Gene Summary

Gene:HOXA13; homeobox A13
Aliases: HOX1, HOX1J
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. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-A13
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

Specific Cancers (8)

Latest Publications: HOXA13 (cancer-related)

Luo H, Wang F, Zha J, et al.
CTCF boundary remodels chromatin domain and drives aberrant
Blood. 2018; 132(8):837-848 [PubMed] Free Access to Full Article Related Publications

Shi Q, Shen L, Dong B, et al.
Downregulation of HOXA13 sensitizes human esophageal squamous cell carcinoma to chemotherapy.
Thorac Cancer. 2018; 9(7):836-846 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemoresistance often develops in esophageal squamous cell carcinoma (ESCC), leading to poor prognosis. HOX genes play a crucial role in embryonic development and cell differentiation. Studies have recently linked HOX with chemoresistance, thus we explored whether HOXA13 is involved in ESCC chemoresistance.
METHODS: One hundred thirty-one ESCC patients who received neoadjuvant chemotherapy were enrolled. HOXA13 expression was examined by immunohistochemistry. RNA interference was used to knock down the HOXA13 expression in KYSE70 and transfected HOXA13 plasmid to overexpress HOXA13 in KYSE510 cells. We examined half-maximal inhibitory concentration of cisplatin, apoptosis, and epithelial-to-mesenchymal transition (EMT) in ESCC cell lines with different HOXA13 expression levels by cell counting kit-8, flow cytometry, and transwell analysis.
RESULTS: The median survival of patients with high HOXA13 expression was significantly shorter than those with low expression (P = 0.027). HOXA13 was associated with worse tumor regression grade (P = 0.009). Low HOXA13 expressed cells decreased the half-maximal inhibitory concentration of cisplatin (P < 0.05), increased cisplatin-induced apoptosis (P < 0.05), and decreased EMT (P < 0.05) compared with high HOXA13 expressed cells. In low HOXA13 expressed cells, cleaved caspase-3 and cleaved PARP expression induced by cisplatin increased, while expression of E-cadherin and Snail protein, markers of EMT, was upregulated and downregulated, respectively. EMT decreased in low HOXA13 expressed cells.
CONCLUSION: High HOXA13 expression was associated with inferior tumor regression grade and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy. HOXA13 increased cisplatin-resistance and promoted EMT in ESCC cells.

Wen Y, Shu F, Chen Y, et al.
The prognostic value of HOXA13 in solid tumors: A meta-analysis.
Clin Chim Acta. 2018; 483:64-68 [PubMed] Related Publications
PURPOSE: The prognostic value of homeobox (HOX) A13 (HOXA13) in cancer remains uncertain due to limitations of sample size and discrete outcome in previous studies. We performed this meta-analysis to explore the prognostic effect of HOXA13 in patients with solid tumors.
METHODS: PubMed, Embase, and Web of Science were searched to identify eligible studies. Hazard ratios (HR) with 95% confidence interval (95%CI) and clinicopathological factors were extracted. Subgroup analysis according to cancer type, sample size and analysis method were also performed.
RESULTS: A total of 844 patients with solid tumor from 9 eligible studies were incorporated in the meta-analysis. We found that high HOXA13 expression level was significantly associated with poor overall survival (OS) in human cancer (HR = 2.23; 95%CI: 1.74-2.85), and significantly related to poorer histological grade (odds ratio (OR) = 2.03, 95%CI: 1.40-2.96), positive lymph node metastasis (OR = 1.96, 95%CI: 1.26-3.02) and more advanced tumor-node-metastasis (TNM) stage (OR = 3.92, 95%CI: 2.46-6.22).
CONCLUSION: Our meta-analysis suggests that HOXA13 might be a valuable biomarker of poor prognosis and a potential therapeutic target for human solid tumors.

Han Y, Song C, Wang J, et al.
HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway.
Mol Carcinog. 2018; 57(6):722-734 [PubMed] Related Publications
5-FU-based chemotherapy is recently most recommended as the first-line treatment for gastric cancer (GC). However, 5-FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5-FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5-FU. Moreover, dehydrogenase/reductase 2 (DHRS2) was identified as a downstream gene of HOXA13. HOXA13 played a role of carcinogenesis through directly down-regulating DHRS2 to increase MDM2. Furthermore, HOXA13 conferred 5-FU resistance through MRP1 by a p53-dependent pathway. Therefore, HOXA13 might serve as a potential signature that recognized patients who were insensitive to 5-FU, and timely recommended them to other chemotherapy regimens.

Sun Y, Hu B, Wang Q, et al.
Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR-216a.
Cell Death Dis. 2018; 9(2):85 [PubMed] Free Access to Full Article Related Publications
Despite progress in treatment of small cell lung cancer (SCLC), its multidrug chemoresistance and poor prognosis still remain. Recently, we globally assessed long non-coding RNAs (lncRNAs) for contributions to SCLC chemoresistance using microarray data, in vitro and in vivo assays. Here we reported that HOTTIP, encoding a lncRNA that is frequently amplified in SCLC, was associated with SCLC cell chemosensitivity, proliferation, and poor prognosis of SCLC patients. Moreover, mechanistic investigations showed that HOTTIP functioned as an oncogene in SCLC progression by binding miR-216a and abrogating its tumor-suppressive function in this setting. On the other hand, HOTTIP increased the expression of anti-apoptotic factor BCL-2, another important target gene of miR-216a, and jointly enhanced chemoresistance of SCLC by regulating BCL-2. Taken together, our study established a role for HOTTIP in SCLC progression and chemoresistance suggest its candidacy as a new diagnostic and prognostic biomarker for clinical management of SCLC.

Luo Z, Rhie SK, Lay FD, Farnham PJ
A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13.
Cell Rep. 2017; 21(6):1411-1417 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ∼42% of the susceptibility to PCa. We analyzed a PCa risk region located at 7p15.2 to gain insight into the mechanisms by which this noncoding region may affect gene regulation and contribute to PCa risk. We performed Hi-C analysis and demonstrated that this region has long-range interactions with the HOXA locus, located ∼873 kb away. Using the CRISPR/Cas9 system, we deleted a 4-kb region encompassing several PCa risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was performed to gain further insight into the mechanisms by which this risk element affects PCa risk.

Quagliata L, Quintavalle C, Lanzafame M, et al.
High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models.
Lab Invest. 2018; 98(1):95-105 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.

Wu DC, Wang SSW, Liu CJ, et al.
Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.
Stem Cells. 2017; 35(10):2115-2128 [PubMed] Related Publications
Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128.

Dong Y, Cai Y, Liu B, et al.
HOXA13 is associated with unfavorable survival and acts as a novel oncogene in prostate carcinoma.
Future Oncol. 2017; 13(17):1505-1516 [PubMed] Related Publications
AIM: To investigate the clinical relevance and functional role of HOXA13 in prostate cancer Methods: PCR, western blot and immunohistochemistry were performed to determine the expression. Kaplan-Meier and Cox regression survival analyses investigated the clinical relevance. Cell viability, flow cytometry and transwell assays were used to determine the functional roles.
RESULTS: HOXA13 expression is sharply increased in carcinoma tissues and is significantly associated with poor prognosis of prostate cancer patients. Interestingly, nucleus not cytoplasm HOXA13 expression is associated with unfavorable survival of the patients. Furthermore, nucleus HOXA13 expression represents an unfavorable and independent prognosis factor of histological grade 2 or Gleason grade <8 patients. Functionally, forced expression of HOXA13 obviously promotes tumor cell proliferation, migration and invasion, whereas inhibits tumor cell apoptosis.
CONCLUSION: HOXA13 is an unfavorable prognostic factor and a novel oncogene for prostate cancer.

Lin C, Wang Y, Wang Y, et al.
Transcriptional and posttranscriptional regulation of HOXA13 by lncRNA HOTTIP facilitates tumorigenesis and metastasis in esophageal squamous carcinoma cells.
Oncogene. 2017; 36(38):5392-5406 [PubMed] Related Publications
The long non-coding RNA, HOTTIP, has an important role in tumorigenesis. It is known that HOTTIP regulates HOX gene family; however, its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we investigated the role of HOTTIP in ESCC and observed that HOTTIP/HOXA13 was upregulated in ESCC and promoted cell proliferation and metastasis in vivo and in vitro. Interestingly, harboring a miR-30b-binding site, HOTTIP as a molecular sponge mainly regulated miR-30b level in the nucleus and modulated the repression of HOXA13 mediated by miR-30b in the cytoplasm, resulting in the positive HOTTIP/HOXA13 correlation. In addition, HOTTIP upregulated snail1 by competitively binding miR-30b, subsequently promoting epithelial-mesenchymal transition (EMT) and invasion. HOTTIP directly bound the adaptor protein WDR5 and drove histone H3 lysine 4 trimethylation and HOXA13 gene transcription in ESCC cells. In conclusion, our findings indicated that HOTTIP modulated HOXA13 at both the transcriptional and posttranscriptional levels in ESCC cells and HOTTIP-miR-30b-HOXA13 axis may serve as potential diagnostic markers or drug targets for ESCC therapies.

Saha SS, Chowdhury RR, Mondal NR, et al.
Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7.
Oncotarget. 2017; 8(22):36591-36602 [PubMed] Free Access to Full Article Related Publications
The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

Qu LP, Zhong YM, Zheng Z, Zhao RX
CDH17 is a downstream effector of HOXA13 in modulating the Wnt/β-catenin signaling pathway in gastric cancer.
Eur Rev Med Pharmacol Sci. 2017; 21(6):1234-1241 [PubMed] Related Publications
OBJECTIVE: In this study, we investigated the mechanism underlying co-upregulation of HOXA13 and CDH17 in gastric cancer, the signaling pathway in which HOXA13 and CDH17 involve in and their functional role in gastric cancer cells.
MATERIALS AND METHODS: Relevant microarrays investigated the dysregulated genes in gastric cancer tissues were searched in ArrayExpress. The co-expression of HOXA13 and CDH17 was analyzed in the gastric cancer patient cohort in TCGA database using cBioportal and UCSC Xena. The regulative effect of HOXA13 on CDH17 expression was examined by dual luciferase assay. The involvement of HOXA13 and CDH17 in the Wnt/beta-catenin signaling pathway was assessed by Western blotting. The functional role of HOXA13 and CDH17 in gastric cancer cells were studied by CCK-8 assay of cell growth, Transwell assay of cell invasion and flow cytometry of active caspase-3.
RESULTS: HOXA13 and CDH17 expression are upregulated and are highly correlated in gastric cancer tissues. HOXA13 overexpression significantly increased CDH17 mRNA and protein expression and also significantly increased the transcription activity of the luciferase reporter with integrate HOXA13 binding sites. HOXA13 shRNA and CDH17 shRNA had similar effect on reducing the expression of beta-catenin, while shCDH17 abrogated HOXA13 induced upregulation of beta-catenin. HOXA13 shRNA and CDH17 shRNA decreased cell proliferation and invasion and increased cell apoptosis in SGC-7901 cells.
CONCLUSIONS: HOXA13 can elevate CDH17 transcription via binding to its promoter. CDH17 is a downstream effector of HOXA13 in modulating the Wnt/beta-catenin signaling pathway in gastric cancer cells. Both HOXA13 shRNA and CDH17 shRNA can decrease gastric cancer cell proliferation and invasion and increase their apoptosis.

Chandrasekaran G, Hwang EC, Kang TW, et al.
Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer.
Sci Rep. 2017; 7:43830 [PubMed] Free Access to Full Article Related Publications
The human HOXB13 gene encodes a 284 amino acid transcription factor belonging to the homeobox gene family containing a homeobox and a HoxA13 N-terminal domain. It is highly linked to hereditary prostate cancer, the majority of which is manifested as a result of a Single Nucleotide Polymorphism (SNP). In silico analysis of 95 missense SNP's corresponding to the non-homeobox region of HOXB13 predicted 21 nsSNP's to be potentially deleterious. Among 123 UTR SNPs analysed by UTRScan, rs543028086, rs550968159, rs563065128 were found to affect the UNR_BS, GY-BOX and MBE UTR signals, respectively. Subsequent analysis by PolymiRTS revealed 23 UTR SNPs altering the miRNA binding site. The complete HOXB13_M26 protein structure was modelled using MODELLER v9.17. Computational analysis of the 21 nsSNP's mapped into the HOXB13_M26 protein revealed seven nsSNP's (rs761914407, rs8556, rs138213197, rs772962401, rs778843798, rs770620686 and rs587780165) seriously resulting in a damaging and deleterious effect on the protein. G84E, G135E, and A128V resulted in increased, while, R215C, C66R, Y80C and S122R resulted in decreased protein stability, ultimately predicted to result in the altered binding patterns of HOXB13. While the genotype-phenotype based effects of nsSNP's were assessed, the exact biological and biochemical mechanism driven by the above predicted SNPs still needs to be extensively evaluated by in vivo and GWAS studies.

He YX, Song XH, Zhao ZY, Zhao H
HOXA13 upregulation in gastric cancer is associated with enhanced cancer cell invasion and epithelial-to-mesenchymal transition.
Eur Rev Med Pharmacol Sci. 2017; 21(2):258-265 [PubMed] Related Publications
OBJECTIVE: In this study, we investigated the association between HOXA13 dysregulation and gastric cancer progression. We also explored the functional role of HOXA13 in invasion and epithelial-to-mesenchymal transition (EMT) of gastric cancer cells and the possible signaling pathway it might involve in.
MATERIALS AND METHODS: The microarray (E-GEOD-19826) examined the transcription profiles of 12 adjacent normal/tumor-matched gastric tissues was downloaded from the ArrayExpress and reanalyzed. Immunohistochemistry (IHC) staining was performed to assess HOXA13 expression in 23 stage I and 69 stage II/III/IV gastric cancer tissues. The human gastric cancer cell line AGS and SGC-7901 cells were transfected with HOXA13 siRNA and then were subjected to detection of epithelial and mesenchymal markers and cell invasion. The involvement of HOXA13 in TGF-β signaling was further studied.
RESULTS: HOXA13 is one of the most upregulated genes in gastric cancer tissues compared to adjacent normal tissues. Also, HOXA13 is further upregulated in the higher stage tumors. HOXA13 staining was significantly stronger in stage II/III/IV tumors than in stage I tumors. HOXA13 siRNA significantly restored the epithelial property and reduced the mesenchymal property of the cancer cells. Transwell assay showed that HOXA13 siRNA impaired the invasion capability of the cancer cells. The gastric cancer cells with HOXA13 knockdown had decreased expression of p-SMAD2 and p-SMAD3.
CONCLUSIONS: This study provides additional evidence about the association between HOXA13 upregulation and gastric cancer progression. Also, we showed that HOXA13 contributes to invasion and EMT of gastric cancer cells via the TGF-b signaling pathway.

Chandrasekaran G, Hwang EC, Kang TW, et al.
In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer.
Chem Biol Drug Des. 2017; 90(2):188-199 [PubMed] Related Publications
The human HOXB13 gene encodes a transcription factor containing a DNA-binding homeobox domain and a HoxA13 N-terminal domain. SNP is considered to be the primary genetic cause for hereditary prostate cancer (PCa). The study of functional nsSNPs would give an insight into the exact cause underlying the onset of hereditary PCa and possible methodologies for the cure or early management of the disease. Several in silico tools were used to screen and map the deleterious nsSNPs to the protein structure for predicting the structure-function effects. Among the 23 homeobox nsSNPs, sift predicted 20, whereas PolyPhen, panther, and provean predicted 21 nsSNP's as deleterious. W63R, D244N, K239Q, P222R, K218R, and G216C were found to have higher energy values than the native 2CRA. The RMSD value showed increased deviation for T253P(2.53 Å), P222R(2.27 Å), G216C(2.15 Å), K218R(1.66 Å), and K239Q(1.62 Å). The I-Mutant showed increase in the stability of R258C, S254T, S250L, K239Q, and Q227E. Ramachandran plot showed mutants P222R, G216C, W263R, and K218R having drastically unfavorable pattern of amino acid residues. The presence of these mutations may result in the altered structure and function of the transcription factor; however, the exact mechanism and pathology of those predicted nsSNPs should further be validated by in vivo experiments and population-based studies.

Hu H, Chen Y, Cheng S, et al.
Dysregulated expression of homebox gene HOXA13 is correlated with the poor prognosis in bladder cancer.
Wien Klin Wochenschr. 2017; 129(11-12):391-397 [PubMed] Related Publications
BACKGROUND: The homeobox (HOX) genes have been implicated playing important roles in many human cancers. HOXA13 is a member of HOX genes that encode transcription factors regulating embryonic development and cell fate. In the present study, we aimed to investigate the expression and prognostic significance of HOXA13 in bladder cancer.
METHODS: Immunohistochemical staining was initially performed to screen the differentially expressed HOXA13 between bladder cancer tissues and paired adjacent non-cancerous tissues. Subsequent Western blotting analysis validation was conducted using tissue samples from patients with bladder cancer.
RESULTS: The expression level of HOXA13 was significantly higher in bladder cancer tissues compared to that in adjacent non-cancerous tissues (P < 0.001). The χ
CONCLUSIONS: The results of our study show that high expression of HOXA13 is associated with the progression of bladder cancer and that HOXA13 might serve as a biomarker for prognosis of bladder cancer.

Joo MK, Park JJ, Chun HJ
Impact of homeobox genes in gastrointestinal cancer.
World J Gastroenterol. 2016; 22(37):8247-8256 [PubMed] Free Access to Full Article Related Publications
Homeobox genes, including

Kelly Z, Moller-Levet C, McGrath S, et al.
The prognostic significance of specific HOX gene expression patterns in ovarian cancer.
Int J Cancer. 2016; 139(7):1608-17 [PubMed] Related Publications
HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials.

Wang SS, Wuputra K, Liu CJ, et al.
Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer.
Oncotarget. 2016; 7(24):36049-36064 [PubMed] Free Access to Full Article Related Publications
To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13-HOTTIP-IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.

Chang S, Liu J, Guo S, et al.
HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression.
Oncol Rep. 2016; 35(6):3577-85 [PubMed] Related Publications
A long non-coding RNA named HOTTIP (HOXA transcript at the distal tip) coordinates the activation of various 5' HOXA genes which encode master regulators of development through targeting the WDR5/MLL complex. HOTTIP acts as an oncogene in several types of cancers, whereas its biological function in gastric cancer has never been studied. In the present study, we investigated the role of HOTTIP in gastric cancer. We found that HOTTIP was upregulated in gastric cancer cell lines. Knockdown of HOTTIP in gastric cancer cells inhibited cell proliferation, migration and invasion. Moreover, downregulation of HOTTIP led to decreased expression of homeobox protein Hox-A13 (HOXA13) in gastric cancer cell lines. HOXA13 was involved in HOTTIP‑induced malignant phenotypes of gastric cancer cells. Our data showed that the levels of HOTTIP and HOXA13 were both markedly upregulated in gastric cancer tissues compared with their counterparts in non-tumorous tissues. Furthermore, the expression levels of HOTTIP and HOXA13 were both higher in gastric cancer which was poorly differentiated, at advanced TNM stages and exhibited lymph node-metastasis. Spearman analyses indicated that HOTTIP and HOXA13 had a highly positive correlation both in non-tumor mucosae and cancer lesions. Collectively, these findings suggest that HOTTIP and HOXA13 play important roles in gastric cancer progression and provide a new insight into therapeutic treatment for the disease.

Zhang SR, Yang JK, Xie JK, Zhao LC
Long noncoding RNA HOTTIP contributes to the progression of prostate cancer by regulating HOXA13.
Cell Mol Biol (Noisy-le-grand). 2016; 62(3):84-8 [PubMed] Related Publications
Prostate cancer is a leading cause of cancer-related mortality in men worldwide and there is a lack of effective treatment options for advanced (metastatic) prostate cancer. Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. However, little is known about the molecular mechanism of lncRNA-HOTTIP-mediated prostate cancer cell proliferation and apoptosis. The aim of this study was to elucidate the involvement of lncRNA HOTTIP in prostate cancer tumorigenesis and further investigate the role of HOXA13 in this process. Here, we showed that HOTTIP silencing inhibited cell survival pathway in vitro and in vivo by reducing the protein expression of Bcl-2 and enhancing Bax. We further demonstrated that knockdown of HOTTIP inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phase. Additionally, depletion of HOXA13 by RNA interference (si-HOXA13) revealed that HOTTIP silencing suppressed cell growth at least partly through regulating HOXA13. In conclusion, down-regulation of HOTTIP and HOXA13 was associated with cell growth and cell cycle, and exerts tumor-suppressive functions in the genesis and progression of prostate cancer, providing a potential attractive therapeutic approach for this malignancy.

Ge Y, Yan X, Jin Y, et al.
MiRNA-192 [corrected] and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma.
PLoS Genet. 2015; 11(12):e1005726 [PubMed] Free Access to Full Article Related Publications
Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to study how miRNAs impact lncRNAs expression and its biological significance in hepatocellular carcinoma (HCC). LncRNA HOTTIP is a vital oncogene in HCC, one of the deadliest cancers worldwide. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expression via the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays. Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients. In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonizing endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo mouse xenograft model also support the tumor suppressor role of both miRNAs. Besides the known targets (multiple 5' end HOX A genes, i.e. HOXA13), glutaminase (GLS1) was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in HCC. Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencingGLS1, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition. These results elucidate that the miR-192/-204-HOTTIP axis might be an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications.

Duan R, Han L, Wang Q, et al.
HOXA13 is a potential GBM diagnostic marker and promotes glioma invasion by activating the Wnt and TGF-β pathways.
Oncotarget. 2015; 6(29):27778-93 [PubMed] Free Access to Full Article Related Publications
Homeobox (HOX) genes, including HOXA13, are involved in human cancer. We found that HOXA13 expression was associated with glioma grade and prognosis. Bioinformatics analysis revealed that most of the HOXA13-associated genes were enriched in cancer-related signaling pathways and mainly involved in the regulation of transcription. We transfected four glioma cell lines with Lenti-si HOXA13. HOXA13 increased cell proliferation and invasion and inhibited apoptosis. HOXA13 decreased β-catenin, phospho-smad2, and phospho-smad3 in the nucleus and increased phospho-β-catenin in the cytoplasm. Furthermore, downregulation of HOXA13 in orthotopic tumors decreased tumor growth. We suggest that HOXA13 promotes glioma progression in part via Wnt- and TGF-β-induced EMT and is a potential diagnostic biomarker for glioblastoma and an independent prognostic factor in high-grade glioma.

Cheng Y, Jutooru I, Chadalapaka G, et al.
The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.
Oncotarget. 2015; 6(13):10840-52 [PubMed] Free Access to Full Article Related Publications
HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors.

Li Z, Zhao X, Zhou Y, et al.
The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer.
J Transl Med. 2015; 13:84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The human genome encodes many long non-coding RNAs (lncRNAs). However, their biological functions, molecular mechanisms, and the prognostic value associated with pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. Here, we identify a fundamental role for the lncRNA HOXA transcript at the distal tip (HOTTIP) in the progression and chemoresistance of PDAC.
METHODS: High-throughput microarrays were performed to detect the expression profiles of lncRNAs and messenger RNAs in eight human PDAC tissues and four pancreatic tissues. Quantitative real-time PCR was used to determine the levels of HOTTIP and HOXA13 transcripts in PDAC cell lines and 90 PDAC samples from patients. HPDE6 cells (immortalized human pancreatic ductal epithelial cells) and corresponding adjacent non-neoplastic tissues were used as controls, respectively. The functions of HOTTIP and HOXA13 in cell proliferation, invasion, and epithelial-mesenchymal transition were evaluated by targeted knockdown in vitro. CCK-8 assays, colony formation assays, and xenografts in nude mice were used to investigate whether targeted silencing of HOTTIP could sensitize pancreatic cancer cells to gemcitabine. Immunohistochemistry was performed to investigate the relationship between HOXA13 expression and patient outcome.
RESULTS: Microarray analyses revealed that HOTTIP was one of the most significantly upregulated lncRNAs in PDAC tissues compared with pancreatic tissues. Quantitative PCR further verified that HOTTIP levels were increased in PDAC cell lines and patient samples compared with controls. Functionally, HOTTIP silencing resulted in proliferation arrest by altering cell-cycle progression, and impaired cell invasion by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Additionally, inhibition of HOTTIP potentiated the antitumor effects of gemcitabine in vitro and in vivo. Furthermore, knockdown of HOXA13 by RNA interference (siHOXA13) revealed that HOTTIP promoted PDAC cell proliferation, invasion, and chemoresistance, at least partly through regulating HOXA13. Immunohistochemistry results revealed that higher HOXA13 expression was correlated with lymph node metastasis, poor histological differentiation, and decreased overall survival in PDAC patients.
CONCLUSIONS: As a crucial tumor promoter, HOTTIP promotes cell proliferation, invasion, and chemoresistance by modulating HOXA13. Therefore, the HOTTIP/HOXA13 axis is a potential therapeutic target and molecular biomarker for PDAC.

Kavalieris L, O'Sullivan PJ, Suttie JM, et al.
A segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma.
BMC Urol. 2015; 15:23 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hematuria can be symptomatic of urothelial carcinoma (UC) and ruling out patients with benign causes during primary evaluation is challenging. Patients with hematuria undergoing urological work-ups place significant clinical and financial burdens on healthcare systems. Current clinical evaluation involves processes that individually lack the sensitivity for accurate determination of UC. Algorithms and nomograms combining genotypic and phenotypic variables have largely focused on cancer detection and failed to improve performance. This study aimed to develop and validate a model incorporating both genotypic and phenotypic variables with high sensitivity and a high negative predictive value (NPV) combined to triage out patients with hematuria who have a low probability of having UC and may not require urological work-up.
METHODS: Expression of IGFBP5, HOXA13, MDK, CDK1 and CXCR2 genes in a voided urine sample (genotypic) and age, gender, frequency of macrohematuria and smoking history (phenotypic) data were collected from 587 patients with macrohematuria. Logistic regression was used to develop predictive models for UC. A combined genotypic-phenotypic model (G + P INDEX) was compared with genotypic (G INDEX) and phenotypic (P INDEX) models. Area under receiver operating characteristic curves (AUC) defined the performance of each INDEX: high sensitivity, NPV >0.97 and a high test-negative rate was considered optimal for triaging out patients. The robustness of the G + P INDEX was tested in 40 microhematuria patients without UC.
RESULTS: The G + P INDEX offered a bias-corrected AUC of 0.86 compared with 0.61 and 0.83, for the P and G INDEXs respectively. When the test-negative rate was 0.4, the G + P INDEX (sensitivity = 0.95; NPV = 0.98) offered improved performance compared with the G INDEX (sensitivity = 0.86; NPV = 0.96). 80% of patients with microhematuria who did not have UC were correctly triaged out using the G + P INDEX, therefore not requiring a full urological work-up.
CONCLUSION: The adoption of G + P INDEX enables a significant change in clinical utility. G + P INDEX can be used to segregate hematuria patients with a low probability of UC with a high degree of confidence in the primary evaluation. Triaging out low-probability patients early significantly reduces the need for expensive and invasive work-ups, thereby lowering diagnosis-related adverse events and costs.

Pan TT, Jia WD, Yao QY, et al.
Overexpression of HOXA13 as a potential marker for diagnosis and poor prognosis of hepatocellular carcinoma.
Tohoku J Exp Med. 2014; 234(3):209-19 [PubMed] Related Publications
HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.

Ma RL, Shen LY, Chen KN
Coexpression of ANXA2, SOD2 and HOXA13 predicts poor prognosis of esophageal squamous cell carcinoma.
Oncol Rep. 2014; 31(5):2157-64 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer, and is the sixth leading cause of cancer-related mortality among all types of cancers. Previously, we found that the homeobox A13 gene (HOXA13) plays a crucial role in the carcinogenesis of ESCC and both Annexin A2 (ANXA2) and superoxide dismutase 2 (SOD2) were its potential targets. Samples from 258 patients from two independent cohorts were collected. RT-qPCR and immunohistochemistry (IHC) were used to detect the expression levels of HOXA13, ANXA2 and SOD2. Kaplan‑Meier survival curve analysis and Cox proportional hazards regression model were employed to determine their prognostic significance. Results showed that ESCC tissues had higher ANXA2 and SOD2 mRNA and protein levels than the non-cancerous tissues. ANXA2 and SOD2 were found to be positively correlated with HOXA13 expression not only at the mRNA level but also at the protein level. In both the study cohort and the validation cohort, the median overall survival time of patients with high expression of HOXA13, ANXA2 and SOD2 was shorter than the survival time of the patients with low expression. The Cox proportional hazards model revealed that both TNM stage and coexpression of HOXA13/ANXA2/SOD2 are independent predictors of overall survival of ESCC patients. In conclusion, the present study demonstrated that ANXA2 and SOD2 are potential target genes of HOXA13 and their coexpression predicts the poor prognosis of ESCC patients.

Quagliata L, Matter MS, Piscuoglio S, et al.
Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.
Hepatology. 2014; 59(3):911-23 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n=52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13.
CONCLUSION: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC.

Kang JU
Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma.
Mol Med Rep. 2013; 8(5):1373-8 [PubMed] Related Publications
Chromosomal alterations are a predominant genomic force contributing to the development of lung adenocarcinoma (ADC). High density genomic arrays were conducted to identify critical genetic landmarks that may be important mediators in the formation or progression of early‑stage ADC. In this study, the most noteworthy and consistent observation was a copy number gain on the short arm of chromosome 7, which was detected in 85.7% (12/14) of cases. Notably, three distinct regions of amplification were identified between the 7p22.3 and q11.2 regions in 28.6% (4/14) of cases; at a size of 4.1 Mbp (7p22.3‑p21.1), 2.6 Mbp (7p15.2-p14.1) and 1.5 Mbp (7p12.3‑p11.2). Variations of the 7p11.2 locus that encodes EGFR are known to be oncogenic. Furthermore, potential target genes were identified that were previously not assumed to be involved in the pathogenesis of ADC, including CALM1P2 (7p11.2), HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13 (7p15.2) and LOC442586, LOC442589, LOC442282, FAM20C and LOC442651 (7p22.3). The present study determined critical regions on the 7p arm of chromosome 7, which were implicated in ADC. The pattern of rearrangements on the 7p arm may be a consequence of the high density of potential targets and the identified genes at the 7p regions may aid in the development of therapeutic targets for ADC.

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