Homeobox genes: a molecular link between development and cancer

Nunes, Fábio Daumas; Almeida, Fernanda Campos Souza de; Tucci, Renata; Sousa, Suzana Cantanhede Orsini Machado de

doi:10.1590/s1517-74912003000100018

Cited by 85 publications

(65 citation statements)

References 35 publications

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“…The intricate relationship between normal cell development and carcinogenesis has long been under scrutiny (51). As they are master regulators of embryogenesis, the deregulation of homeobox genes has profound effects on the cellular phenotype and may lead to tissue neoplasia (55,57).…”

Section: Discussionmentioning

confidence: 99%

Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Tan

Chang

Chng

et al. 2012

Molecular and Cellular Biology

160

142

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The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1-and AR-coregulated genes include those found in the "protein trafficking" process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Tan

Chang

Chng

et al. 2012

Molecular and Cellular Biology

160

142

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“…Quantitative analysis showed the expression level of HOXA7 was significantly higher in the granulosa tumor cell line, KGN, compared to primary hGCs and SVOG cells. It has been reported that many cancers, including leukemia, colon, skin, prostate, breast and ovarian cancers, have shown alterations in the expression patterns of HOX genes [30,32]. The overexpression of HOX genes has been widely associated with a variety of ovarian carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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BackgroundHomeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited.MethodsTo determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay.ResultsOur results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect.ConclusionsOur present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.

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“…The absent or aberrant expression of tissue-specific HOX genes has been implicated in cancer development [4]. Changes in HOX gene expression have been documented in small-cell lung cancer, breast cancer, prostate cancer, colorectal cancer, esophageal cancer, and kidney cancer [5][6][7]. Despite the observance of these changes little is known about the regulation of the HOX genes in adult tissues and how the genes become deregulated in cancerous tissues.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of the HOXB13 promoter region

Cross

Burmester

2007

Med Oncol

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Homeobox (HOX) genes are crucial regulators of cell growth and differentiation. These genes initiate and control gene expression cascades that drive development. More recently, the absent or aberrant expression of HOX genes has been implicated in cancer development. Despite the observance of these expression changes, the regulation of the HOX genes in adult tissues and how these genes become deregulated in cancerous tissues still needs much investigation. We characterized the promoter region of the HOXB13 gene. A 3 kb region upstream of the HOXB13 gene, which included the 5'UTR, increased reporter gene expression in LNCaP cells by approximately 99 fold over the promoterless control construct. A highly conserved 179 base pair fragment containing only the 5'UTR of the HOXB13 gene constituted a minimal promoter in the LNCaP cell line. Strong promoter activity was seen in the presence or absence of testosterone, although testosterone exposure did decrease expression in LNCaP cells by 50%. In an androgen insensitive cell line Du145, no sensitivity to testosterone was detected and a consistent low basal level of expression was observed. Since HOXB13 expression is highly tissue specific, we investigated the ability of the promoter to drive expression in tissues other than prostate. We observed highest expression in LNCaP cells with low levels of expression in lung, retinoblastoma, and colon cancer cells and higher expression in MCF7 breast cancer cells.

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Homeobox genes: a molecular link between development and cancer

Cited by 85 publications

References 35 publications

Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Functional characterization of the HOXB13 promoter region

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