Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HOXA1 (cancer-related)
Bell D, Raza SM, Bell AH, et al.Whole-transcriptome analysis of chordoma of the skull base.
Virchows Arch. 2016; 469(4):439-49 [PubMed
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Fourteen skull base chordoma specimens and three normal specimens were microdissected from paraffin-embedded tissue. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using whole-transcriptome shotgun sequencing. Using strict criteria, 294 differentially expressed transcripts were found, with 28 % upregulated and 72 % downregulated. The transcripts were annotated using NCBI Entrez Gene and computationally analyzed with the Ingenuity Pathway Analysis program. From these significantly changed expressions, the analysis identified 222 cancer-related transcripts. These 294 differentially expressed genes and non-coding RNA transcripts provide here a set to specifically define skull base chordomas and to identify novel and potentially important targets for diagnosis, prognosis, and therapy of this cancer. Significance Genomic profiling to subtype skull base chordoma reveals potential candidates for specific biomarkers, with validation by IHC for selected candidates. The highly expressed developmental genes T, LMX1A, ZIC4, LHX4, and HOXA1 may be potential drivers of this disease.
BACKGROUND: HOXA1 is a member of the Homeobox gene family, which encodes a group of highly conserved transcription factors that are important in embryonic development. However, it has been reported that HOXA1 exhibits oncogenic properties in many malignancies. This study focused on the expression and clinical significance of HOXA1 in gastric cancer (GC).
METHODS: To assess the mRNA and protein expression of HOXA1 and cyclin D1 in GC tissues, we utilized qRT-PCR and western blotting, respectively. The effects of HOXA1 on GC cell proliferation, migration, and invasion, as well as xenograft tumor formation and the cell cycle were investigated in our established stable HOXA1 knockdown GC cell lines. The protein expression of HOXA1 and cyclin D1 was examined by immunohistochemistry using GC tissue microarrays (TMA) to analyze their relationship on a histological level. The Kaplan-Meier method and cox proportional hazards model were used to analyze the relationship of HOXA1 and cyclin D1 expression with GC clinical outcomes.
RESULTS: HOXA1 mRNA and protein expression were upregulated in GC tissues. Knockdown of HOXA1 in GC cells not only inhibited cell proliferation, migration, and invasion in vitro but also suppressed xenograft tumor formation in vivo. Moreover, HOXA1 knockdown induced changes in the cell cycle, and HOXA1 knockdown cells were arrested at the G1 phase, the number of cells in S phase was reduced, and the expression of cyclin D1 was decreased. In GC tissues, high cyclin D1 mRNA and protein expression were detected, and a significant correlation was found between the expression of HOXA1 and cyclin D1. Survival analysis indicated that HOXA1 and cyclin D1 expression were significantly associated with disease-free survival (DFS) and overall survival (OS). Interestingly, patients with tumors that were positive for HOXA1 and cyclin D1 expression showed worse prognosis. Multivariate analysis confirmed that the combination of HOXA1 and cyclin D1 was an independent prognostic indicator for OS and DFS.
CONCLUSION: Our data show that HOXA1 plays a crucial role in GC development and clinical prognosis. HOXA1, alone or combination with cyclin D1, may serve as a novel prognostic biomarker for GC.
Fang S, Gao H, Tong Y, et al.Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells.
Lab Invest. 2016; 96(1):60-8 [PubMed
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Homeobox (HOX) transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), has been reported to play an oncogenic role in various cancers including small cell lung cancer (SCLC). However, it is not known whether HOTAIR can modulate chemoresistance in SCLC. The aim of this study is to investigate the roles of HOTAIR in chemoresistance of SCLC and its possible molecular mechanism. Knockdown of HOTAIR was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on chemoresistance. The results showed that downregulation of HOTAIR increased cell sensitivity to anticancer drugs through increasing cell apoptosis and cell cycle arrest, and suppressed tumor growth in vivo. Moreover, HOXA1 methylation increased in the resistant cells using bisulfite sequencing PCR. Depletion of HOTAIR reduced HOXA1 methylation by decreasing DNMT1 and DNMT3b expression. The interaction between HOTAIR and HOXA1 was validated by RNA immunoprecipitation. Taken together, our study suggested that HOTAIR mediates chemoresistance of SCLC by regulating HOXA1 methylation and could be utilized as a potential target for new adjuvant therapies against chemoresistance.
MicroRNAs (miRNAs) are key regulators of tumor progression. Based on microarray data, we identified miR-99a as a potential tumor suppressor in breast cancer. Expression of miR-99a is frequently down-regulated in breast cancer tissues relative to normal breast tissues. Reduced miR-99a expression was highly associated with lymph node metastasis and shorter overall survival of patients with breast cancer. Gain- and loss-of-function studies revealed that, miR-99a significantly inhibits breast cancer cell proliferation, migration, and invasion. An integrated bioinformatics analysis identified HOXA1 mRNA as the direct functional target of miR-99a, and this regulation was confirmed by luciferase reporter assay. Furthermore, we showed for the first time that HOXA1 expression is elevated in breast cancer tissues. Knockdown of HOXA1 significantly inhibited breast cancer cell proliferation, migration and invasion, and restoration of HOXA1 partially rescued the inhibitory effect of miR-99a in breast cancer cells. Collectively, our data indicate that miR-99a plays a tumor-suppressor role in the development of breast cancer, and could serve as a potential therapeutic target for breast cancer treatment.
Wang H, Liu G, Shen D, et al.HOXA1 enhances the cell proliferation, invasion and metastasis of prostate cancer cells.
Oncol Rep. 2015; 34(3):1203-10 [PubMed
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HOXA1, a member of the HOX gene family, has been implicated in tumor progression. However, the role of HOXA1 in prostate cancer is not well-established. In the present study, we found that HOXA1 was highly expressed in prostate cancer cells. We then repressed the expression of HOXA1 by short hairpin RNA (shRNA) to investigate the function of HOXA1 in prostate cancer cells. Our in vitro data showed that knockdown of HOXA1 attenuated the growth, invasion and migration of prostate cancer DU-145 and PC-3 cells. Furthermore, knockdown of HOXA1 resulted in an increased E-cadherin level and decreased Snail and MMP-3 levels in the DU-145 cells. In addition, knockdown of HOXA1 inhibited activation of ERK1/2 and AKT in the DU-145 cells. Our in vivo data revealed that knockdown of HOXA1 suppressed the growth and metastasis of prostate cancer cells. Collectively, our findings suggest that HOXA1 is involved in the regulation of prostate cancer progression, including cell growth, migration, invasion and metastasis. Thus, downregulation of HOXA1 may be a novel approach for the treatment of prostate cancer.
Chang H, Shin BK, Kim A, et al.DNA methylation analysis for the diagnosis of thyroid nodules - a pilot study with reference to BRAF(V) (600E) mutation and cytopathology results.
Cytopathology. 2016; 27(2):122-30 [PubMed
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OBJECTIVE: Promoter hypermethylation and the BRAF(V) (600E) mutation are both involved in thyroid tumorigenesis. We conducted a pilot study on the diagnosis of thyroid nodules by analysis of promoter hypermethylation status with reference to BRAF(V) (600E) mutation and cytopathology results using formalin-fixed, paraffin-embedded (FFPE) tissues and liquid-based preparation (LBP) thyroid fine needle aspiration (FNA) samples to predict more reliably the possibility of papillary carcinoma.
METHODS: We initially performed MethyLight analysis for 30 genes that are known to be hypermethylated in malignancies using 164 papillary carcinomas and 77 benign tissue samples. Five genes selected from the tissue analysis were subsequently analysed in 75 surgically proven benign and 66 surgically proven papillary carcinoma LBP FNA samples. Samples that showed two or more positive results among the five genes were classified as methylation positive. We also analysed the BRAF(V) (600E) mutation status of the FNA samples.
RESULTS: We identified five genes that were significantly hypermethylated in malignant tissues: PTGS2, HOXA1, TMEFF2, p16 and PTEN. With respect to diagnostic potential, results obtained using the BRAF(V) (600E) mutation test combined with cytological examination were not significantly different from those obtained with cytological examination only. Combining methylation analyses with cytological examination or performing all three tests for diagnoses did not improve significantly the negative predictive values and sensitivity, but a significant decrease in positive predictive value and specificity was observed.
CONCLUSION: Further studies are needed on larger samples to assess the potential value of methylation analysis of thyroid FNA.
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.
Deregulated tyrosine kinase signaling alters cellular homeostasis to drive cancer progression. The emergence of a non-receptor tyrosine kinase (non-RTK), ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) as an oncogenic kinase, has uncovered novel mechanisms by which tyrosine kinase signaling promotes cancer progression. Although early studies focused on ACK1 as a cytosolic effector of activated transmembrane RTKs, wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator. ACK1 interacts with the estrogen receptor (ER)/histone demethylase KDM3A (JHDM2a) complex, which modifies KDM3A by tyrosine phosphorylation to regulate the transcriptional outcome at HOXA1 locus to promote the growth of tamoxifen-resistant breast cancer. It is also well established that ACK1 regulates the activity of androgen receptor (AR) by tyrosine phosphorylation to fuel the growth of hormone-refractory prostate cancers. Further, recent explosion in genomic sequencing has revealed recurrent ACK1 gene amplification and somatic mutations in a variety of human malignancies, providing a molecular basis for its role in neoplastic transformation. In this review, we will discuss the various facets of ACK1 signaling, including its newly uncovered epigenetic regulator function, which enables cells to bypass the blockade to major survival pathways to promote resistance to standard cancer treatments. Not surprisingly, cancer cells appear to acquire an 'addiction' to ACK1-mediated survival, particularly under stress conditions, such as growth factor deprivation or genotoxic insults or hormone deprivation. With the accelerated development of potent and selective ACK1 inhibitors, targeted treatment for cancers harboring aberrant ACK1 activity may soon become a clinical reality.
Rivera C, González-Arriagada WA, Loyola-Brambilla M, et al.Clinicopathological and immunohistochemical evaluation of oral and oropharyngeal squamous cell carcinoma in Chilean population.
Int J Clin Exp Pathol. 2014; 7(9):5968-77 [PubMed
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In oral and oropharyngeal squamous cell carcinoma (OCSCC and OPSCC) exist an association between clinical and histopathological parameters with cell proliferation, basal lamina, connective tissue degradation and surrounding stroma markers. We evaluated these associations in Chilean patients. A convenience sample of 37 cases of OCSCC (n=16) and OPSCC (n=21) was analyzed clinically (TNM, clinical stage) and histologically (WHO grade of differentiation, pattern of tumor invasion). We assessed the expression of p53, Ki67, HOXA1, HOXB7, type IV collagen (ColIV) and carcinoma-associated fibroblast (α-SMA-positive cells). Additionally we conducted a univariate/bivariate analysis to assess the relationship of these variables with survival rates. Males were mostly affected (56.2% OCSCC, 76.2% OPSCC). Patients were mainly diagnosed at III/IV clinical stages (68.8% OCSCC, 90.5% OPSCC) with a predominantly infiltrative pattern invasion (62.9% OCSCC, 57.1% OPSCC). Significant association between regional lymph nodes (N) and clinical stage with OCSCC-HOXB7 expression (Chi-Square test P < 0.05) was observed. In OPSCC a statistically significant association exists between p53, Ki67 with gender (Chi-Square test P < 0.05). In OCSCC and OPSCC was statistically significant association between ki67 with HOXA1, HOXB7, and between these last two antigens (Pearson's Correlation test P < 0.05). Furthermore OPSCC-p53 showed significant correlation when it was compared with α-SMA (Kendall's Tau-c test P < 0.05). Only OCSCC-pattern invasion and OPSCC-primary tumor (T) pattern resulted associated with survival at the end of the follow up period (Chi-Square Likelihood Ratio, P < 0.05). Clinical, histological and immunohistochemical features are similar to seen in other countries. Cancer proliferation markers were associated strongly from each other. Our sample highlights prognostic value of T and pattern of invasion, but the conclusions may be limited and should be considered with caution (small sample). Many cases were diagnosed in the advanced stages of the disease, which suggests that the diagnosis of OCSCC and OPSCC is made late.
Marcato P, Dean CA, Liu RZ, et al.Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling.
Mol Oncol. 2015; 9(1):17-31 [PubMed
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Aldehyde dehydrogenase (ALDH) 1A enzymes produce retinoic acid (RA), a transcription induction molecule. To investigate if ALDH1A1 or ALDH1A3-mediated RA signaling has an active role in breast cancer tumorigenesis, we performed gene expression and tumor xenograft studies. Analysis of breast patient tumors revealed that high levels of ALDH1A3 correlated with expression of RA-inducible genes with retinoic acid response elements (RAREs), poorer patient survival and triple-negative breast cancers. This suggests a potential link between ALDH1A3 expression and RA signaling especially in aggressive and/or triple-negative breast cancers. In MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells, ALDH1A3 and RA increased expression of RA-inducible genes. Interestingly, ALDH1A3 had opposing effects in tumor xenografts, increasing tumor growth and metastasis of MDA-MB-231 and MDA-MB-435 cells, but decreasing tumor growth of MDA-MB-468 cells. Exogenous RA replaced ALDH1A3 in inducing the same opposing tumor growth and metastasis effects, suggesting that ALDH1A3 mediates these effects by promoting RA signaling. Genome expression analysis revealed that ALDH1A3 induced largely divergent gene expression in MDA-MB-231 and MDA-MB-468 cells which likely resulted in the opposing tumor growth effects. Treatment with DNA methylation inhibitor 5-aza-2'deoxycytidine restored uniform RA-inducibility of RARE-containing HOXA1 and MUC4 in MDA-MB-231 and MDA-MB-468 cells, suggesting that differences in epigenetic modifications contribute to differential ALDH1A3/RA-induced gene expression in breast cancer. In summary, ALDH1A3 induces differential RA signaling in breast cancer cells which affects the rate of breast cancer progression.
Sharma G, Agarwal SMIdentification of critical microRNA gene targets in cervical cancer using network properties.
Microrna. 2014; 3(1):37-44 [PubMed
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miRNAs are short non-coding RNAs which function as oncogenes or tumour suppressor gene and regulate gene expression by controlling targets that play role in cancer development and progression. Numerous recent studies have established an association of abnormal expression of miRNA with cervical cancer progression. Although the number of reported deregulated miRNA in cervical cancer is increasing, only a few associations between miRNA and their targets have been studied in cervical cancer. Therefore, we performed a systematic analysis of known dysregulated miRNAs involved in cervical cancer so as to identify critical miRNA targets that could pave way for therapeutic solutions. In this study, miRNAs reported to be dysregulated in cervical cancer were collected and their targets predicted using TargetScan, PicTar and miRanda. These targets were subsequently compared with previously curated gene dataset involved in cervical cancer to derive the putative target dataset. We then compared network properties (composed of degree, betweenness centrality, closeness centrality and clustering coefficient) of the putative, validated and human protein-protein interaction network. Based on the topological properties genes were ranked and observed that the gene targets BIRC5 (survivin), HOXA1 and RARB presenting with high Novoseek score of Genecards were enriched in cervical cancer. BIRC5 is an anti- apoptotic protein while HOXA1 and RARB are transcription factors which play critical role in altering the level of cell cycle and apoptosis associated proteins. Also, miRNA-mRNA network was constructed and it was found that miR-203 and miR-30b could target these genes. The analysis indicates that the genes BIRC5, HOXA1 and RARB are critical targets that play an important regulatory role in cervical cancer pathogenesis.
Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.
Xiao F, Bai Y, Chen Z, et al.Downregulation of HOXA1 gene affects small cell lung cancer cell survival and chemoresistance under the regulation of miR-100.
Eur J Cancer. 2014; 50(8):1541-54 [PubMed
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Chemoresistance is often developed in small cell lung cancer (SCLC) patients and leads to poor prognosis. Hox genes, a highly conserved family, play a crucial role in apoptosis, receptor signalling and differentiation. MicroRNAs (miRNAs) have also been shown to play a crucial role in these biological processes by regulating the target genes. Several studies reported that both Hox genes and miRNAs are involved in chemoresistance. The aim of our study is to characterise the clinical significance and functional roles of HOXA1 in SCLC. Expression of HOXA1 was examined in 63 cases of SCLC tissues and 29 cases of blood by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) methods. Multivariate analysis confirmed the prognostic significance of HOXA1 in SCLC patients. Restoration of HOXA1 expression was carried out in SCLC multidrug resistant cell line H69AR and its parental cell line H69 to assess its influence on chemoresistance. Luciferase reporter assay was used to assess HOXA1 as a target of miR-100. The results showed that HOXA1 was expressed in 46% (29/63) of SCLC. Low HOXA1 expression was associated with the poor prognosis of SCLC (P<0.05 by the Fisher's Exact Test) and the shorter survival rate (P<0.001 by the Kaplan-Meier method). HOXA1 expression on both mRNA and protein levels significantly correlated with chemotherapy response. Enforced expression of HOXA1 in resistant H69AR cells led to increased chemosensitivity through increasing cell apoptosis and cell-cycle arrest. Inhibition of HOXA1 expression using HOXA1 siRNA in H69 cells resulted in cell resistance to therapeutic drugs through reducing drug-induced cell apoptosis accompanied with cell cycle arrest. Expression of endogenous miR-100 was significantly elevated in resistant H69AR cells and negatively related with HOXA1 expression. The expression of HOXA1 in SCLC tissues correlated inversely with the expression levels of miR-100. Reporter assays confirmed that miR-100 targeted predicted sites in 3'-untranslated region (3'-UTR) of HOXA1 gene. Our data suggested that HOXA1-mediated SCLC chemoresistance is under the regulation of miR-100. HOXA1 may be a prognostic predictor and potential therapeutic target in human SCLC.
BACKGROUND: MicroRNAs act as posttranscriptional regulators of gene expression in many biological processes. Their deregulations occur commonly in gastric cancer (GC). Although DNA methylation constitutes an important mechanism for microRNA deregulation in cancer, this field largely remains unexplored.
METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was extracted from the tissues of 100 patients with GC and four gastric cancer cell lines. The expression levels of miR-10a were determined by real-time PCR with specific TaqMan probes. Moreover, a functional analysis of miR-10a in regulating cell proliferation, migration and invasion was performed. Subsequently, quantitative methylation-specific PCR (qMSP) was used to detect the DNA methylation status in the CpG islands upstream of miR-10a. In this study, we found that the expression of miR-10a in GC cells was lower than that in normal cells, which was due to the hypermethylation of the CpG islands upstream of miR-10a. We also validated the slightly lower expression of miR-10a in GC tissues than their adjacent non-neoplastic tissues in 100 GC patients and confirmed the hypermethylation of CpG islands upstream of miR-10a in some patients. Furthermore, re-introduction of miR-10a into GC cells was able to inhibit cell proliferation, migration and invasion. Bioinformatic and immunoblot analysis indicated that the tumor suppressor roles of miR-10a in GC cells were possibly through targeting HOXA1.
CONCLUSIONS/SIGNIFICANCE: Our data indicate that miR-10a acts as a tumor suppressor in GC cells and is partially silenced by DNA hypermethylation in GC, suggesting that miR-10a may serve as a potential diagnostic or therapeutic target of GC.
DeInnocentes P, Perry AL, Graff EC, et al.Characterization of HOX gene expression in canine mammary tumour cell lines from spontaneous tumours.
Vet Comp Oncol. 2015; 13(3):322-36 [PubMed
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Spatial/temporal controls of development are regulated by the homeotic (HOX) gene complex and require integration with oncogenes and tumour suppressors regulating cell cycle exit. Spontaneously derived neoplastic canine mammary carcinoma cell models were investigated to determine if HOX expression profiles were associated with neoplasia as HOX genes promote neoplastic potential in human cancers. Comparative assessment of human and canine breast cancer expression profiles revealed remarkable similarity for all four paralogous HOX gene clusters and several unlinked HOX genes. Five canine HOX genes were overexpressed with expression profiles consistent with oncogene-like character (HOXA1, HOXA13, HOXD4, HOXD9 and SIX1) and three HOX genes with underexpressed profiles (HOXA11, HOXC8 and HOXC9) were also identified as was an apparent nonsense mutation in HOXC6. This data, as well as a comparative analysis of similar data from human breast cancers suggested expression of selected HOX genes in canine mammary carcinoma could be contributing to the neoplastic phenotype.
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.
Zhan M, Qu Q, Wang G, et al.Let-7c inhibits NSCLC cell proliferation by targeting HOXA1.
Asian Pac J Cancer Prev. 2013; 14(1):387-92 [PubMed
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OBJECTIVE: The aim of the present study was to explore mechanisms by which let-7c suppresses NSCLC cell proliferation.
METHODS: The expression level of let-7c was quantified by qRT-PCR. A549 and H1299 cells were transfected with let-7c mimics to restore the expression of let-7c. The effects of let-7c were then assessed by cell proliferation, colony formation and cell cycle assay. Mouse experiments were used to confirm the effect of let-7c on tumorigenicity in vivo. Luciferase reporter assays and Western blotting were performed to identify target genes for let-7c.
RESULTS: HOXA1 was identified as a novel target of let-7c. MTS, colony formation and flow cytometry assays demonstrated that forced expression of let-7c inhibited NSCLC cell proliferation by inducing G1 arrest in vitro, consistent with inhibitory effects induced by knockdown of HOXA1. Mouse experiments demonstrated that let-7c expression suppressed tumorigenesis. Furthermore, we found that let-7c could regulate the expression of HOXA1 downstream effectors CCND1, CDC25A and CDK2.
CONCLUSIONS: Collectively, these results demonstrate let-7c inhibits NSCLC cell proliferation and tumorigenesis by partial direct targeting of the HOXA1 pathway, which suggests that restoration of let-7c expression may thus offer a potential therapeutic intervention strategy for NSCLC.
Wardwell-Ozgo J, Dogruluk T, Gifford A, et al.HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome.
Oncogene. 2014; 33(8):1017-26 [PubMed
] Free Access to Full Article Related Publications
Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFβ) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1's ability to potently downregulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de-differentiates cells into a pro-invasive cell state concomitant with TGFβ activation. Our analysis of publicly available data sets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFβ therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention.
Hou L, Xu B, Mohankumar KM, et al.The prolactin receptor mediates HOXA1-stimulated oncogenicity in mammary carcinoma cells.
Int J Oncol. 2012; 41(6):2285-95 [PubMed
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The HOX genes are a highly conserved subgroup of homeodomain-containing transcription factors that are crucial to normal development. Forced expression of HOXA1 results in oncogenic transformation of immortalized human mammary cells with aggressive tumour formation in vivo. Microarray analysis identified that the prolactin receptor (PRLR) was significantly upregulated by forced expression of HOXA1 in mammary carcinoma cells. To determine prolactin (PRL) involvement in HOXA1‑induced oncogenicity in mammary carcinoma cells (MCF-7), we examined the effect of human prolactin (hPRL)-initiated PRLR signal transduction on changes in cellular behaviour mediated by HOXA1. Forced expression of HOXA1 in MCF-7 cells increased PRLR mRNA and protein expression. Forced expression of HOXA1 also enhanced hPRL-stimulated phosphorylation of both STAT5A/B and p44/42 MAPK, and increased subsequent transcriptional activity of STAT5A and STAT5B, and Elk-1 and Sap1a, respectively. Moreover, forced expression of HOXA1 in MCF-7 cells enhanced the hPRL‑stimulated increase in total cell number as a consequence of enhanced cell proliferation and cell survival, and also enhanced hPRL-stimulated anchorage-independent growth in soft agar. Increased anchorage-independent growth was attenuated by the PRLR antagonist ∆1-9-G129R‑hPRL. In conclusion, we have demonstrated that HOXA1 increases expression of the cell surface receptor PRLR and enhances PRLR-mediated signal transduction. Thus, the PRLR is one mediator of HOXA1‑stimulated oncogenicity in mammary carcinoma cells.
Pilato B, Pinto R, De Summa S, et al.HOX gene methylation status analysis in patients with hereditary breast cancer.
J Hum Genet. 2013; 58(1):51-3 [PubMed
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Cancer development is related not only to genetic alterations but also to aberrant epigenetic changes that could lead to heritable gene patterns critical for neoplastic initiation and progression. Knowledge of epigenetic regulation in cancer cells is useful for both the understanding of carcinogenesis and for the possibility of using epigenetic drugs. HOX genes deregulation have a crucial role in oncogenesis process and tumor suppression. In this report, the methylation of HOXA1, HOXA9, HOXA10, HOXB13, HNF1B, OTX1, TLX1 genes have been analyzed in patients with hereditary breast cancer. This is the first study analyzing BRCA mutational status of patients with respect to methylation of HOX genes. HOXA10 has been found to be methylated in all patients analyzed but never in healthy subjects. With respect to clinical pathological information, hypermethylation of all studied genes, with the exception of OTX1, was significantly associated with absence of HER2 neu expression (P<0.05). Moreover, hypermethylation of HOXB13, HOXA10 and HOXA1 was associated with a high proliferation index (Mib1≥10%, P<0.05) and hypermethylation of HOXB13 and HOXA10 also with high expression of estrogen and progesterone receptors. These preliminary data suggest a possible involvement of HOX genes in familial breast cancer as marker helpful to identify high-risk patients.
Breitinger C, Maethner E, Garcia-Cuellar MP, Slany RKThe homeodomain region controls the phenotype of HOX-induced murine leukemia.
Blood. 2012; 120(19):4018-27 [PubMed
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HOX proteins are widely involved in hematopoietic development. These transcription factors combine a conserved DNA-binding homeobox with a divergent N-terminus that mediates interaction with variable cofactors. The resulting combinatorial diversity is thought to be responsible for mammalian HOX specificity. Contrasting this proposed mechanism for normal HOX function, here we demonstrate that, in the context of hematopoietic immortalization and leukemogenesis, individual HOX properties are governed almost exclusively by the homeodomain. Swap experiments between HOXA1 and HOXA9, 2 members of nonrelated paralog groups, revealed that gene expression patterns of HOX transformed cells in vitro are determined by the nature of the homeodomain. Similar results were seen in vivo during HOX-mediated leukemogenesis. An exchange of the homeodomains was sufficient to convert the slow, low-penetrance phenotype of HOXA1-induced leukemia to the aggressive fast-acting disease elicited by HOXA9 and vice versa. Mutation and deletion studies identified several subregions within the DNA binding domain responsible for paralog specificity. Previously defined binding sites for PBX cofactors within the exchangeable, nonhomeobox segment were dispensable for in vitro oncogenic HOX activity but affected in vivo disease development. The transcriptional activator domain shared by HOXA1 and HOXA9 at the very N-terminus proved essential for all transformation.
Noman MZ, Buart S, Romero P, et al.Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.
Cancer Res. 2012; 72(18):4629-41 [PubMed
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Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve.
Zha TZ, Hu BS, Yu HF, et al.Overexpression of HOXA1 correlates with poor prognosis in patients with hepatocellular carcinoma.
Tumour Biol. 2012; 33(6):2125-34 [PubMed
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HOXA1 overexpression is sufficient for malignant transformation of nontumorigenic epithelial cells. It is known that HOXA1, which was upregulated in squamous cell carcinomas, affects both cell growth and death. The forced expression of HOXA1 in human breast cancer cells results in increased cell growth activity. However, it has not been reported in hepatocellular carcinoma (HCC). In this study, we used immunohistochemistry to compare HOXA1 protein expression in HCC and normal liver tissues and further analyzed HOXA1 protein expression in 156 clinicopathologically characterized HCC cases. We stably knocked down the endogenous expression level of HOXA1 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells, we examined in vitro cell growth by the MTT assay, anchorage-independent growth through a soft agar colony formation assay and cell migration/invasion by transwell and Boyden chamber assay. In addition, we also investigated in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Our results showed that the protein expression level of HOXA1 was markedly higher in HCC tissues than that in normal liver tissue (P = 0.019). In addition, a high expression level of HOXA1 protein was positively correlated with the T classification (P < 0.001), the N classification (P < 0.001), distant metastasis (P = 0.004), and the clinical stage (P < 0.001) of HCC patients. Patients with higher HOXA1 expression showed a significantly shorter overall survival time compared with patients with low HOXA1 expression. Multivariate analysis suggested that HOXA1 expression might be an independent prognostic indicator (P < 0.001) for the survival of patients with HCC. HOXA1-specific shRNA (shHOXA1) successfully knocked down HOXA1 endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHOXA1 cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, and cell migration and invasion (P < 0.05). In vivo, the xenograft transplants from shHOXA1 cells gave rise to much smaller tumors compared with those from shCtrl cells. Collectively, high HOXA1 expression is associated with poor overall survival in patients with HCC. The downregulation of HOXA1 inhibits growth, anchorage-independent growth, and migration and invasion of HepG2 cells.
Recent research has revealed various molecular markers in lung cancer. However, the organizational principles underlying their genetic regulatory networks still await investigation. Here we performed Network Component Analysis (NCA) and Pathway Crosstalk Analysis (PCA) to construct a regulatory network in human lung cancer (A549) cells which were treated with 50 uM motexafin gadolinium (MGd), a metal cation-containing chemotherapeutic drug for 4, 12, and 24 hours. We identified a set of key TFs, known target genes for these TFs, and signaling pathways involved in regulatory networks. Our work showed that putative interactions between these TFs (such as ESR1/Sp1, E2F1/Sp1, c-MYC-ESR, Smad3/c-Myc, and NFKB1/RELA), between TFs and their target genes (such as BMP41/Est1, TSC2/Myc, APE1/Sp1/p53, RARA/HOXA1, and SP1/USF2), and between signaling pathways (such as PPAR signaling pathway and Adipocytokines signaling pathway). These results will provide insights into the regulatory mechanism of MGd-treated human lung cancer cells.
BACKGROUND: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.
METHODS: In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.
RESULTS: We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).
CONCLUSION: Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.
Ohuchida K, Mizumoto K, Lin C, et al.MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene.
Ann Surg Oncol. 2012; 19(7):2394-402 [PubMed
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BACKGROUND: There is increasing evidence that microRNAs are differentially expressed in many types of cancers. Despite progress in analyses of microRNAs in several types of cancers, the functional contributions of microRNAs to pancreatic cancer remain unclear.
METHODS: In the present study, the expression levels of specific microRNAs identified by microarray analyses were examined in a panel of 15 pancreatic cancer cell lines. We then investigated the functional roles of these microRNAs in the proliferation and invasion of pancreatic cancer cells.
RESULTS: Based on the microarray data, we found frequent and marked overexpression of miR-10a, miR-92, and miR-17-5p in pancreatic cancer cell lines. Microdissection analyses revealed that miR-10a was overexpressed in pancreatic cancer cells isolated from a subset of primary tumors (12 of 20, 60%) compared with precursor lesions and normal ducts (P<.01). In vitro experiments revealed that miR-10a inhibitors decreased the invasiveness of pancreatic cancer cells (P<.01), but had no effect on their proliferation. Inhibition of HOXA1, a target of miR-10a, promoted the invasiveness of pancreatic cancer cells (P<.01).
CONCLUSIONS: The present data suggest that miR-10a is overexpressed in a subset of pancreatic cancers and is involved in the invasive potential of pancreatic cancer cells partially via suppression of HOXA1.
Park SY, Kwon HJ, Choi Y, et al.Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes.
Mod Pathol. 2012; 25(2):185-96 [PubMed
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Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44+/CD24- and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44+/CD24- and ALDH1+ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors than in CD44+/CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.
Cho HS, Toyokawa G, Daigo Y, et al.The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene.
Int J Cancer. 2012; 131(3):E179-89 [PubMed
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A number of histone demethylases have been identified and biochemically characterized, yet their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. In this study, we describe important roles for the histone demethylase KDM3A, also known as JMJD1A, in human carcinogenesis. Expression levels of KDM3A were significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p < 0.0001), when assessed by real-time PCR. We confirmed that some other cancers including lung cancer also overexpressed KDM3A, using cDNA microarray analysis. Treatment of cancer cell lines with small interfering RNA targeting KDM3A significantly knocked down its expression and resulted in the suppression of proliferation. Importantly, we found that KDM3A activates transcription of the HOXA1 gene through demethylating histone H3 at lysine 9 di-methylation by binding to its promoter region. Indeed, expression levels of KDM3A and HOXA1 in several types of cancer cell lines and bladder cancer samples were statistically correlated. We observed the down-regulation of HOXA1 as well as CCND1 after treatment with KDM3A siRNA, indicating G(1) arrest of cancer cells. Together, our results suggest that elevated expression of KDM3A plays a critical role in the growth of cancer cells, and further studies may reveal a cancer therapeutic potential in KDM3A inhibition.
Chung JH, Lee HJ, Kim BH, et al.DNA methylation profile during multistage progression of pulmonary adenocarcinomas.
Virchows Arch. 2011; 459(2):201-11 [PubMed
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Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.
Park SY, Kwon HJ, Lee HE, et al.Promoter CpG island hypermethylation during breast cancer progression.
Virchows Arch. 2011; 458(1):73-84 [PubMed
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This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions [flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS)] to invasive ductal carcinoma (IDC). We performed MethyLight analysis for the methylation status of 57 promoter CpG island loci in 20 IDCs and their paired normal breast tissues. After selecting 15 CpG island loci showing breast cancer-specific DNA methylation, another set of normal breast tissue (n = 10), ADH/FEA (n = 30), DCIS (n = 35), and IDC (n = 30) of the breast were analyzed for these loci. We found six new methylation markers of breast cancer, namely DLEC1, GRIN2B, HOXA1, MT1G, SFRP4, and TMEFF2, in addition to APC, GSTP1, HOXA10, IGF2, RARB, RASSF1A, RUNX3, SCGB3A1 (HIN-1), and SFRP1. The number of methylated genes increased stepwise from normal breast to ADH/FEA and DCIS, while IDC did not differ from DCIS. Methylation levels and frequencies of APC, DLEC1, HOXA1, and RASSF1A promoter CpG islands were significantly higher in ADH/FEA than in normal breast tissue. GRIN2B, GSTP1, HOXA1, RARB, RUNX3, SFRP1, and TMEFF2 showed higher methylation levels and frequencies in DCIS than in ADH/FEA. DICS and IDC did not differ in the methylation levels or frequencies for most CpG island loci except SFRP1 and HOXA10. Our findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and was similar in IDC and DCIS, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.