Disordered expression of HOX genes in human non-small cell lung cancer

Abe, Miki; Hamada, Jun Ichi; Takahashi, Osamu; Takahashi, Yōko; Tada, Mitsuhiro; Miyamoto, Masaki; Morikawa, Toshiaki; Kondo, Satoshi; Moriuchi, Tetsuya

doi:10.3892/or.15.4.797

Cited by 66 publications

(79 citation statements)

References 12 publications

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“…Additionally, the knockdown of HOXA1 inhibited growth of cells and induced G1 arrest. These results demonstrate that, similar to previous studies, HOXA1 plays a role as a proto-oncogene in NSCLC cells (Abe et al, 2006;Cho et al, 2012).…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have suggested that HOXA1 is overexpressed in various cancers, including breast, liver, oral and lung cancer (Chariot et al, 1996;Abe et al, 2006;Bitu et al, 2012;Zha et al, 2012). The forced expression of HOXA1 promoted oncogenic transformation by modulating the p44/42 MAP kinase pathway and bcl-2 in MCF-10 cells (Mohankumar et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

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Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

Zhan

Qu²,

Guo³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

Zhan

Qu²,

Guo³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…Here we have shown that disrupting the interaction between HOX and PBX proteins is sufficient to cause apoptosis in the NSCLC-derived cell lines, A549 and H23. Although earlier studies have also shown HOX genes to be dysregulated in NSCLC (Abe et al, 2006), to our knowledge this is the first report to describe these changes in a comprehensive manner allowing a direct comparison between expression in normal lung tissue, primary tumours and derived cell lines. This reveals that there is a large increase in transcription in most HOX genes of the HOXC and HOXD families when comparing normal lung tumour with primary tumours, and furthermore, this change is also present in A549 and H23, indicating that there has been a stable change in the transcriptome.…”

Section: Discussionmentioning

confidence: 98%

“…A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells.…”

mentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC. The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues in early development (Iimura and Pourquié, 2007), and also have key regulatory roles in adult haematopoietic stem cells and their descendants (Abramovich and Humphries, 2005). In addition, HOX genes are often overexpressed in malignant cells and are known to act as oncogenes in some haematopoietic malignancies (Eklund, 2007).Repeated duplication events have given rise to 39 HOX genes in mammals, divided into four groups (A -D) in tightly linked clusters on different chromosomes (Hoegg and Meyer, 2005). The HOX genes are also divided into paralogue groups -genes that have the equivalent position in each cluster (1 -13) -thus HOXA1, for example, is the 3 0 most gene in cluster A (Scott, 1993). Whereas some HOX genes have distinct functions in specific contexts, many others have overlapping or redundant functions, both during early development (McIntyre et al, 2007) and in malignant cells (Eklund, 2007). This redundancy in HOX function is based in part upon the binding of similar DNA sequences and also on the interaction of HOX proteins with a common set of co-factors including PBX and MEIS. PBX and MEIS modify the DNA-binding specificity of HOX proteins, influence the regulation of transcription and are required for many aspects of HOX function (Moens and Selleri, 2006).In addition to haematological malignancies, the HOX genes are also expressed at high levels in many other solid malignancies, although with the exception of melanoma (Morgan et al, 2007), they are not known to have an oncogenic function. A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells. Further, we show that antagonising HOX/PBX binding in the NSCLC cell lines A549 (Lieber et al, 1976) and H23 (Little et al, 1983) induces apoptosis in vitro and causes significant tumour shrinkage in A549 nude mouse models.

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“…The short arm of chromosome 7 is implicated as being involved in the initiation and/or progression of ADC and has been suggested to include critical cancer related genes in ADC (16)(17)(18). Job et al (15) demonstrated that the high frequency of copy number gains on chromosome 7p contained CARD11, ETV1 and IKZF1 genes in 78-92% of the ADCs observed.…”

Section: Discussionmentioning

confidence: 99%

Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma

Kang

2013

Molecular Medicine Reports

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Abstract. 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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Disordered expression of HOX genes in human non-small cell lung cancer

Cited by 66 publications

References 12 publications

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma

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