Original ArticlesDMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell
Introduction
Lung cancer is one of the most common malignancies and also is the leading cause of cancer-related death globally [1,2]. As the predominant histological subtype of lung cancer, lung adenocarcinoma (LUAD) accounts for approximately 40% of lung cancer cases [3]. Despite tremendous advances have been made in the diagnosis and treatment of LUAD [4], the prognosis of LUAD patients remains poor, with a 5-year overall survival rate less than 20% [5]. The molecular etiology of LUAD is complicated and multiple genomic alterations function in cancer growth [6,7]; however, the functional impact of most genomic alterations on tumor growth of LUAD remains unknown [8]. Better understanding of these alterations is critical for the advance of diagnostic markers and therapeutic targets for LUAD patients.
The progression of cancer is closely linked to activation of oncogenes and inactivation of tumor suppressor genes [[9], [10], [11], [12]]. To screen for novel functional oncogenes in LUAD, we analyzed The Cancer Genome Atlas (TCGA) and found that DMBX1 (diencephalon/mesencephalon homeobox 1) might be a potential oncogene in LUAD and correlated with the prognosis of LUAD patients. DMBX1 is located on Chromosome 1p33 and encodes a member of the bicoid sub-family of homeodomain-containing transcription factors [13]. It has been well known that transcription factors control the rate of transcription of genetic information from DNA to messenger RNA and many of them function as proto-oncogenes or tumor suppressors in cancers [[14], [15], [16]]. DMBX1 was firstly identified as a novel member of the homeobox family in 2002 [17]. The follow-up studies showed that DMBX1 played an important role in postnatal survival, growth [18], the development of the limb [19], the central nervous system [[20], [21], [22]]and was essential in agouti-related protein action [23]. Many homeobox genes play a role in early embryonic development and meanwhile participate in the tumorigenesis of cancers [[24], [25], [26]], just like the role of carcino-embryonic antigen (CEA) in gastroenteric tumors [27]. It makes great sense to further study the function and mechanism of DMBX1 in LUAD.
In recent years DMBX1 was found to regulate cell cycle exit and differentiation of progenitor cells during midbrain and retinal development [[28], [29], [30]]. It is well-known that a well-balanced cell cycle progression is necessary for cell proliferation, while dysregulation of the cell cycle components may lead to tumor formation [31]. Consistently with the research in progenitor cells, we found that DMBX1 promoted tumor proliferation and regulated cell cycle progression in LUAD. Further study indicated that DMBX1 exerted its oncogenic role via repressing OTX2-mediated transcription of p21, a well-known cyclin-dependent kinase inhibitor and a tumor suppressor. Together, the current study revealed DMBX1 as an important regulator of tumor growth in LUAD and might provide diagnostic markers and therapeutic targets for LUAD patients.
Section snippets
Bioinformatics analysis
The two TCGA dataset, named TCGA_LUNG_exp_HiseqV2-2015-02-24 and TCGA_LUAD_exp_Hi-SeqV2-2015-02-24, were downloaded from the UCSC Cancer Browser (https://genomecancer.ucsc.edu/) [32]. The normalized gene expression was obtained from “genomicMatrix” file and the clinicopathological information was acquired from “clinical_data” file. For Reactome pathway analysis, a total of 112 genes (Table S1) highly co-expressed (Spearman's correlation score >0.35) with DMBX1 in LUAD (http://www.cbioportal.org/
DMBX1 was identified as a potential oncogene in LUAD
To screen for aberrant-expressed genes in LUAD, we analyzed two TCGA dataset, TCGA_LUNG_exp_HiseqV2-2015-02-24 and TCGA_LUAD_exp_Hi-SeqV2-2015-02-24. Three candidate genes (PITX2, DMBX1 and HOXC13) were identified using the following screening criteria: fold change >10 (Tumor/Normal) and tumor expression >3 (Fig. 1A). PITX2 and HOXC13 have been studied in lung cancer [[37], [38], [39], [40]] but DMBX1 remains functionally unknown. Further analysis of TCGA dataset revealed that DMBX1 was
Discussion
The poor prognosis of lung adenocarcinoma is largely due to late diagnosis and indistinct mechanism of cancer development [44,45]. And cancer growth is the consequence of multiple, cooperative genomic alterations, including epigenetic alteration, genomic instability and transcriptional alterations [8,46]. Numerous alterations have been catalogued by whole genome sequencing, but the effect of most alterations still remains unknown [47]. In the past decades, significant efforts have been made in
List of abbreviations
LUAD: lung adenocarcinoma; Co-IP: co-immunoprecipitation; ChIP: chromatin immunoprecipitation; TCGA: The Cancer Genome Atlas.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Competing interests
The authors declare that they have no competing interests.
Funding
This research was supported by the National Natural Science Foundation of China (81672869), Jiangsu Provincial Special Program of Medical Science Funding (BL2012030), Jiangsu Provincial Science Foundation (BK20161596), Jiangsu Provincial Medical Outstanding Talent (Lin Xu) and
Acknowledgements
Not applicable.
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Jing Luo, Yu Yao and Kaichao Liu contributed equally to this work.