Gene Summary

Gene:HOXA11; homeobox A11
Aliases: HOX1, HOX1I, RUSAT1
Summary:In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is involved in the regulation of uterine development and is required for female fertility. Mutations in this gene can cause radio-ulnar synostosis with amegakaryocytic thrombocytopenia. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-A11
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: HOXA11 (cancer-related)

Yao Y, Chen X, Lu S, et al.
Circulating Long Noncoding RNAs as Biomarkers for Predicting Head and Neck Squamous Cell Carcinoma.
Cell Physiol Biochem. 2018; 50(4):1429-1440 [PubMed] Related Publications
BACKGROUND/AIMS: The anatomical complexity of the head and neck region and the lack of sufficiently specific and sensitive biomarkers often lead to the diagnosis of head and neck squamous cell carcinoma (HNSCC) at advanced stages. To identify novel biomarkers for early diagnosis of primary HNSCC through a minimally invasive method, we investigated circulating long noncoding RNA (lncRNA) levels in plasma of HNSCC patients.
METHODS: The global lncRNA expression profiles of HNSCC patients were measured using microarray and next-generation RNA-sequencing (RNA-seq) data from both circulating and tissue samples. The diagnosis prediction model based on the lncRNA signatures and clinical features was evaluated by multi-stage validation and risk score analysis.
RESULTS: The data showed that 432 lncRNA transcripts were differentially expressed by fold changes of > 4 in circulating samples and 333 in tissues samples, respectively. Only 12 lncRNAs consistently emerged in these two kinds of samples. After the risk score analysis including a multistage validation, we identified three lncRNAs, namely, HOXA11-AS, LINC00964 and MALAT1, which were up-regulated in the plasma of HNSCC patients compared with those in healthy controls with merged areas under the curve (AUCs) in training and validation sets of 0.925 and 0.839, respectively.
CONCLUSION: HOXA11-AS, LINC00964 and MALAT1 might be potential circulating biomarkers for the early detection of HNSCC in the future.

Shen X, Bai H, Zhu H, et al.
Long Non-Coding RNA MEG3 Functions as a Competing Endogenous RNA to Regulate HOXA11 Expression by Sponging miR-181a in Multiple Myeloma.
Cell Physiol Biochem. 2018; 49(1):87-100 [PubMed] Related Publications
BACKGROUND/AIMS: Long non-coding RNA maternally expressed gene 3 (MEG3) has been reported to play an essential role in cancer progression and metastasis. However, the overall biological role and regulatory mechanism of MEG3 in multiple myeloma (MM) development and progression remains largely ill-defined.
METHODS: MEG3 and miR-181a expression of MM patients were analyzed by publicly available MM data sets. Cell counting kit-8 and flow cytometry analysis were used to identify the function of MEG3 on MM in vitro. Additionally, we conducted tumor formation experiments in mice models to explain the role of MEG3 on MM in vivo. Then, several mechanism experiments, including dual-luciferase reporter assay and RNA immunoprecipitation were performed to evaluate the emulative relationship between MEG3 and miR-181a.
RESULTS: In this research, we found that MEG3 was downregulated in MM patients, which was linked with tumor progression. In addition, we demonstrated that miR-181a was overexpressed in MM patients in consistent with its cancer-promoting function. Importantly, several mechanism experiments revealed that MEG3, acting as an endogenous competitive RNA, could contend with miR-181a to inhibit tumor progression. Furthermore, as the target mRNA of miR-181a, homeobox gene A11(HOXA11) could be positively regulated by MEG3 through sponging miR-181a competitively in vitro.
CONCLUSION: Our present work supplies the first discovery of a MEG3/miR-181a/HOXA11 regulatory network in MM and highlights that MEG3 may serve as a promising target for MM therapy in the future.

Yang X, Deng Y, He RQ, et al.
Upregulation of HOXA11 during the progression of lung adenocarcinoma detected via multiple approaches.
Int J Mol Med. 2018; 42(5):2650-2664 [PubMed] Free Access to Full Article Related Publications
The altered expression of homeobox (HOX)A11 has been observed in various malignant tumor types, but it has remained to be determined in human lung adenocarcinoma (LUAD). In the present study, the expression of HOXA11 in LUAD and the potential associated mechanisms were assessed. Data from The Cancer Genome Atlas and Oncomine microarrays were gathered and in‑house polymerase chain reaction data were produced to investigate the altered expression of HOXA11 in LUAD and its association with various clinicopathological characteristics. Genes co‑expressed with HOXA11 were also identified by searching the cBioPortal and Multi Experiment Matrix databases, and performing a bioinformatics analysis, through which the potential molecular mechanisms of HOXA11 in LUAD were explored. The data analyses indicated that HOXA11 was overexpressed in the LUAD samples, and together with its co‑expressed genes, it was indicated to participate in various key signaling pathways, including the focal adhesion, extracellular matrix‑receptor interaction, axon guidance and small cell lung cancer signaling pathways. Furthermore, collagen type III α 1 chain (COL3A1), ephrin B2 (EFNB2), integrin subunit α 8 (ITGA8) and syndecan 2 (SDC2) were confirmed to be differentially expressed in LUAD vs. normal controls at the mRNA and protein level. Of note, LUAD patients with low expression of HOXA11 and ITGB1 had better overall survival rates. The present study indicated that HOXA11 may function as an oncogene in LUAD, and HOXA11 protein probably combines with ITGB1, COL3A1, EFNB2, ITGA8 and SDC2 to have a role in the focal adhesion pathway.

Zhao X, Li X, Zhou L, et al.
LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via modulating miR-454-3p/Stat3.
Cancer Sci. 2018; 109(10):3068-3079 [PubMed] Free Access to Full Article Related Publications
Over the past several years, long non-coding RNAs (lncRNAs) have attracted more and more attention due to their special functions. They are vital biomarkers in multiple diseases. LncRNA HOMEOBOX A11 (HOXA11) has been found to be aberrantly expressed in some kinds of malignant tumors. In this study, we mainly discuss the oncogenic role of it in promoting malignant progression and chemoresistance in lung adenocarcinoma (LUAD) cells. The expression of HOXA11-AS was much stronger in cisplatin-resistant LUAD cells. Based on The Cancer Genome Atlas database, patients with high expression of HOXA11-AS had shorter survival time. Additionally, knockdown of HOXA11-AS caused positive changes in cell activities of LUAD. For example, cell proliferation and migration were weakened, the epithelial mesenchymal transition process was reversed, and apoptosis was induced. These changes were more obvious in cells treated with cisplatin. Next, the HOXA11-AS/miR-454-3p/Stat3 (signal transducer and activator of transcription 3) pathway was found to influence the cisplatin resistance of LUAD cells. HOXA11-AS specifically acted as a competing endogenous RNA (ceRNA) in LUAD cells. The combinations among these three genes were demonstrated. Finally, rescue assays were applied to demonstrate the ceRNA pattern consisting of HOXA11-AS, miR-454-3p and Stat3. In conclusion, lncRNA HOXA11-AS acted as a ceRNA to promote cisplatin resistance of human LUAD cells via the miR-454-3p/Stat3 axis.

Yang JX, Liu B, Yang BY, Meng Q
Long non-coding RNA homeobox (HOX) A11-AS promotes malignant progression of glioma by targeting miR-124-3p.
Neoplasma. 2018; 65(4):505-514 [PubMed] Related Publications
Glioma is the most common and serious form of primary tumor in adult central nervous system. HOXA11-AS is a LncRNA located in the HOXA gene cluster. In the present study, we investigated the expression and function of LncRNA HOXA11-AS in glioma tissues and cells. We found that LncRNA HOXA11-AS expression was markedly elevated in glioma tissues compared to normal brain tissues. The LncRNA HOXA11-AS expression in cases of high-grade glioma was significantly higher than that in cases of low-grade. Patients with high LncRNA HOXA11-AS expression had shorter OS time than those with low LncRNA HOXA11-AS expression. Moreover, silencing LncRNA HOXA11-AS inhibited cell proliferation, increased apoptosis, and inhibited invasion and migration of glioma cells. Overexpression of LncRNA HOXA11- AS increased cell proliferation, decreased apoptosis, and increased invasion and migration of glioma cells. miR-124-3p has relevant binding sites in HOXA11-AS. Silencing HOXA11-AS significantly increased miR-124-3p expression. The miR-124-3p overexpression decreased the luciferase activity of the pMIR luciferase reporter containing HOXA11-AS-WT but not HOXA11-AS-MUT. Moreover, miR-124-3p was pulled down by HOXA11-AS probe. miR-124-3p mimics inhibited cell proliferation, increased apoptosis, and inhibited invasion and migration of glioma cells. miR-124-3p mimics significantly suppressed overexpression of HOXA11-AS-induced increase of proliferation, decrease of apoptosis and increase of invasion and migration. miR-124-3p inhibitors suppressed the effect of siHOXA11-AS on proliferation, apoptosis, invasion and migration. In summary, the findings highlight the importance of LncRNA HOXA11-AS/miR-124-3p axis in the regulation of glioma progression. LncRNA HOXA11-AS/miR-124-3p might serve as a potential therapeutic target in glioma treatment in the future.

Zhang R, Zhang TT, Zhai GQ, et al.
Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis.
World J Surg Oncol. 2018; 16(1):109 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study was carried out to discover the underlying role that HOXA11 plays in lung squamous cancer (LUSC) and uncover the potential corresponding molecular mechanisms and functions of HOXA11-related genes.
METHODS: Twenty-three clinical paired LUSC and non-LUSC samples were utilized to examine the level of HOXA11 using quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of HOXA11 was systematically analyzed based on 475 LUSC and 18 non-cancerous adjacent tissues from The Cancer Genome Atlas (TCGA) database. A total of 102 LUSC tissues and 121 non-cancerous tissues were available from Oncomine to explore the expressing profiles of HOXA11 in LUSC. A meta-analysis was carried out to further assess the differential expression of HOXA11 in LUSC, including in-house qRT-PCR data, expressing data extracted from TCGA and Oncomine databases. Moreover, the enrichment analysis and potential pathway annotations of HOXA11 in LUSC were accomplished via Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of hub genes and according correlations with HOXA11 were assessed to further explore the biological role of HOXA11 in LUSC.
RESULTS: HOXA11 expression in LUSC had a tendency to be upregulated in comparison to adjacent non-cancerous tissues by qRT-PCR. TCGA data displayed that HOXA11 was remarkably over-expressed in LUSC compared with that in non-LUSC samples, and the area under curves (AUC) was 0.955 (P < 0.001). A total of 1523 co-expressed genes were sifted for further analysis. The most significant term enriched in the KEGG pathway was focal adhesion. Among the six hub genes of HOXA11, including PARVA, ILK, COL4A1, COL4A2, ITGB1, and ITGA5, five (with the exception of COL4A1) were significantly decreased compared with the normal lung tissues. Moreover, the expression of ILK was negatively related to HOXA11 (r = - 0.141, P = 0.002).
CONCLUSION: High HOXA11 expression may lead to carcinogenesis and the development of LUSC. Furthermore, co-expressed genes might affect the prognosis of LUSC.

Um SW, Kim Y, Lee BB, et al.
Genome-wide analysis of DNA methylation in bronchial washings.
Clin Epigenetics. 2018; 10:65 [PubMed] Free Access to Full Article Related Publications
Background: The objective of this study was to discover DNA methylation biomarkers for detecting non-small lung cancer (NSCLC) in bronchial washings and understanding the association between DNA methylation and smoking cessation.
Methods: DNA methylation was analyzed in bronchial washing samples from 70 NSCLCs and 53 hospital-based controls using Illumina HumanMethylation450K BeadChip. Methylation levels in these bronchial washings were compared to those in 897 primary lung tissues of The Cancer Genome Atlas (TCGA) data.
Results: Twenty-four CpGs (
Conclusions: The present study suggests that NSCLC may be detected by analyzing methylation changes of seven CpGs in bronchial washings. Furthermore, smoking cessation may lead to decreased DNA methylation in nonmalignant bronchial epithelial cells in a gene-specific manner.

Shahrabi S, Behzad MM, Jaseb K, Saki N
Thrombocytopenia in leukemia: Pathogenesis and prognosis.
Histol Histopathol. 2018; 33(9):895-908 [PubMed] Related Publications
Leukemias, a heterogeneous group of hematological disorders, are characterized by ineffective hematopoiesis and morphologic abnormalities of hematopoietic cells. Thrombocytopenia is a common problem among leukemia types that can lead to hemorrhagic complications in patients. The purpose of this review article is to identify the conditions associated with the incidence of thrombocytopenia in leukemias. It can be stated that although translocations have been considered responsible for this complication in many studies, other factors such as bone marrow failure, genes polymorphism, a mutation in some transcription factors, and the adverse effects of treatment could be associated with pathogenesis and poor prognosis of thrombocytopenia in leukemias. Considering the importance of thrombocytopenia in leukemias, it is hoped that the recognition of risk factors increasing the incidence of this complication in leukemic patients would be useful for prevention and treatment of this disorder.

Sun Y, Zeng C, Gan S, et al.
LncRNA HOTTIP-Mediated HOXA11 Expression Promotes Cell Growth, Migration and Inhibits Cell Apoptosis in Breast Cancer.
Int J Mol Sci. 2018; 19(2) [PubMed] Free Access to Full Article Related Publications
As the most common cause of cancer death in women, the pathogenesis of breast cancer still remains unclear. Here, we reported a long non-coding RNA (lncRNA), HOTTIP (HOXA transcript at the distal tip), that may play an important role in the pathogenesis of breast cancer. Using gain-and-loss-of experiments in vitro and in vivo, we observed the marked upregulation of HOTTIP/HOXA11 in the breast cancer cell line, MCF-7, and the downregulation of HOTTIP or HOXA11, which might inhibit cell proliferation and migration but promote cell apoptosis in breast cancer MCF-7 cells. In addition, by further rescue experiments with HOXA11 overexpression, we uncovered a novel potential regulatory mechanism between HOTTIP and one of its physical HOXA clusters, HOXA11. Hence, HOTTIP may mediate, at least partly, HOXA11 expression involved in cell growth, migration, and apoptosis of breast cancer MCF-7 cells.

Yu W, Peng W, Jiang H, et al.
LncRNA HOXA11-AS promotes proliferation and invasion by targeting miR-124 in human non-small cell lung cancer cells.
Tumour Biol. 2017; 39(10):1010428317721440 [PubMed] Related Publications
Long non-coding RNAs have been implicated in human cancer but their mechanisms of action are mainly undocumented. In this study, we found that HOXA11-AS expression was upregulated in non-small cell lung cancer tissues and cell lines. High levels of HOXA11-AS expression were correlated with larger tumor size and lymph node metastasis. Functional analysis revealed that HOXA11-AS promotes non-small cell lung cancer cell proliferation and invasion. In particular, HOXA11-AS functions as a competing endogenous RNA to regulate transcriptional factor Sp1 expression via sponging miR-124. Collectively, our findings reveal an oncogenic role for HOXA11-AS in non-small cell lung cancer tumorigenesis.

Xu C, He T, Li Z, et al.
Regulation of HOXA11-AS/miR-214-3p/EZH2 axis on the growth, migration and invasion of glioma cells.
Biomed Pharmacother. 2017; 95:1504-1513 [PubMed] Related Publications
BACKGROUND: Glioma is one of the most common and aggressive malignant tumors in central nervous system. Recently, long non-coding RNA (lncRNA) HOXA11-AS has been reported to be an oncogenic gene in multiple cancers. However, the molecular mechanisms of HOXA11-AS involved in cancer progression of human glioma remain unknown.
MATERIALS AND METHODS: The expression levels of HOXA11-AS in 45 paired primary glioma tissues and cell lines were examined by quantitative real-time PCR, and the correlation between HOXA11-AS expression and clinicopathologic characteristics of patients with glioma were analyzed. HOXA11-AS was knockdown in glioma cells by transfection with HOXA11-AS siRNA, and cell proliferation, migration and invasion were detected. The tumor growth of xenografts with HOXA11-AS knockdown glioma cells was also analyzed.
RESULTS: The expression levels of HOXA11-AS were significantly up-regulated in glioma tissues and cell lines compared with that in adjacent normal brain tissues and normal human astrocytes (NHA). High expression of HOXA11-AS was correlated with shorter overall survival in patients with glioma. Knockdown of HOXA11-AS inhibited glioma cell proliferation, migration and invasion in vitro, and tumor growth in vivo. In addition, we demonstrated that HOXA11-AS functioned as a competing endogenous RNA (ceRNA) for miR-214-3p, which in turn positively regulated the expression of its direct target EZH2.
CONCLUSIONS: We demonstrated that HOXA11-AS acted as an oncogenic lncRNA that promoted cell growth and metastasis of glioma through regulating miR-214-3p/EZH2 axis. These results suggested HOXA11-AS may serve as an efficient marker and a potential therapeutic target for glioma.

Li N, Yang M, Shi K, Li W
Long non-coding RNA HOXA11-AS in human cancer: A meta-analysis.
Clin Chim Acta. 2017; 474:165-170 [PubMed] Related Publications
BACKGROUND: Homeobox A11 antisense (HOXA11-AS), a newly identified lncRNA, is up-regulated in various carcinomas. We conducted the present meta-analysis to explore the potential of HOXA11-AS as a common predictive biomarker for metastasis and prognosis in malignant tumors.
METHODS: A systematic literature search on the online electronic databases of PubMed, Web of Science, and Embase was carried out to determine relevant studies (as of July 9, 2017). The pooled hazard ratios (HRs)/odds rates (ORs), and their 95% confidence intervals (CIs) were used to evaluate the relationship.
RESULTS: A total of 608 patients from seven studies were included in the current meta-analysis. The pooled results indicated that high HOXA11-AS expression was related to poor overall survival (OS) (HR=2.02, 95% CI: 1.48-2.75, P<0.001) and progression-free survival (PFS) (HR=1.91, 95% CI: 1.15-3.17, P=0.012). Further analyses reveal that patients with high HOXA11-AS expression are prone to develop distant metastasis (DM) (OR=6.05, 95% CI: 1.66-22.06, P=0.006).
CONCLUSIONS: This meta-analysis showed that increased expression of HOXA11-AS is a risk factor for poor clinical outcomes in numerous tumors and may act as a novel biomarker for poor prognosis and metastasis in cancers.

Cui Y, Yi L, Zhao JZ, Jiang YG
Long Noncoding RNA HOXA11-AS Functions as miRNA Sponge to Promote the Glioma Tumorigenesis Through Targeting miR-140-5p.
DNA Cell Biol. 2017; 36(10):822-828 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been proved as important regulators in many diseases, including cancers. HOXA11 antisense RNA (HOXA11-AS) is a novel identified lncRNA associated with cancer progression. However, the role of HOXA11-AS in glioma remains poorly understood and needs to be elucidated. The purpose of this study is to investigate the role and regulating mechanism of HOXA11-AS on gliomagenesis. Expression of HOXA11-AS was significantly upregulated in glioma tissue and cell lines compared with the adjacent normal tissue and cells. Moreover, patients with high HOXA11-AS expression had a shorter survival and poorer prognosis than that of lower expression. Loss-of-function experiments revealed that HOXA11-AS knockdown inhibited the proliferation, induced cell cycle arrest at G0/G1 phase, and enhanced the apoptosis. Bioinformatics prediction forecast that miR-140-5p directly targeted HOXA11-AS at 3'-UTR, which was confirmed by luciferase reporter assay. In vitro rescue experiment assays, miR-140-5p inhibitor transfection, could reverse the function of HOXA11-AS knockdown on the proliferation, cell cycle arrest, and apoptosis. Taken together, the present study illustrates that the pathway of HOXA11-AS sponging miR-140-5p might play a vital regulating role in the development and progression of glioma.

Yu J, Hong JF, Kang J, et al.
Promotion of LncRNA HOXA11-AS on the proliferation of hepatocellular carcinoma by regulating the expression of LATS1.
Eur Rev Med Pharmacol Sci. 2017; 21(15):3402-3411 [PubMed] Related Publications
OBJECTIVE: To investigate the expression levels of lncRNA HOXA11-AS in HCC tissues and cells, and to explore its biological role in the development and progression of HCC.
PATIENTS AND METHODS: We detected the relative expression level of HOXA11-AS in 72 HCC tissues and cells by the real-time quantitative PCR (qRT-PCR) assay. After interference with HOXA11-AS expression in HCC cells, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clone formation, flow cytometry and an established nude mice transplanted tumor model were used to detect the biological behavior of HCC cells. qRT-PCR and Western blotting assays were used to detect the expression level of large tumor suppressor kinases 1 (LATS1). The subcellular localization of HOXA11-AS in HCC was detected by separating nuclei from the cytoplasm. The molecular mechanism of HOXA11-AS was regulated by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip) experiments.
RESULTS: qRT-PCR assays showed that HOXA11-AS was relatively highly expressed in HCC tissues and cells. In vivo and in vitro experiments showed that HOXA11-AS could inhibit the proliferation of HCC cells, promote their apoptosis and retard the cell cycle progression from G1 to G0 phase. qRT-PCR and Western blotting assays results showed that LATS1 genes were the downstream target genes of HOXA11-AS. RIP and CHIP experiments showed that HOXA11-AS inhibited the expression of LATS1 genes by binding enhancer of zeste homolog 2 (EZH2) proteins.
CONCLUSIONS: HOXA11-AS inhibited the malignant transcription of the LATS1 genes and promoted the malignant proliferation of HCC cells. Interactions among HOXA11-AS, PRC2, and LATS1 may provide a new target for the treatment of HCC.

Su JC, Hu XF
Long non‑coding RNA HOXA11‑AS promotes cell proliferation and metastasis in human breast cancer.
Mol Med Rep. 2017; 16(4):4887-4894 [PubMed] Related Publications
Breast cancer is one of the most frequently occurring malignancies in female cancers worldwide, however, its detailed mechanism of tumorigenesis remains to be elucidated. Long non-coding RNAs (LncRNAs) have previously been demonstrated to be important in multiple cancers, including breast cancer. The present study aimed to elucidate the molecular mechanism of the effects of the novel Lnc RNA HOXA11‑AS, on cell proliferation and metastasis in breast cancer. The data revealed that the relative transcript level of HOXA11‑AS was upregulated in vivo and in vitro in models of breast cancer. Knockdown of HOXA11‑AS in MDA‑MB‑231 and MDA‑MB‑436 breast cancer cell lines inhibited the formation of cell colonies and arrested the cell cycle at the G0/G1 phase. Depletion of HOXA11‑AS using two specific short interfering (si)RNAs against HOXA11‑AS (siHOXA11‑AS‑1 and siHOXA11‑AS‑2) additionally suppressed the cell proliferative rate. Furthermore, transwell assays and wound‑healing analysis revealed that siRNA transfection inhibited cell migration and invasion by ~50% in the two cell lines. The results of the present study demonstrated the oncogenic role of HOXA11‑AS in breast cancer, providing novel clues for the future clinical diagnosis and treatment of early stage breast cancer patients.

Lu Q, Zhao N, Zha G, et al.
LncRNA HOXA11-AS Exerts Oncogenic Functions by Repressing p21 and miR-124 in Uveal Melanoma.
DNA Cell Biol. 2017; 36(10):837-844 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been reported to play vital roles in various human cancers. The aim of this study was to explore the critical role of lncRNA HOXA11-AS in uveal melanoma (UM) progression. Briefly, we found that HOXA11-AS is overexpressed in UM tissues and cells; HOXA11-AS could regulate UM cell growth, invasion, and apoptosis. Mechanistically, RNA immunoprecipitation demonstrated that HOXA11-AS could simultaneously interact with enhancer of zeste homolog 2 (EZH2) to suppress its target p21 protein expression. In addition, we demonstrated that HOXA11-AS functioned as a molecular sponge for miR-124, and overexpression of miR-124 attenuated the proliferation and invasion-promoting effect of HOXA11-AS. Collectively, our findings reveal an oncogenic role for HOXA11-AS in UM tumorigenesis.

Zhang Y, Chen WJ, Gan TQ, et al.
Clinical Significance and Effect of lncRNA HOXA11-AS in NSCLC: A Study Based on Bioinformatics, In Vitro and in Vivo Verification.
Sci Rep. 2017; 7(1):5567 [PubMed] Free Access to Full Article Related Publications
HOXA11 antisense RNA (HOXA11-AS) has been shown to be involved in tumorigenesis and development of different cancers. However, the role of HOXA11-AS in non-small cell lung cancer (NSCLC) remains unclear. In this study, we firstly explored and confirmed the expression of HOXA11-AS in NSCLC tissues and cells. Cytometry, CCK-8, cell scratch, migration, Matrigel invasion and flow cytometry assays were performed to determine the biological impact of HOXA11-AS in vitro. Furthermore, a chick embryo chorioallantoic membrane (CAM) model of NSCLC was constructed to explore the effect of HOXA11-AS on tumorigenicity and angiogenesis in vivo. Additionally, bioinformatics analyses were performed to investigate the prospective pathways of HOXA11-AS co-expressed genes. As results, HOXA11-AS was markedly highly expressed in NSCLC tissues and cells. Furthermore, the proliferation, migration, invasion, tumorigenic and angiogenic ability of NSCLC cells were all inhibited and apoptosis was induced after HOXA11-AS knock-down. HOXA11-AS RNAi also led to cell cycle arrest on G0/G1 or G2/M phase. In addition, the non-small cell lung cancer pathway might be involved in regulating the co-expressed genes of HOXA11-AS in NSCLC. These results indicate that HOXA11-AS plays pivotal roles in NSCLC and it can become a novel therapeutic direction for treating NSCLC.

Li Y, Kang K, Krahn JM, et al.
A comprehensive genomic pan-cancer classification using The Cancer Genome Atlas gene expression data.
BMC Genomics. 2017; 18(1):508 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Cancer Genome Atlas (TCGA) has generated comprehensive molecular profiles. We aim to identify a set of genes whose expression patterns can distinguish diverse tumor types. Those features may serve as biomarkers for tumor diagnosis and drug development.
METHODS: Using RNA-seq expression data, we undertook a pan-cancer classification of 9,096 TCGA tumor samples representing 31 tumor types. We randomly assigned 75% of samples into training and 25% into testing, proportionally allocating samples from each tumor type.
RESULTS: We could correctly classify more than 90% of the test set samples. Accuracies were high for all but three of the 31 tumor types, in particular, for READ (rectum adenocarcinoma) which was largely indistinguishable from COAD (colon adenocarcinoma). We also carried out pan-cancer classification, separately for males and females, on 23 sex non-specific tumor types (those unrelated to reproductive organs). Results from these gender-specific analyses largely recapitulated results when gender was ignored. Remarkably, more than 80% of the 100 most discriminative genes selected from each gender separately overlapped. Genes that were differentially expressed between genders included BNC1, FAT2, FOXA1, and HOXA11. FOXA1 has been shown to play a role for sexual dimorphism in liver cancer. The differentially discriminative genes we identified might be important for the gender differences in tumor incidence and survival.
CONCLUSIONS: We were able to identify many sets of 20 genes that could correctly classify more than 90% of the samples from 31 different tumor types using TCGA RNA-seq data. This accuracy is remarkable given the number of the tumor types and the total number of samples involved. We achieved similar results when we analyzed 23 non-sex-specific tumor types separately for males and females. We regard the frequency with which a gene appeared in those sets as measuring its importance for tumor classification. One third of the 50 most frequently appearing genes were pseudogenes; the degree of enrichment may be indicative of their importance in tumor classification. Lastly, we identified a few genes that might play a role in sexual dimorphism in certain cancers.

López JI, Angulo JC, Martín A, et al.
A DNA hypermethylation profile reveals new potential biomarkers for the evaluation of prognosis in urothelial bladder cancer.
APMIS. 2017; 125(9):787-796 [PubMed] Related Publications
DNA hypermethylation has emerged as a molecular biomarker for the evaluation of cancer diagnosis and prognosis. We define a methylation signature of bladder cancer and evaluate whether this profile assesses prognosis of patients. Genome-wide methylation analysis was performed on 70 tumor and 10 normal bladder samples. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Thirty-three genes were significantly hypermethylated in ≥10% of the tumors. Three clusters of patients were characterized by their DNA methylation profile, one at higher risk of dead of disease (p = 0.0012). Association between cluster distribution and stage (p = 0.02) or grade (p = 0.02) was demonstrated. Hypermethylation of JAK3 and absence of hypermethylation of EYA4, GAT6, and SOX1 were associated with low-grade non-invasive disease. On the other hand, in high-grade invasive disease hypermethylation of CSPG2, HOXA11, HOXA9, HS3ST2, SOX1, and TWIST1 was associated with muscle invasiveness. A panel of hypermethylated genes including APC, CSPG2, EPHA5, EYA4, HOXA9, IPF1, ISL1, JAK3, PITX2, SOX1, and TWIST1 predicted cancer-specific survival and SOX1 (HR = 3.46), PITX2 (HR = 4.17), CSPG2 (HR = 5.35), and JAK3 hypermethylation (HR = 0.19) did so independently. Silencing of genes by hypermethylation is a common event in bladder cancer and could be used to develop diagnostic and prognostic markers. Combined hypermethylation of SOX1, PITX2, or CSPG2 signals patients at higher risk of death from bladder cancer.

Cui M, Wang J, Li Q, et al.
Long non-coding RNA HOXA11-AS functions as a competing endogenous RNA to regulate ROCK1 expression by sponging miR-124-3p in osteosarcoma.
Biomed Pharmacother. 2017; 92:437-444 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been strongly associated with various types of cancer. this study was to explore the critical role of lncRNA HOXA11-AS in osteosarcoma (OS) progression. Briefly, we should that the expression of HOXA11-AS was upregulated in OS tissues and cell lines. The high expression of HOXA11-AS was associated with advanced clinical stage, distant metastasis and poor overall survival of OS. In addition, We found that HOXA11-AS silencing suppressed OS cells proliferation, invasion and induced cell arrest in G0/G1 phase. Furthermore, our data showed that HOXA11-AS acts as an endogenous sponge by directly binding miR-124-3p, and decreasing the expression of miR-124-3p. Moreover, we found that HOXA11-AS may regulate tumor progression by affecting miR-124-3p targets, and ROCK1 expression. To conclude, our study helps to elucidate the effectiveness of HOXA11-AS promotion on OS cell proliferation and metastasis. A better understanding of interaction mechanism between HOXA11-AS-miR-124-3p-ROCK1 signaling axis may be a step forward in the development of new therapeutic strategies for the treatment of OS.

Liu Z, Chen Z, Fan R, et al.
Over-expressed long noncoding RNA HOXA11-AS promotes cell cycle progression and metastasis in gastric cancer.
Mol Cancer. 2017; 16(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as critical regulators in a variety of human cancers, including gastric cancer (GC). However, the function and mechanisms responsible for these molecules in GC are not fully understood. In our previous study, we found that GC associated lncRNA HOXA11-AS is significantly upregulated in GC tissues. Over-expressed HOXA11-AS promotes GC cells proliferation and invasion through scaffolding the chromatin modification factors PRC2, LSD1 and DNMT1.
METHODS: HOXA11-AS expression levels in GC cells was detected by quantitative real-time PCR (qPCR). HOXA11-AS siRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate HOXA11-AS expression. In vitro and in vivo assays were performed to investigate the functional role of HOXA11-AS in GC cells cell cycle progression, invasion and metastasis. RIP and ChIP assays were used to determine the mechanism of HOXA11-AS's regulation of underlying targets.
RESULTS: We found that knockdown of HOXA11-AS induced GC cells G0/G1 phase arrest and suppressed GC cells migration, invasion and metastasis in vivo. Moreover, mechanistic investigation showed that HOXA11-AS could interact with WDR5 and promote β-catenin transcription, bind with EZH2 and repress P21 transcription, and induce KLF2 mRNA degradation via interacting with STAU1.
CONCLUSIONS: Taken together, these findings show that HOXA11-AS not only could promote GC cells migration and invasion in vitro, but also promotes GC cells metastasis in vivo, at least in part, by regulating β-catenin and KLF2.

Wang L, Cui Y, Sheng J, et al.
Epigenetic inactivation of HOXA11, a novel functional tumor suppressor for renal cell carcinoma, is associated with RCC TNM classification.
Oncotarget. 2017; 8(13):21861-21870 [PubMed] Free Access to Full Article Related Publications
Epigenetic inactivation of HOXA11, a putative tumor suppressor, is frequently observed in a number of solid tumors, but has not been described in RCC (renal cell carcinoma). In this study, we investigated the expression, epigenetic changes and the function of HOXA11 in human renal cell carcinoma (RCC). HOXA11 was silenced or down-regulated in RCC cell lines and tissues. Methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS) revealed that the HOXA11 promoter was hypermethylated in 5/6 RCC cell lines. Demethylation treatment resulted in demethylation of the promoter and increased HOXA11 expression in these cell lines. HOXA11 methylation was also detected in 68/95 (70.5%) primary RCC tumors, but only rare adjacent non-malignant renal tissues (13%, 3/23) showed hypermethylation of promoter. We also found that the methylation of HOXA11 was associated with higher TNM classification of RCC (p<0.05). Ectopic expression of HOXA11 led to significant inhibition of proliferation, colony formation, migration and invasion abilities and induced RCC cells apoptosis. Moreover, HOXA11 was found to inhibit Wnt signaling. Thus, our study demonstrated that HOXA11 function as a tumor suppressor in RCC, while it is frequently silenced by promoter methylation in RCC.

Li Q, Chen C, Ren X, Sun W
DNA methylation profiling identifies the HOXA11 gene as an early diagnostic and prognostic molecular marker in human lung adenocarcinoma.
Oncotarget. 2017; 8(20):33100-33109 [PubMed] Free Access to Full Article Related Publications
DNA hypermethylation plays important roles in carcinogenesis by silencing key genes. The goal of our study was to identify pivotal genes using MethyLight and assessed their diagnostic and prognostic values in lung adenocarcinoma (AD). In the present study, we detected DNA methylation at sixteen loci promoter regions in twenty one pairs of primary human lung AD tissues and adjacent non-tumor lung (AdjNL) tissues using the real-time PCR (RT-PCR)-based method MethyLight. By comparing the sixteen analyzed loci in lung AD tissues and AdjNL and non-tumor (NL) tissues, we found that, among the six genes identified with hypermethylation, the HOXA11, CDKN2A-EX2 and EYA4 genes showed highly promising DNA hypermethylation diagnostic markers in the lung AD tissues. Moreover, comparing lung AD tissues (> 2 cm in diameter) to the AdjNL or AD in situ (AIS) tissues by RT-qPCR and immunohistochemistry revealed that HOXA11 expression was significantly increased. A further study showed that HOXA11 expression was controlled by methylation in the promoter region in human lung tumor cell lines. Aberrant hypermethylation and the methylation-induced down-regulation of HOXA11 may promote tumor progression. Our results suggested that HOXA11 might be a diagnostic and prognostic marker in patients with lung AD.

Xia B, Shan M, Wang J, et al.
Homeobox A11 hypermethylation indicates unfavorable prognosis in breast cancer.
Oncotarget. 2017; 8(6):9794-9805 [PubMed] Free Access to Full Article Related Publications
Homeobox A11 (HOXA11) is one of the hypermethylated genes in breast cancer and its function in breast tumorigenesis remains elusive. In this study, we analyzed the methylation status of HOXA11 in 264 paired breast cancer and normal tissue as well as in matched serum samples by MethyLight assay. Further, the function of HOXA11 in breast tumorigenesis was analyzed by cell proliferation and migration assays. We found that HOXA11 was hypermethylated in cancer tissues (45.08%), especially in invasive ductal carcinomas (P<0.001), patients with a family history of cancer (P=0.033), cases with metastatic lymph nodes (P=0.004) and P53 positive group (P=0.017). Kaplan-Meier survival analysis and Cox regression analysis revealed that HOXA11 hypermethylation is an independent predictor of poor outcomes. The over expression of HOXA11 suppressed cell growth in MDA-MB-231, MCF7, SKBR3 and BT474 cells. In conclusion, the hypermethylation of HOXA11 is an independent prognostic biomarker in breast cancer. Additionally, HOXA11 can be a potential tumor suppressor.

Kim HJ, Eoh KJ, Kim LK, et al.
The long noncoding RNA HOXA11 antisense induces tumor progression and stemness maintenance in cervical cancer.
Oncotarget. 2016; 7(50):83001-83016 [PubMed] Free Access to Full Article Related Publications
Recent research has focused on the impact of long noncoding RNA (lncRNA) in cervical carcinogenesis. However, whether HOXA11 antisense (HOXA11-AS) is involved in cervical cancer remains to be elucidated. In the present study, we examined HOXA11-AS expression levels in cervical cancer patients and determined the relationships between HOXA11-AS expression and clinicopathological factors. We also investigated the bio-functional consequences of HOXA11-AS overexpression both in vitro and in vivo. HOXA11-AS expression was significantly greater in tissues from patients with cervical cancer than in control patients (P<0.001). Multivariate analysis showed that high HOXA11-AS was an independent prognosticator of overall survival (Hazard ratio=2.450, P=0.032). HOXA11-AS overexpression enhanced cell proliferation, migration, and tumor invasion in vitro, whereas HOXA11-AS knockdown inhibited these biologic aggressive features. These adverse changes were accompanied by characteristics of epithelial-mesenchymal transition (EMT). In vivo xenograft experiments using the siHOXA11-AS-transfected HeLa cells revealed that HOXA11-AS strongly induced tumor growth. Furthermore, we found that HOXA11-AS knockdown decreased cancer stemness and triggered the EMT program. In conclusion, HOXA11-AS overexpression correlated with poor survival in patients with cervical cancer. Thus, HOXA11-AS may be a pivotal target for exploring novel cervical cancer therapeutics.

Yim GW, Kim HJ, Kim LK, et al.
Long Non-coding RNA
Cancer Res Treat. 2017; 49(3):656-668 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The biological function of long non-coding RNAs (lncRNAs) is only partially understood; therefore, in this study, we investigated the expression of the novel

Se YB, Kim SH, Kim JY, et al.
Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma.
Cancer Res Treat. 2017; 49(2):387-398 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation.
RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (
CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

Makker A, Goel MM, Nigam D, et al.
Endometrial Expression of Homeobox Genes and Cell Adhesion Molecules in Infertile Women With Intramural Fibroids During Window of Implantation.
Reprod Sci. 2017; 24(3):435-444 [PubMed] Related Publications
This study was designed to examine the expression and cellular distribution of homeobox ( HOX) genes ( HOXA10 and HOXA11) and cell adhesion molecules (E-cadherin, N-cadherin, and β-catenin) during the window of implantation in infertile women with noncavity-distorting intramural (IM) fibroids (n = 18) and in fertile controls (n = 12). Quantitative real-time polymerase chain reaction and immunohistochemistry were used to evaluate the messenger RNA (mRNA) levels and protein expression, respectively. When compared to fertile controls, reduced HOXA10 and HOXA11 transcript and protein levels were observed in infertile women. However, changes only in the expression of HOXA10 mRNA (-1.72-fold; P = .03) and stromal protein ( P = .001) were statistically significant. Significantly lower E-cadherin mRNA (-10.97-fold; P = .02) and protein levels were seen in infertile patients. E-cadherin immunostaining was significantly reduced both in the luminal ( P = .048) and in the glandular ( P = .014) epithelium of endometrium from infertile patients when compared to controls. No significant change was observed either in the mRNA levels or in the immunoexpression of N-cadherin and β-catenin. However, a trend toward lower N-cadherin expression in the luminal epithelium ( P = .054) and decreased β-catenin expression in the glandular epithelium ( P = .070) was observed in infertile patients. The present findings suggest that altered endometrial HOXA10 and E-cadherin mRNA and protein expression observed in infertile women with IM fibroids during the mid-secretory phase might impair endometrial receptivity leading to infertility in these patients.

Wang Q, Zhang J, Liu Y, et al.
A novel cell cycle-associated lncRNA, HOXA11-AS, is transcribed from the 5-prime end of the HOXA transcript and is a biomarker of progression in glioma.
Cancer Lett. 2016; 373(2):251-9 [PubMed] Related Publications
The comprehensive lncRNA expression signature in glioma has not yet been fully elucidated. We performed a high-throughput microarray to detect the ncRNA expression profiles of 220 human glioma tissues. Here, we found that a novel lncRNA, HOXA11-AS, was the antisense transcript of the HOX11 gene. It was shown that HOXA11-AS was closely associated with glioma grade and poor prognosis. Multivariate Cox regression analysis revealed that HOXA11-AS was an independent prognostic factor in glioblastoma multiforme patients, and its expression was correlated with the glioma molecular subtypes of the Cancer Genome Atlas. Gene set enrichment analysis indicated that the gene sets most correlated with HOXA11-AS expression were involved in cell cycle progression. Over-expression of the HOXA11-AS transcript promoted cell proliferation in vitro, while knockdown of HOXA11-AS expression repressed cell proliferation via regulation of cell cycle progression. The growth-promoting and growth-inhibiting effects of HOXA11-AS were also demonstrated in a xenograft mouse model. Our data confirms, for the first time, that HOXA11-AS is an important long non-coding RNA that primarily serves as a prognostic factor for glioma patient survival. HOXA11-AS could serve as a biomarker for identifying glioma molecular subtypes and as therapeutic target for glioma patients.

Unlu C, Celik O, Celik N, Otlu B
Expression of Endometrial Receptivity Genes Increase After Myomectomy of Intramural Leiomyomas not Distorting the Endometrial Cavity.
Reprod Sci. 2016; 23(1):31-41 [PubMed] Related Publications
This study was designed to investigate whether endometrial receptivity genes are altered in infertile patients with intramural leiomyomas (IM) not distorting the endometrial cavity undergoing myomectomy. We measured endometrial HOXA-10, HOXA-11, LIF, ITGB3, and ITGAV messenger RNA (mRNA) expressions levels before and after myomectomy/metroplasty during mid-luteal phase in participants with IM, submucosal leiomyomas (SM), and septate uterus and fertile participants without fibroids. Initial endometrial sampling was obtained at the time of surgery, and second sampling was obtained 3 months after myomectomy/metroplasty. Expressions of each gene were evaluated using real-time reverse transcriptase polymerase chain reaction (RT-PCR). A trend toward decreased endometrial HOXA-10, HOXA-11, and ITGAV mRNA expression was detected in both SM and IM groups before myomectomy when compared to both fertile group and septate uterus. However, the differences failed to show statistical significance. After myomectomy of IM, we have detected 12.8-fold increase in endometrial HOXA-10 mRNA expression and 9.0-fold increase in endometrial HOXA-11 mRNA expression. This increase in endometrial HOXA-10 and 11 mRNA expression was significant. Accordingly, 2 patients having intramural fibroids greater than 5 cm were able to remain pregnant after myomectomy. Conversely, submucosal myomectomy did not cause any significant effect on endometrial receptivity markers. Likewise, all markers of endometrial receptivity remained unchanged after metroplasty. Myomectomy of IM have favorable effect on endometrial HOXA-10 and 11 mRNA expression.

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