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LncRNA HOXA-AS2 and its molecular mechanisms in human cancer
Clinica Chimica Acta 485 (2018) 229–233
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Review
LncRNA HOXA-AS2 and its molecular mechanisms in human cancer ⁎
⁎
T
Jicai Wang, Zhilei Su, Shounan Lu, Wen Fu, Zhifa Liu, Xingming Jiang , Sheng Tai
Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
A R T I C LE I N FO
A B S T R A C T
Keywords: lncRNA HOXA-AS2 Diagnosis Therapeutic target Prognosis
Long non-coding RNAs (lncRNAs), a novel class of noncoding RNAs, are commonly defined as RNA molecules more than 200 nucleotides in length. Emerging research indicated that lncRNA played a vital role in human tumorigenesis and progression by serving as tumor oncogenes or suppressors. LncRNA has been shown to get involved in participate various biological processes, such as cell growth, anti-apoptosis, migration and invasion. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) is a novel cancer-related lncRNA. It was recently found to exhibit aberrant expression in a variety of malignancies, including breast cancer, gastric cancer, gallbladder carcinoma, hepatocellular carcinoma and pancreatic cancer. The oncogenicity of lncRNA HOXA-AS2 mainly inhibits or promotes the expression of related genes through direct or indirect pathways, suggesting that HOXAAS2 likely represents a feasible biomarker or therapeutic target in human cancers. In this review, we summarize current evidences concerning the biological functions and mechanisms of HOXA-AS2 during tumor development.
1. Introduction As a global major public health problem, cancer has always been one of the leading causes of death worldwide and the focus of clinical studies [1]. Based on recent data about cancer statistics, approximately 1,685,210 new cancer cases were diagnosed in the America alone in 2016 and 595,690 cancer patients died [2]. In the past few years, the molecular basis of cancer has been extensively researched. Accumulating evidences indicated that long non-coding RNAs (lncRNAs) played numerous roles in the normal cellular biology, as well as in several phases of pathological processes [3,4]. Protein-coding genes account for less than 2% of the entire genome on the basis of the draft of the human genome project. More than 70% of the gene sequences are transcribed into RNAs in higher eukaryotic genomes. As we know, RNA plays a crucial part in the expression and regulation of genome through the activity of protein-coding genes and non-protein coding RNAs (ncRNAs). While these ncRNAs account for most of the RNAs [5–8]. Owing to recent advances in genome sequencing technologies, long ncRNAs (RNA transcripts longer than 200
nucleotides in length) have been implicated as critical regulators in diverse human diseases [9–14]. LncRNAs, which are usually divided into five categories including sense, antisense, bidirection, intron and intergenic region, are mainly transcribed by RNA polymerase II and lack an obvious open reading frame [15,16]. The functions of lncRNAs, which include gene imprinting, histone modification, chromatin remodeling, transcriptional activation, transcriptional interference, nuclear transport, and cell cycle regulation, depend on their subcellular localization [17–21]. LncRNAs are also reported that they may work as sponges by competitively binding to microRNAs (miRNAs) and consequently inhibiting their functions [22,23]. Multiple studies have been reported that lncRNAs are aberrantly expressed in refractory tumors in unclear pathogenesis [24–26]. LncRNAs dysregulation generally contribute to tumors development by promotion, proliferation, invasion and metastasis of tumor cells [27,28]. Besides, lncRNAs may be as potential therapeutic targets and biomarkers for diagnosis, prognostic evaluation or treatment, owing to their characteristics of high efficiency, high tissue specificity and elevated stability [29,30]. Long noncoding RNA HOXA
Abbreviations: APL, Acute promyelocytic leukemia; ATRA, All trans retinoic acid; Bax, BCL2-Associated X; BC, Breast cancer; Bcl-2, B-cell lymphoma-2; c-Myc, MYC proto-oncogene; CRC, Colorectal cancer; DDIT3, DNA damage inducible transcript 3; EGFR, Epidermal growth factor receptor; EMT, Epithelial-mesenchymal transition; EZH2, Enhaner of zeste homolog 2; GBC, Gallbladder carcinoma; GC, Gastric cancer; HCC, Hepatocellular carcinoma; HOXA-AS2, HOXA cluster antisense RNA2; KLF2, Kruppel like factor 2; lncRNAs, Long non-coding RNAs; LSD1, Lysine specific demethylase 1; miRNAs, microRNAs; MMP-2/9, Matrix metalloproteinase2/9; ncRNAs, Non-protein coding RNAs; NF-kB, Nuclear factor kappa B subunit; PC, Pancreatic cancer; P13K/AKT, Phosphoinositide 3- kinase/protein kinase B; PLK3, Polo-like kinase 3; PRC2, Polycomb repressive complex 2; RELA, NF-kB subunit; TGF-β, Transforming growth factor β; TGFBR2, Transforming growth factor beta receptor 2; TRAIL, TNF-related apoptosis-inducing ligand; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VE-cadherin, Vascular endothelial-cadherin; VM formation, Vasculogenic mimicry formation ⁎ Corresponding authors. E-mail addresses: [email protected] (X. Jiang), [email protected] (S. Tai). https://doi.org/10.1016/j.cca.2018.07.004 Received 26 May 2018; Received in revised form 28 June 2018; Accepted 3 July 2018 Available online 04 July 2018 0009-8981/ © 2018 Published by Elsevier B.V.
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Table 1 Functional characterization of lncRNA HOXA-AS2 in various cancers. Cancer types
Expression
Functions
Hepatocellular carcinoma Gastric cancer Colorectal cancer Gallbladder carcinoma Breast cancer Promyelocytic leukemia Pancreatic cancer Malignant glioma
Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated
Proliferation, migration, Proliferation Proliferation Proliferation, migration, Proliferation, migration, Anti-apoptosis Proliferation Proliferation, migration, VM formation
invasion
invasion invasion
invasion,
Related genes
Role
Refs
c-Myc, Bcl-2, Bax P21, PLK3, DDIT3, EZH2, PRC2 P21, KLF2, EZH2, LSD1 E-cadherin, Vimentin, N-cadherin, EMT miR-520c-3p, TGFBR2, RELA TRAIL EZH2, LSD1 miR-373, EGFR, MMP-2,VE-cadherin, MMP-9, P13K/AKT
Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene
34 40 44,45 50 53 54 55 56
Bax: BCL2-Associated X, Bcl-2: B-cell lymphoma-2, c-Myc: MYC proto-oncogene, DDIT3: DNA damage inducible transcript 3, EGFR: epidermal growth factor receptor, EMT: epithelial-mesenchymal transition, EZH2: enhaner of zeste homolog 2, KLF2: kruppel like factor 2, LSD1: lysine specific demethylase 1, MMP-2/9: matrix metalloproteinase-2/9, P13K/AKT: phosphoinositide 3- kinase/protein kinase B, PLK3: polo-like kinase 3, PRC2: polycomb repressive complex 2, RELA: NF-kB subunit, TGFBR2: transforming growth factor beta receptor 2, TRAIL: TNF-related apoptosis-inducing ligand, VE-cadherin: vascular endothelial-cadherin, VM formation: vasculogenic mimicry formation. Table 2 Clinical significance of lncRNA HOXA-AS2 in various cancers. Cancer types
Overexpression of lncRNA HOXA-AS2
Refs
Hepatocellular carcinoma Gastric cancer Colorectal cancer Gallbladder carcinoma Breast cancer
Advanced TNM stages, poorer survival, larger tumor size and shorter overall survival Larger tumor size higher clinical stage and poor prognosis Larger tumor size, advanced pathological stage, early lymph node metastasis and poor prognosis Larger tumor size, advanced pathological stage and early lymph node metastasis Greater depth of invasion, higher TNM stages, more frequent lymphatic metastasis, positive distant metastasis and poorer postoperative survival – – –
34 40 44,45 50 53
Promyelocytic leukemia pancreatic cancer Malignant glioma
54 55 56
2.2. Gastric cancer
cluster antisense RNA2 (lncRNA HOXA-AS2), which is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster, is a promising candidate among all tumor-related lncRNAs. LncRNA HOXA-AS2 is overexpressed in numerous human cancers (Tables 1 and 2). In this review, we summarize current evidences regarding the abnormal expression, functions and regulation mechanisms of lncRNA HOXA-AS2 and discuss its potential clinical value.
Gastric cancer (GC) is one of the most common malignancies worldwide, being the third main cause of cancer-related deaths [35–38]. With the medical technology development, early treatment of GC has achieved significant success. However, early diagnosis of GC is still difficult. Most patients of GC presented with advanced stage at the time of diagnosis, resulting in poor prognosis and low long-term survival rate [39]. Therefore, identifying novel GC biomarkers is crucial for improving diagnosis and prognostic evaluation. Xie et al. [40] demonstrated that expression of HOXA-AS2 was elevated in GC tissues compared with that in paired adjacent noncancerous tissues. Upregulated HOXA-AS2 was dramatically associated with larger tumor size, higher TNM stage and poor prognosis. HOXA-AS2 could promote GC cells proliferation in vitro and tumorigenesis in vivo. Further analysis showed that silencing HOXA-AS2 promoted G1 arrest and caused apoptosis of GC cells. These findings indicated that HOXA-AS2 exhibited a crucial role in early diagnosis and treatment of GC. HOXA-AS2 is expected to be a novel diagnostic and curative target. However, further studies are needed to elucidate biological function of HOXA-AS2 in GC cells.
2. LncRNA HOXA-AS2 deregulation in human cancers 2.1. Hepatocellular carcinoma Hepatocellular carcinoma (HCC), which causes approximately 600,000 deaths each year, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Chronic hepatitis B/C virus infections are the significant development factors of HCC. Frequent intrahepatic and extrahepatic metastases lead to the low resectability, poor prognosis and high recurrence rate in the early stage [31–33]. Therefore, in order to identify novel biomarkers and therapeutic targets, it is vital to explore the key molecular mechanisms involved in the initiation and progression of HCC. Wang et al. [34] demonstrated that expression levels of HOXA-AS2 were markedly upregulated in 112 HCC tissues and 4 cell lines compared with those in adjacent normal hepatic tissues and hepatocyte cell line. Moreover, high HOXA-AS2 expression was significantly associated with advanced TNM stages, poorer survival, larger tumor size, and shorter overall survival. Functionally, knocking down HOXA-AS2 significantly repressed proliferation, colony formation, migration and invasion of HCC cells and obviously induced cancer cells apoptosis. Therefore, HOXAAS2 may be a promising oncogenic lncRNA in HCC, suggesting its potential utilities as a prognostic marker or a therapeutic target. Further studies are needed to elucidate the specific regulatory mechanism of HOXA-AS2 in HCC development.
2.3. Colorectal cancer Colorectal cancer (CRC), which affects more than 1.2 million people every year, is the third most common malignant tumor and the fourth most frequent cause of cancer-related deaths in the world [41]. It is estimated that 20% of the patients exhibit metastases (survival rate of less than 5 years) when being diagnosed [42,43]. Meanwhile, one of the biggest obstacles is lack of molecular biomarkers for CRC cells progression. As such, the development of sensitive and specific biomarkers would be of great clinical relevance significance for CRC. Ding et al. [44] reported that expression of HOXA-AS2 was increased at least twofold in the CRC tissues compared with non-tumor controls. Incremental HOXA-AS2 was closely related to bigger tumor size, advanced 230
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considerable threat to human health. Glioblastoma patients generally have low median survival times. Gao et al. [56] found that HOXA-AS2 was upregulated in glioma samples and promoted biological behaviors of malignant glioma and vasculogenic mimicry (VM) formation via the miR-373/epidermal growth factor receptor (EGFR) axis.
TNM stage, lymph node metastasis and poor prognosis. Upregulation of HOXA-AS2 promotes CRC cells proliferation in vitro. Downregulation of HOXA-AS2 promotes a significant arrest in the G0/G1-phase, with an obvious reduction in the number of S-phase cells in vitro. Moreover, flow cytometric analysis and microscopic analysis of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) demonstrated that the silence of HOXA-AS2 expression significantly increased in CRC cells apoptosis. Li et al. [45] also confirmed that HOXA-AS2 was overexpressed in CRC. Patients with upregulated HOXA-AS2 had a poorer prognosis. These results suggest that lncRNA HOXA-AS2 is a potential oncogenic lncRNA in CRC. However, a further larger sample studies are needed to support these results.
3. Regulating mechanisms of HOXA-AS2 An increasing number of reports shown that overexpression of HOXA-AS2 had leading role in malignancies and exhibited its oncogenic activity by inducing cancer cells proliferation, migration, invasion and anti-apoptosis. Wang et al. [34], by western blot detection, found that depletion of HOXA-AS2 led to the increase of BCL2-Associated X (Bax) expression. Low HOXA-AS2 caused significant decrease of B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), indicating that the HOXA-AS2 played a positive role in HCC proliferation. Moreover, the authors identified, by western blot analysis, that HOXA-AS2-mediated cells migration and invasion through activating AKT-MMP pathway. The epithelial-mesenchymal transition (EMT) is an imperative mechanism in cancer metastasis. Zhang et al. [50] demonstrated that overexpression of HOXA-AS2 in GBC made the expression levels of Vimentin significantly increase, whereas expression of E-cadherin markedly decreased. This result illustrated that HOXA-AS2 promoted the migration and invasion of GBC cells via regulating EMT. During hematopoiesis, maladjustment of apoptosis may promote leukemogenesis. Zhao et al. [54] showed that knockdown of HOXA-AS2, by transducing shRNAs, resulted in increase of TNF-related apoptosis-inducing ligand (TRAIL) levels, demonstrating that ATRA induction of HOXAAS2 suppressed ATRA-induced apoptosis, possibly through a TRAILmediated pathway. The ceRNA regulatory network is a main mechanism of HOXA-AS2 in cancer development. LncRNA HOXA-AS2 can abolish miRNAs endogenous suppressive effect on key targets and serve as sponges for miRNAs. Fang et al. [53] reported that HOXA-AS2 functioned as a ceRNA of miR-520-3p to modulate expression of RELA (NF-kB subunit) and transforming growth factor beta receptor 2 (TGFBR2) through the transforming growth factor β (TGF-β) and nuclear factor kappa B subunit (NF-kB) signalling pathway, suggesting that the HOXA-AS2/miR520c-3p axis participated in BC progression. Similarly, Gao et al. [56] found that HOXA-AS2 contributed to vasculogenic mimicry (VM) formation and malignant glioma behavior formation by downregulating miR-373. MiR-373 targeted EGFR and suppressed the activity levels of vascular endothelial-cadherin (VE-cadherin), as well as decreased the expression of levels matrix metalloproteinase (MMP)-2 and MMP-9, via inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway. Furthermore, HOXA-AS2 could bind with EZH2 to regulate downstream target genes and modulate tumorigenesis and progression. Xie et al. [40] discovered, by ChIP assays, that EZH2 could directly bind to P21, DDIT3 (DNA damage inducible transcript 3) and PLK3 (polo-like kinase 3) promoter regions, and then induce H3K27me3 modification, implying that overexpression of HOXA-AS2 promoted GC cells growth through epigenetically silencing transcription of P21, PLK3 and DDIT3. Similarly, Ding et al. [44] also found that HOXA-AS2 could directly bind with EZH2 and LSD1 to silence expression of P21 and KLF2 (kruppel like factor 2). Further results of chromatin immunoprecipitation analysis confirmed that EZH2, LSD1 could directly bind to P21 and KLF2 (two tumor suppressor) promoter regions and then induce H3K27 trimethylated. The results indicated that HOXA-AS2 promoted CRC cells proliferation was a manner of silence p21 and KLF2 transcription by binding to EZH2, LSD1. Moreover, HOXA-AS2 bound with EZH2 and LSD1 to form lncRNA-HOXA-AS2/EZH2/LSD1 complex and then promoted PC cells proliferation.
2.4. Gallbladder carcinoma Gallbladder carcinoma (GBC), which has an increased incidence in developed countries now, is the most common malignancy of the biliary tract with extremely poor prognoses [46,47]. GBC is usually diagnosed at advanced stage with lymph-node metastases due to the early stages of GBC progression are largely asymptomatic [48]. Finally, these patients died from metastatic diseases [49]. Therefore, it is crucial to elucidate the mechanism of GBC biology and identify novel biomarkers for patients with GBC. Zhang et al. [50] revealed that expression of HOXA-AS2 in GBC tissues is significantly higher than that of in normal paired tissues. High HOXA-AS2 expression in GBC was noticeably related with larger tumor size, advanced pathological stage, and early lymph node metastasis. Contrarily, Knockdown of HOXA-AS2 significantly inhibited GBC cells proliferation by causing G1-phase arrest and promoting apoptosis. Functionally, HOXA-AS2 was associated with proliferation, migration and invasion. Therefore, HOXA-AS2 could act as a functional oncogene in GBC and a potential therapeutic target to inhibit GBC metastasis. 2.5. Breast cancer Breast cancer (BC), which is a malignant tumor originating from breast tissues, is the most common cancer with gradually increased incidence in women all over the world [51,52]. BC seriously threatens women's health and gradually becomes a social problem. Hence, the exploration of molecular mechanisms, the development of reliable biomarkers, and tumor progression in BC should be a priority. Fang et al. [53] discovered that HOXA-AS2 was upregulated in BC and associated with invasion, lymphatic metastasis, distant metastasis, TNM stages, and postoperative survival. Functionally, HOXA-AS2 played the role in cell proliferation, migration and invasion, suggesting that it might be a potential prognostic and therapeutic target in breast cancer. 2.6. Promyelocytic leukemia Zhao et al. [54] discovered that expression of HOXA-AS2 was increased in NB4 cells treated with all trans retinoic acid (ATRA) and transcript of HOXA-AS2 was expressed in NB4 promyelocytic leukemia cells. Knockdown of HOXA-AS2 could increase the proportion of apoptotic cells. These results demonstrate that HOXA-AS2 function as apoptosis repressor in ATRA-treated NB4 cells. Furthermore, HOXAAS2 could provide insight into further therapeutic target for acute promyelocytic leukemia (APL) or other myeloid malignancies. 2.7. Pancreatic cancer and malignant glioma Pancreatic cancer (PC) is one of the deadliest solid malignancies with poor prognosis. PC causes approximately 330,000 deaths per year, according to the GLOBOCAN 2012 expected numbers. Lian et al. [55] found that lncRNA-HOXA-AS2/enhaner of zeste homolog 2 (EZH2)/ lysine specific demethylase 1 (LSD1) complex might function as an oncogene, which promoted PC cells growth. Malignant gliomas are a 231
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Fig. 1. HOXA-AS2 mediates mechanisms involved in cancer progression.
4. Conclusion
References
Thousands of lncRNAs, as a novel class of ncRNAs, have been revealed to be crucial regulators of human gene expression. LncRNA HOXA-AS2, a tumor promotion gene, is involved in altering cellular functions such as cell proliferation, apoptosis, migration and invasion. The regulatory mechanisms of HOXA-AS2 are extremely complicated and multi-step, including induction of the EMT; direct inhibition (Bax)/ promotion (c-Myc and Bcl-2) of gene expression; activating AKT-MMP signalling pathways, EZH2 and LSD1; and indirect inhibition of gene expression by competitively binding miRNAs (Fig. 1). In terms of clinical application, aberrant expression of HOXA-AS2 has a close connection with poorer clinicopathological characteristics, so it may function as a potential tumor marker for diagnosis and prognosis. However, physicochemical stability and expression level of HOXA-AS2 in serum or other biological samples have not been clearly validated. Because, molecular targeted therapy has stronger tumor specificity and lower systemic toxicity than traditional cytotoxic chemotherapy. HOXA-AS2 is confoundedly promising. In short, it is still in the early stage about the research of HOXA-AS2. Further specific molecular mechanisms and larger sample studies should be focused. As a practical drug target, lncRNA HOXA-AS2 is hoped ultimately to achieve clinical application in this field.
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Funding This study was funded by Wu Jieping Medical Foundation for Clinical Scientific Research (NO. 320.6750.1245), National Natural Science Foundation of China (NO. 81602088), China Postdoctoral Science Foundation (NO. 2017 M621305), Heilongjiang Postdoctoral Science Foundation (NO. LBH-Z16096), Health and Family Planning Commission Research Project of Heilongjiang Province (NO. 2016049), and Innovative Science Foundation of Harbin Medical University (NO. 2016LCZX09).
Declaration of conflict of interest None.
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Review
LncRNA HOXA-AS2 and its molecular mechanisms in human cancer ⁎
⁎
T
Jicai Wang, Zhilei Su, Shounan Lu, Wen Fu, Zhifa Liu, Xingming Jiang , Sheng Tai
Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
A R T I C LE I N FO
A B S T R A C T
Keywords: lncRNA HOXA-AS2 Diagnosis Therapeutic target Prognosis
Long non-coding RNAs (lncRNAs), a novel class of noncoding RNAs, are commonly defined as RNA molecules more than 200 nucleotides in length. Emerging research indicated that lncRNA played a vital role in human tumorigenesis and progression by serving as tumor oncogenes or suppressors. LncRNA has been shown to get involved in participate various biological processes, such as cell growth, anti-apoptosis, migration and invasion. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) is a novel cancer-related lncRNA. It was recently found to exhibit aberrant expression in a variety of malignancies, including breast cancer, gastric cancer, gallbladder carcinoma, hepatocellular carcinoma and pancreatic cancer. The oncogenicity of lncRNA HOXA-AS2 mainly inhibits or promotes the expression of related genes through direct or indirect pathways, suggesting that HOXAAS2 likely represents a feasible biomarker or therapeutic target in human cancers. In this review, we summarize current evidences concerning the biological functions and mechanisms of HOXA-AS2 during tumor development.
1. Introduction As a global major public health problem, cancer has always been one of the leading causes of death worldwide and the focus of clinical studies [1]. Based on recent data about cancer statistics, approximately 1,685,210 new cancer cases were diagnosed in the America alone in 2016 and 595,690 cancer patients died [2]. In the past few years, the molecular basis of cancer has been extensively researched. Accumulating evidences indicated that long non-coding RNAs (lncRNAs) played numerous roles in the normal cellular biology, as well as in several phases of pathological processes [3,4]. Protein-coding genes account for less than 2% of the entire genome on the basis of the draft of the human genome project. More than 70% of the gene sequences are transcribed into RNAs in higher eukaryotic genomes. As we know, RNA plays a crucial part in the expression and regulation of genome through the activity of protein-coding genes and non-protein coding RNAs (ncRNAs). While these ncRNAs account for most of the RNAs [5–8]. Owing to recent advances in genome sequencing technologies, long ncRNAs (RNA transcripts longer than 200
nucleotides in length) have been implicated as critical regulators in diverse human diseases [9–14]. LncRNAs, which are usually divided into five categories including sense, antisense, bidirection, intron and intergenic region, are mainly transcribed by RNA polymerase II and lack an obvious open reading frame [15,16]. The functions of lncRNAs, which include gene imprinting, histone modification, chromatin remodeling, transcriptional activation, transcriptional interference, nuclear transport, and cell cycle regulation, depend on their subcellular localization [17–21]. LncRNAs are also reported that they may work as sponges by competitively binding to microRNAs (miRNAs) and consequently inhibiting their functions [22,23]. Multiple studies have been reported that lncRNAs are aberrantly expressed in refractory tumors in unclear pathogenesis [24–26]. LncRNAs dysregulation generally contribute to tumors development by promotion, proliferation, invasion and metastasis of tumor cells [27,28]. Besides, lncRNAs may be as potential therapeutic targets and biomarkers for diagnosis, prognostic evaluation or treatment, owing to their characteristics of high efficiency, high tissue specificity and elevated stability [29,30]. Long noncoding RNA HOXA
Abbreviations: APL, Acute promyelocytic leukemia; ATRA, All trans retinoic acid; Bax, BCL2-Associated X; BC, Breast cancer; Bcl-2, B-cell lymphoma-2; c-Myc, MYC proto-oncogene; CRC, Colorectal cancer; DDIT3, DNA damage inducible transcript 3; EGFR, Epidermal growth factor receptor; EMT, Epithelial-mesenchymal transition; EZH2, Enhaner of zeste homolog 2; GBC, Gallbladder carcinoma; GC, Gastric cancer; HCC, Hepatocellular carcinoma; HOXA-AS2, HOXA cluster antisense RNA2; KLF2, Kruppel like factor 2; lncRNAs, Long non-coding RNAs; LSD1, Lysine specific demethylase 1; miRNAs, microRNAs; MMP-2/9, Matrix metalloproteinase2/9; ncRNAs, Non-protein coding RNAs; NF-kB, Nuclear factor kappa B subunit; PC, Pancreatic cancer; P13K/AKT, Phosphoinositide 3- kinase/protein kinase B; PLK3, Polo-like kinase 3; PRC2, Polycomb repressive complex 2; RELA, NF-kB subunit; TGF-β, Transforming growth factor β; TGFBR2, Transforming growth factor beta receptor 2; TRAIL, TNF-related apoptosis-inducing ligand; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VE-cadherin, Vascular endothelial-cadherin; VM formation, Vasculogenic mimicry formation ⁎ Corresponding authors. E-mail addresses: [email protected] (X. Jiang), [email protected] (S. Tai). https://doi.org/10.1016/j.cca.2018.07.004 Received 26 May 2018; Received in revised form 28 June 2018; Accepted 3 July 2018 Available online 04 July 2018 0009-8981/ © 2018 Published by Elsevier B.V.
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Table 1 Functional characterization of lncRNA HOXA-AS2 in various cancers. Cancer types
Expression
Functions
Hepatocellular carcinoma Gastric cancer Colorectal cancer Gallbladder carcinoma Breast cancer Promyelocytic leukemia Pancreatic cancer Malignant glioma
Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated
Proliferation, migration, Proliferation Proliferation Proliferation, migration, Proliferation, migration, Anti-apoptosis Proliferation Proliferation, migration, VM formation
invasion
invasion invasion
invasion,
Related genes
Role
Refs
c-Myc, Bcl-2, Bax P21, PLK3, DDIT3, EZH2, PRC2 P21, KLF2, EZH2, LSD1 E-cadherin, Vimentin, N-cadherin, EMT miR-520c-3p, TGFBR2, RELA TRAIL EZH2, LSD1 miR-373, EGFR, MMP-2,VE-cadherin, MMP-9, P13K/AKT
Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene Oncogene
34 40 44,45 50 53 54 55 56
Bax: BCL2-Associated X, Bcl-2: B-cell lymphoma-2, c-Myc: MYC proto-oncogene, DDIT3: DNA damage inducible transcript 3, EGFR: epidermal growth factor receptor, EMT: epithelial-mesenchymal transition, EZH2: enhaner of zeste homolog 2, KLF2: kruppel like factor 2, LSD1: lysine specific demethylase 1, MMP-2/9: matrix metalloproteinase-2/9, P13K/AKT: phosphoinositide 3- kinase/protein kinase B, PLK3: polo-like kinase 3, PRC2: polycomb repressive complex 2, RELA: NF-kB subunit, TGFBR2: transforming growth factor beta receptor 2, TRAIL: TNF-related apoptosis-inducing ligand, VE-cadherin: vascular endothelial-cadherin, VM formation: vasculogenic mimicry formation. Table 2 Clinical significance of lncRNA HOXA-AS2 in various cancers. Cancer types
Overexpression of lncRNA HOXA-AS2
Refs
Hepatocellular carcinoma Gastric cancer Colorectal cancer Gallbladder carcinoma Breast cancer
Advanced TNM stages, poorer survival, larger tumor size and shorter overall survival Larger tumor size higher clinical stage and poor prognosis Larger tumor size, advanced pathological stage, early lymph node metastasis and poor prognosis Larger tumor size, advanced pathological stage and early lymph node metastasis Greater depth of invasion, higher TNM stages, more frequent lymphatic metastasis, positive distant metastasis and poorer postoperative survival – – –
34 40 44,45 50 53
Promyelocytic leukemia pancreatic cancer Malignant glioma
54 55 56
2.2. Gastric cancer
cluster antisense RNA2 (lncRNA HOXA-AS2), which is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster, is a promising candidate among all tumor-related lncRNAs. LncRNA HOXA-AS2 is overexpressed in numerous human cancers (Tables 1 and 2). In this review, we summarize current evidences regarding the abnormal expression, functions and regulation mechanisms of lncRNA HOXA-AS2 and discuss its potential clinical value.
Gastric cancer (GC) is one of the most common malignancies worldwide, being the third main cause of cancer-related deaths [35–38]. With the medical technology development, early treatment of GC has achieved significant success. However, early diagnosis of GC is still difficult. Most patients of GC presented with advanced stage at the time of diagnosis, resulting in poor prognosis and low long-term survival rate [39]. Therefore, identifying novel GC biomarkers is crucial for improving diagnosis and prognostic evaluation. Xie et al. [40] demonstrated that expression of HOXA-AS2 was elevated in GC tissues compared with that in paired adjacent noncancerous tissues. Upregulated HOXA-AS2 was dramatically associated with larger tumor size, higher TNM stage and poor prognosis. HOXA-AS2 could promote GC cells proliferation in vitro and tumorigenesis in vivo. Further analysis showed that silencing HOXA-AS2 promoted G1 arrest and caused apoptosis of GC cells. These findings indicated that HOXA-AS2 exhibited a crucial role in early diagnosis and treatment of GC. HOXA-AS2 is expected to be a novel diagnostic and curative target. However, further studies are needed to elucidate biological function of HOXA-AS2 in GC cells.
2. LncRNA HOXA-AS2 deregulation in human cancers 2.1. Hepatocellular carcinoma Hepatocellular carcinoma (HCC), which causes approximately 600,000 deaths each year, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Chronic hepatitis B/C virus infections are the significant development factors of HCC. Frequent intrahepatic and extrahepatic metastases lead to the low resectability, poor prognosis and high recurrence rate in the early stage [31–33]. Therefore, in order to identify novel biomarkers and therapeutic targets, it is vital to explore the key molecular mechanisms involved in the initiation and progression of HCC. Wang et al. [34] demonstrated that expression levels of HOXA-AS2 were markedly upregulated in 112 HCC tissues and 4 cell lines compared with those in adjacent normal hepatic tissues and hepatocyte cell line. Moreover, high HOXA-AS2 expression was significantly associated with advanced TNM stages, poorer survival, larger tumor size, and shorter overall survival. Functionally, knocking down HOXA-AS2 significantly repressed proliferation, colony formation, migration and invasion of HCC cells and obviously induced cancer cells apoptosis. Therefore, HOXAAS2 may be a promising oncogenic lncRNA in HCC, suggesting its potential utilities as a prognostic marker or a therapeutic target. Further studies are needed to elucidate the specific regulatory mechanism of HOXA-AS2 in HCC development.
2.3. Colorectal cancer Colorectal cancer (CRC), which affects more than 1.2 million people every year, is the third most common malignant tumor and the fourth most frequent cause of cancer-related deaths in the world [41]. It is estimated that 20% of the patients exhibit metastases (survival rate of less than 5 years) when being diagnosed [42,43]. Meanwhile, one of the biggest obstacles is lack of molecular biomarkers for CRC cells progression. As such, the development of sensitive and specific biomarkers would be of great clinical relevance significance for CRC. Ding et al. [44] reported that expression of HOXA-AS2 was increased at least twofold in the CRC tissues compared with non-tumor controls. Incremental HOXA-AS2 was closely related to bigger tumor size, advanced 230
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considerable threat to human health. Glioblastoma patients generally have low median survival times. Gao et al. [56] found that HOXA-AS2 was upregulated in glioma samples and promoted biological behaviors of malignant glioma and vasculogenic mimicry (VM) formation via the miR-373/epidermal growth factor receptor (EGFR) axis.
TNM stage, lymph node metastasis and poor prognosis. Upregulation of HOXA-AS2 promotes CRC cells proliferation in vitro. Downregulation of HOXA-AS2 promotes a significant arrest in the G0/G1-phase, with an obvious reduction in the number of S-phase cells in vitro. Moreover, flow cytometric analysis and microscopic analysis of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) demonstrated that the silence of HOXA-AS2 expression significantly increased in CRC cells apoptosis. Li et al. [45] also confirmed that HOXA-AS2 was overexpressed in CRC. Patients with upregulated HOXA-AS2 had a poorer prognosis. These results suggest that lncRNA HOXA-AS2 is a potential oncogenic lncRNA in CRC. However, a further larger sample studies are needed to support these results.
3. Regulating mechanisms of HOXA-AS2 An increasing number of reports shown that overexpression of HOXA-AS2 had leading role in malignancies and exhibited its oncogenic activity by inducing cancer cells proliferation, migration, invasion and anti-apoptosis. Wang et al. [34], by western blot detection, found that depletion of HOXA-AS2 led to the increase of BCL2-Associated X (Bax) expression. Low HOXA-AS2 caused significant decrease of B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), indicating that the HOXA-AS2 played a positive role in HCC proliferation. Moreover, the authors identified, by western blot analysis, that HOXA-AS2-mediated cells migration and invasion through activating AKT-MMP pathway. The epithelial-mesenchymal transition (EMT) is an imperative mechanism in cancer metastasis. Zhang et al. [50] demonstrated that overexpression of HOXA-AS2 in GBC made the expression levels of Vimentin significantly increase, whereas expression of E-cadherin markedly decreased. This result illustrated that HOXA-AS2 promoted the migration and invasion of GBC cells via regulating EMT. During hematopoiesis, maladjustment of apoptosis may promote leukemogenesis. Zhao et al. [54] showed that knockdown of HOXA-AS2, by transducing shRNAs, resulted in increase of TNF-related apoptosis-inducing ligand (TRAIL) levels, demonstrating that ATRA induction of HOXAAS2 suppressed ATRA-induced apoptosis, possibly through a TRAILmediated pathway. The ceRNA regulatory network is a main mechanism of HOXA-AS2 in cancer development. LncRNA HOXA-AS2 can abolish miRNAs endogenous suppressive effect on key targets and serve as sponges for miRNAs. Fang et al. [53] reported that HOXA-AS2 functioned as a ceRNA of miR-520-3p to modulate expression of RELA (NF-kB subunit) and transforming growth factor beta receptor 2 (TGFBR2) through the transforming growth factor β (TGF-β) and nuclear factor kappa B subunit (NF-kB) signalling pathway, suggesting that the HOXA-AS2/miR520c-3p axis participated in BC progression. Similarly, Gao et al. [56] found that HOXA-AS2 contributed to vasculogenic mimicry (VM) formation and malignant glioma behavior formation by downregulating miR-373. MiR-373 targeted EGFR and suppressed the activity levels of vascular endothelial-cadherin (VE-cadherin), as well as decreased the expression of levels matrix metalloproteinase (MMP)-2 and MMP-9, via inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway. Furthermore, HOXA-AS2 could bind with EZH2 to regulate downstream target genes and modulate tumorigenesis and progression. Xie et al. [40] discovered, by ChIP assays, that EZH2 could directly bind to P21, DDIT3 (DNA damage inducible transcript 3) and PLK3 (polo-like kinase 3) promoter regions, and then induce H3K27me3 modification, implying that overexpression of HOXA-AS2 promoted GC cells growth through epigenetically silencing transcription of P21, PLK3 and DDIT3. Similarly, Ding et al. [44] also found that HOXA-AS2 could directly bind with EZH2 and LSD1 to silence expression of P21 and KLF2 (kruppel like factor 2). Further results of chromatin immunoprecipitation analysis confirmed that EZH2, LSD1 could directly bind to P21 and KLF2 (two tumor suppressor) promoter regions and then induce H3K27 trimethylated. The results indicated that HOXA-AS2 promoted CRC cells proliferation was a manner of silence p21 and KLF2 transcription by binding to EZH2, LSD1. Moreover, HOXA-AS2 bound with EZH2 and LSD1 to form lncRNA-HOXA-AS2/EZH2/LSD1 complex and then promoted PC cells proliferation.
2.4. Gallbladder carcinoma Gallbladder carcinoma (GBC), which has an increased incidence in developed countries now, is the most common malignancy of the biliary tract with extremely poor prognoses [46,47]. GBC is usually diagnosed at advanced stage with lymph-node metastases due to the early stages of GBC progression are largely asymptomatic [48]. Finally, these patients died from metastatic diseases [49]. Therefore, it is crucial to elucidate the mechanism of GBC biology and identify novel biomarkers for patients with GBC. Zhang et al. [50] revealed that expression of HOXA-AS2 in GBC tissues is significantly higher than that of in normal paired tissues. High HOXA-AS2 expression in GBC was noticeably related with larger tumor size, advanced pathological stage, and early lymph node metastasis. Contrarily, Knockdown of HOXA-AS2 significantly inhibited GBC cells proliferation by causing G1-phase arrest and promoting apoptosis. Functionally, HOXA-AS2 was associated with proliferation, migration and invasion. Therefore, HOXA-AS2 could act as a functional oncogene in GBC and a potential therapeutic target to inhibit GBC metastasis. 2.5. Breast cancer Breast cancer (BC), which is a malignant tumor originating from breast tissues, is the most common cancer with gradually increased incidence in women all over the world [51,52]. BC seriously threatens women's health and gradually becomes a social problem. Hence, the exploration of molecular mechanisms, the development of reliable biomarkers, and tumor progression in BC should be a priority. Fang et al. [53] discovered that HOXA-AS2 was upregulated in BC and associated with invasion, lymphatic metastasis, distant metastasis, TNM stages, and postoperative survival. Functionally, HOXA-AS2 played the role in cell proliferation, migration and invasion, suggesting that it might be a potential prognostic and therapeutic target in breast cancer. 2.6. Promyelocytic leukemia Zhao et al. [54] discovered that expression of HOXA-AS2 was increased in NB4 cells treated with all trans retinoic acid (ATRA) and transcript of HOXA-AS2 was expressed in NB4 promyelocytic leukemia cells. Knockdown of HOXA-AS2 could increase the proportion of apoptotic cells. These results demonstrate that HOXA-AS2 function as apoptosis repressor in ATRA-treated NB4 cells. Furthermore, HOXAAS2 could provide insight into further therapeutic target for acute promyelocytic leukemia (APL) or other myeloid malignancies. 2.7. Pancreatic cancer and malignant glioma Pancreatic cancer (PC) is one of the deadliest solid malignancies with poor prognosis. PC causes approximately 330,000 deaths per year, according to the GLOBOCAN 2012 expected numbers. Lian et al. [55] found that lncRNA-HOXA-AS2/enhaner of zeste homolog 2 (EZH2)/ lysine specific demethylase 1 (LSD1) complex might function as an oncogene, which promoted PC cells growth. Malignant gliomas are a 231
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Fig. 1. HOXA-AS2 mediates mechanisms involved in cancer progression.
4. Conclusion
References
Thousands of lncRNAs, as a novel class of ncRNAs, have been revealed to be crucial regulators of human gene expression. LncRNA HOXA-AS2, a tumor promotion gene, is involved in altering cellular functions such as cell proliferation, apoptosis, migration and invasion. The regulatory mechanisms of HOXA-AS2 are extremely complicated and multi-step, including induction of the EMT; direct inhibition (Bax)/ promotion (c-Myc and Bcl-2) of gene expression; activating AKT-MMP signalling pathways, EZH2 and LSD1; and indirect inhibition of gene expression by competitively binding miRNAs (Fig. 1). In terms of clinical application, aberrant expression of HOXA-AS2 has a close connection with poorer clinicopathological characteristics, so it may function as a potential tumor marker for diagnosis and prognosis. However, physicochemical stability and expression level of HOXA-AS2 in serum or other biological samples have not been clearly validated. Because, molecular targeted therapy has stronger tumor specificity and lower systemic toxicity than traditional cytotoxic chemotherapy. HOXA-AS2 is confoundedly promising. In short, it is still in the early stage about the research of HOXA-AS2. Further specific molecular mechanisms and larger sample studies should be focused. As a practical drug target, lncRNA HOXA-AS2 is hoped ultimately to achieve clinical application in this field.
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Funding This study was funded by Wu Jieping Medical Foundation for Clinical Scientific Research (NO. 320.6750.1245), National Natural Science Foundation of China (NO. 81602088), China Postdoctoral Science Foundation (NO. 2017 M621305), Heilongjiang Postdoctoral Science Foundation (NO. LBH-Z16096), Health and Family Planning Commission Research Project of Heilongjiang Province (NO. 2016049), and Innovative Science Foundation of Harbin Medical University (NO. 2016LCZX09).
Declaration of conflict of interest None.
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