone modifications. HOTAIR functioned as a molecular scaffold [22]. It could recruit the PRC2 complex to the targets, such as histone H3K27 trimethylation or the promoters of epigenetic silencing genes. 3.4. Guide lncRNAs A further archetype of lncRNAs can combine with target proteins to form a ribonucleoprotein complex and then guide them to specific locations. In addition, these lncRNAs can change the expression of neighboring (cis) or distantly located (trans) genes by activation or repression. Guide lncRNAs can lead to these changes in the targeted gene epigenome by regulating of information through DNA fragments. For instance, lncRNAs can function as guiding in cis including COLDAIR, CCND1, and HOTTIP. Moreover, these lncRNAs play a crucial role in trans genes including linc-p21, HOTAIR and Jpx [23]. 4. The functional roles of lncRNAs in endometrial cancer Endometrial cancer is considered to be a multi-factor and multistage process, with genetic alteration accumulated [13]. Given the diversity of function, lncRNAs behave like tumor suppressors or oncogenes, by impinging on miscellaneous cancer-related cellular processes, including cell growth, metastasis, differentiation and stem-ness [12]. Besides, the special functional significance of lncRNAs hint at the possibility of using them as promising biomarkers in clinical cancer therapy. In this section, we will systematically discuss the endometrial cancer-related lncRNAs reported in recent years and their roles in different cancer hallmarks (Fig. 3 and Table 1).
4.2. LncRNAs regulate tumor metastasis LncRNA H19 is one of the highest expressed genes during embryogenesis and placental development, and has been implicated in the pathogenesis of diverse human cancers [42]. H19 was found expressed significantly higher in EC tumor tissues than in normal tissues. Interestingly, Zhao et al indicated that H19 knockdown did not affect the EC cell growth rate, but significantly inhibited the cell migration and invasion [43]. Besides, downregulation H19 could reverse the epithelialmesenchymal transition (EMT), by decreasing snail level and increasing E-cadherin expression without affecting vimentin level. Another group investigated that H19 could enhance the expression of metastasis-promoting genes targeted by let-7, including Hmga2, c-Myc, Igf2bp3, and its expression level was regulated by anti-diabetic drug metformin via DNA methylation [44]. The expression level of LncRNA UCA1 in lymph node metastasis tissue was found higher than that in the proliferative endometrium and primary EC tissues. Besides, the UCA1 expression level was found to be closely correlated with lymph node metastasis, distant metastasis, tumor grade, advanced TNM stage and vessel invasive in EC tissues [45]. LncRNA, colon cancer-associated transcript 2 (CCAT2), was first discovered in colon cancer by promoting tumor growth, metastasis, and chromosomal instability [46]. After analyzing 30 pairs of EC and matched non-cancerous tissues by qRT-PCR, Xie et al found the expression level of CCAT2 was significantly higher in tumor tissues. Moreover, CCAT2 acted as an endogenous sponge by competing for miR-216b to regulate anti-apoptotic gene Bcl-2, thereby affected EC cells growth and metastasis process [47]. The lncRNA ABHD11-AS1 has been reported to be overexpressed in ovarian cancer and gastric cancer tissues [48,49]. In endometrial cancer, ABHD11-AS1 was also found significantly overexpressed. Besides, ABHD11-AS1 regulated EC cell proliferation, cycle, apoptosis and enhanced the invasive and metastatic process, by affecting the expression of CDK1, CDK2, CDK4, Bcl-xl, VEGFA, cyclin D1 and p16 [50,51]. ABHD11-AS1 bound directly to cyclin D1 in the RNA pull down assays, to regulate tumorigenicity in an in vivo model of EC in nude mice. LncRNA LINC00261 was reported to be downregulated in EC. Overexpression LINC00261 decreased these dissociative miRNAs, including miR-182, miR-183, miR-153, miR-27a, and miR-96, leading to increase of FOXO1, as a result of affecting EC cell proliferation, migration, and invasion [52]. LncRNA activated by TGF-β (ATB) has been found to regulate EC cell proliferation and metastasis process by tumor suppressive miRNA-related signals. The high expression level of ATB was correlated with high FIGO stage and poor EC tumor differentiation
4.1. LncRNAs affect tumor growth The lncRNA HOTAIR, transcribed from the antisense strand of chromosome 12 at the HOXC gene cluster, has been investigated in numerous solid tumors [12]. Using lentivirus-mediated siRNA expression system, Huang et al found knockdown of HOTAIR significantly reduced the proliferation and colony numbers of EC cell line HEC-1A [24]. Besides, down-regulation of HOTAIR induced cell cycle arrest at G0/G1 phase. Likewise, HOTAIR was reported interacted with miR-646 in the RNA pull-down assays, to regulate the viability, migration and invasion of EC cells [25]. LncRNA matastasis associated lung adenocarcinoma transcript 1 (MALAT1), was firstly discovered as a prognostic factor for lung cancer metastasis [26]. Overexpressed MALAT1 in EC cell line AN3CA and HEC-1-B enhanced cell proliferation. Furthermore, TUNEL assay showed that MALAT1 knockdown induced a striking increase in apoptotic cell population, compared with control treatment. The expression of MALAT1 is activated by Wnt/β-catenin signaling, and as a direct transcriptional target of Wnt/β-catenin in EC cells [27]. However, another study indicated that MALAT1 levels were lower in most EEC specimens than in non-tumor tissues, and miR-200 family member miR-200c binds to the 3`UTR of MALAT1 to form a MALAT1/miR-200c sponge to facilitate epithelial-to-mesenchymal transition (EMT) in EC cells [28]. Li et al identified long intergenic non-coding RNA lincRNANR_034037 overexpression enhanced EC cell proliferation using colony formation and CCK-8 assays [29]. Besides, xenografts with lincRNANR_034037 overexpressed cells resulted in significant tumor growth. LncRNA MEG3 obviously inhibited EC cell proliferation and tumor growth by inhibiting Notch and PI3K pathway [30,31]. LncRNA BANCR was shown to promote cell proliferation and inhibit apoptosis of EC cells by up-regulating Cyclin D1 and Bcl-2, with significantly increasing the percentage of EC cells in S phase [32]. The expression of lncRNA FER1L4 was significantly reduced in EC 3
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Fig. 3. Overview of the role of representative lncRNAs in EC.
4.3. LncRNAs are involved in maintain of cancer stem cells
[53,54]. Besides, inhibition of ATB in RL95 and HEC1A cells impaired the cell vitality, and increased caspase-3-related tumor apoptosis, by increasing the miR-126 level. Meanwhile, ATB also regulated EC cell migration and invasion by inhibiting Sox2 signals and TGF-β-induced epithelial-mesenchymal transition (EMT) process.
Cancer stem cells (CSCs) are considered as a subpopulation of tumor cells to initiate and sustain tumor growth, with self-renewal and differentiation potential [55]. LncRNA RoR was recently shown to maintain the pluripotency of human embryo stem cells (hESCs). The core
Table 1 LncRNAs implicated in EC. LncRNA
Expression level in EC
Biological function
Molecular function
Refs
MALAT1 lincRNA-NR_034037 HOTAIR
Downregulated Upregulated Upregulated
Signal and decoy Scaffold and guide Signal and decoy
[27,28] [29] [24,25,58,62]
H19 FER1L4 MEG3 BANCR NEAT1 UCA1 LINC00672 TUSC7 CCAT2 ABHD11-AS1 TDRG1 DLEU1 LINC00261 PVT1 PCGEM1 CDKN2B ATB
Upregulated Downregulated Downregulated Upregulated Upregulated Upregulated Downregulated Downregulated Upregulated Upregulated Upregulated Upregulated Downregulated Upregulated Upregulated Upregulated Upregulated
Regulate cell migration, invasion, polarization and proliferation Modulate cell growth Regulate cell proliferation, migration, invasion, EMT, cancer stem cells and cisplatininduced resistance Promote tumor cell migration and invasion Regulate cell proliferation and cell cycle Inhibit endometrial carcinoma tumorigenesis and progression Promote cell proliferation and invasion Promotes cell proliferation, invasion and migration Regulate cell migration and invasion Promote endometrial cancer chemosensitivity Advance chemotherapy sensitivity of endometrial carcinoma Regulate cell growth and metastasis Promote the development of endometrial carcinoma Enhance tumorigenicity in endometrial carcinoma Contribute to the development of endometrial cancer Inhibit endometrial carcinoma cell proliferation, migration and invasion Regulate cell proliferation, migration and invasion Promote the proliferation, migration and invasive Contribute to paclitaxel resistance Regulate cell migration and invasion
Signal Signal Signal and Signal Signal and Signal Scaffold Decoy Decoy Decoy Decoy Signal and Signal and Decoy Signal and Decoy Decoy
[43,44] [33] [30,31] [32] [34,35] [45] [63] [64] [47] [50] [38] [39] [52] [40] [41] [65] [53]
4
decoy decoy
decoy decoy decoy
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resistant HEC1A/CR cell line, which revealed that TUSC7 was involved in chemotherapy resistance. Besides, TUSC7 may act as a potential tumor suppressor to inhibit cell growth and advance chemotherapy sensitivity through targeted silencing of miR-23b. Subsequently, this group found the overexpression of lncRNA CDKN2B-AS was associated with the low sensitivity to paclitaxel of EC patients. CDKN2B-AS knockdown decreased IC50 of paclitaxel in Ishikawa/PA and HEC-1A/ PA cells. Besides, CDKN2B-AS promoted the paclitaxel induced cytotoxicity through miR-125a-5p-Bcl2/MRP4 pathway [65].
transcription factors (TFs), including Nanog, Oct4 and Sox2, were overexpressed in a variety of cancer and essential for maintaining the pluripotency of cancer stem cells (CSCs). Zhou et al found the expression of RoR and core TFs were obviously reduced in all differentiated EC stem cell tumor spheres, suggesting that RoR expression was positively correlated with the levels of undifferentiated tumor spheres [56]. Besides, RoR also acted as an endogenous miRNA sponge by inhibiting miR-145 mediating tumor sphere differentiation. More and more evidence indicates that EMT process induced stem cell activity [57]. HOTAIR was reported to regulate the methylation of multiple genes, which were associated with EMT and stem cell phenotype in colon and breast cancer cell lines. Łuczak et al revealed HOTAIR expression may serve as an independent prognostic factor in EC, but there were no correlations between HOTAIR expression level and EMT or CSC markers for the molecular subtypes of EC patients [58].
4.6. LncRNA and miRNA interaction Both lncRNAs and miRNAs are epigenetic regulators and dysregulated in EC. miRNAs are small (∼19-22 nucleotides), evolutionarily conserved and single-stranded ncRNAs. Braicu et al evaluated miRNA expression pattern in formalin-fixed paraffin-embedded samples from endometriosis and ovarian cancer patients using PCR-array technology [66]. They found higher number of altered miRNAs in endometriosis versus ovarian cancer tissue. miRNAs could regulate mRNA translation or stability by base-pairing with miRNA response elements in the 3`UTR of the target transcript within the RNA-induced silencing complex. Besides, lncRNAs could act as sponges for miRNAs, which are called ceRNAs, and decoys for proteins. Several lncRNAs bind to miRNAs by interfering with this mechanism, thus blocking their action on target mRNAs. For example, overexpression LINC00261 decreased these dissociative miRNAs, including miR-182, miR-183, miR-153, miR-27a, and miR-96, leading to increase of FOXO1, as a result of affecting EC cell proliferation, migration, and invasion [52].
4.4. LncRNAs act as molecular based classification of endometrial cancer Endometrial cancer is generally classified into two subtypes, endometrioid endometrial carcinoma (EEC, type I) and non‑endometrioid endometrial carcinoma (NEEC, type II), classificated by different patterns of pathogenesis, molecular alterations, and clinical outcome [16]. Besides, the studies about the etiology of EC using traditional immunohistochemistry and Sanger sequencing methods have identified the mutations of PTEN, KRAS and CTNNB1 genes [59]. Although several genetic alterations and mutations have been associated with increased risk and poor clinical outcomes of EC, new molecular classification markers need to be identified for early diagnosis and treatment purpose. Using next-generation sequencing methods, Ravo et al detected the differential expression level of lncRNAs between the EC patients’ tumor samples and six paired normal tissues. Besides, they compared and validated these results with different EC datasets of TCGA database. Totally, they identified 80 lncRNAs statistically distributed in five clusters, with a higher fold expression, reflecting tumor grade stratification and different survival trend [60]. Another group also reported the lncRNA subgroup classification of EC by unsupervised clustering and integrative analysis of EC primary tumors dataset [61]. They identified three lncRNAs subgroups, which were correlated with clinico-genomic tumor aberrations. The subgroups lncRNAs were named basal-like, luminal-like and CTNNB1-enriched subgroups. Basal-like subgroup was characterized by aggressive tumors with higher pathological grade, TNM stage and somatic mutations in trithorax-group genes (MLL, MLL2 and MLL3). In contrast to the basallike subgroup, progesterone (PGR) and estrogen receptor (ESR1) genes in luminal-like subgroup were highly up-regulated in the EC. CTNNB1enriched subgroup was similar to that of the CTNNB1-enriched liver cancer subgroup.
5. Future perspective LncRNA, as a relatively recent discovery in the RNA world, has become rapidly evident and plays a pivotal role in EC development and progression. However, the molecular mechanisms and functions of the vast majority of lncRNAs in EC remain uncharacterized. With the deepening understanding of lncRNAs function, lncRNAs are in the focus of intensive study. LncRNAs can regulate cellular biological processes through a variety of different molecular mechanisms [11,12]. LncRNAs not only act as miRNA sponges to regulate gene expression, but also bind to chromatin to promote epigenetic regulation function. Besides, they interact with RNA-binding proteins to monitor multiple cellular processes. LncRNAs also perform multifaceted functions in facilitating EC development by controlling tumor growth, invasion and chemoresistance. More and more experiments proved that lncRNAs could serve as crucial regulators in the initiation and development of EC. They also exhibit large potential to be developed as therapeutic targets and novel biomarkers for EC. Although studies on the relationship between EC and lncRNAs are still at preliminary stage. We believe that with the rapid advancements in technology and increasing knowledge on lncRNAs, elucidation of its roles in EC would further extend our understanding of the mechanisms underlying EC development, occurrence, diagnosis and treatment.
4.5. LncRNAs contributes to EC chemoresistance Cisplatin, one of the platinum drug, is regarded as the first choice for EC. However, due to the development of chemoresistance, it limits cisplatin efficacy in clinical chemotherapy. The expression level of LncRNA HOTAIR was found significantly decreased in cisplatin-resistant EC cell Ishikawa [62]. Besides, HOTAIR can reverse the chemoresistance of Ishikawa cells to cisplatin by regulation of autophagy process with influencing MDR, Beclin-1 and P-gp expression. Paclitaxel is regarded as the primary single chemotherapeutic agent for the treatment of advanced and recurrent EC. Overexpression of LncRNA LINC00672 was found to decrease the paclitaxel IC50 and promote the chemosensitivity of EC cells in vitro and in vivo, with no effect on another two chemotherapeutic drugs carboplatin and cisplatin [63]. Shang et al reported that the expression level of lncRNA TUSC7 was much lower in resistant patients to chemotherapy cisplatin (CDDP) and paclitaxel (Taxol) than that in sensitive patients [64]. TUSC7 overexpression enhanced the chemotherapy sensitivity of chemotherapy-
6. Conclusions In this review, we summarize the known functional roles of lncRNAs in EC. We believe that lncRNAs might act as diagnostic biomarkers and therapeutic targets of EC in the future. Funding This study was supported by grants from the National Natural Science Foundation of China grants (Grant No. 81702780). This work was also supported by the Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University. 5
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Declaration of Competing Interest The authors declared no conflict of interest.
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Acknowledgment [30]
We thank for the support from Academy of Medical Sciences of Zhengzhou University Translational Medicine platform.
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