HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

Cheng, Sheue-yann; Qian, Fengying; Huang, Qin; Wei, Lan; Fu, Ya-Wen; Du, Yuchen

doi:10.1038/s41419-018-0497-x

Cited by 32 publications

(27 citation statements)

References 43 publications

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“…HOXA4 (Homeobox A4) belongs to the Homeobox gene family of transcription factors associated with cell differentiation and embryonic development control . HOXA4 regulation seems to associate with lung cancer cell proliferation, migration, and invasion in vitro and in vivo, besides poor prognosis in patients . We identified that the inferred regulatory unit of HOXA4 is enriched with differentially expressed genes and its activity was suppressed in tumor tissues compared to control tissues.…”

Section: Discussionmentioning

confidence: 92%

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

Bastiani

Klamt

2019

Cancer Medicine

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Background Lung adenocarcinoma is the major cause of cancer‐related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment. Methods We used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case‐control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning. Results The regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival. Conclusion Using an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.

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Section: Discussionmentioning

confidence: 92%

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

Bastiani

Klamt

2019

Cancer Medicine

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“…Wnt signaling induces ß-catenin translocation to the nucleus to form the ß-catenin/T-cell factor transcriptional activator which activates a number of target genes including survivin, cyclin D1, c-Myc and VEGF. The elevated expression of Wnt/ß-catenin downstream effectors then enhances cell proliferation [34][35][36] . Sustained-hypoxia-induced cancer progression via Wnt/ß-catenin signaling has been reported in various cancers including lung, liver, kidney and bladder [37][38][39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

Kang

Kwon

Kim

et al. 2020

Sci Rep

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the purpose of this study was to evaluate whether obstructive sleep apnea (oSA)-related chronic intermittent hypoxia (CIH) influences lung cancer progression and to elucidate the associated mechanisms in a mouse model of lung cancer. C57/BL6 mice in a CIH group were exposed to intermittent hypoxia for two weeks after tumor induction and compared with control mice (room air). Hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VeGf) and metastasis-related matrix metalloproteinases (MMp) were measured. the expression levels of several hypoxia-related pathway proteins including HIF-1α, Wnt/ß-catenin, the nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin-eRK were measured by western blot. the number (p < 0.01) and volume (p < 0.05) of tumors were increased in the CIH group. The activity of MMP-2 was enhanced after CIH treatment. The level of VEGF was increased significantly in the CIH group (p < 0.05). ß-catenin and Nrf2 were translocated to the nucleus and the levels of downstream effectors of Wnt/ß-catenin signaling increased after iH exposure. ciH enhanced proliferative and migratory properties of tumors in a mouse model of lung cancer. ß-catenin and Nrf2 appeared to be crucial mediators of tumor growth. Obstructive sleep apnea (OSA) is characterized by recurrent occlusion of the upper airway during sleep leading to chronic intermittent hypoxia (CIH). OSA is a highly prevalent sleep disorder affecting at least 3% to 7% of the adult population 1. OSA has been shown to be associated with morbidities including metabolic syndrome, systemic hypertension, pulmonary vascular disease, ischemic heart disease and congestive heart failure 2. In addition, OSA-related CIH has been suggested to affect tumor development and progression 3. OSA has been implicated in the increasing incidence of certain types of solid malignancies. In a Spanish cohort, increased overnight hypoxia as a surrogate of OSA severity was associated with increased cancer incidence in selected populations 4-6. Also, OSA was associated with increased cancer mortality in a community-based sample 7. The association between OSA and lung cancer has been evaluated. OSA-related CIH induced resistance to apoptosis and increased metastasis in lung cancer cells, in a manner related to hypoxia inducible factor 1α (HIF-1α) 8. The role of immune cells has been suggested as a potential mechanism linking OSA and cancer. Almendros et al. demonstrated that CIH induced changes in host immune responses are related to adverse cancer outcomes. CIH increases the mobilization of tumor-associated macrophages (TAMs) into tumors, and induces macrophages to transform from an anti-tumor phenotype (M1) to a tumor-promoting phenotype (M2) 9. Cyclooxygenase-2 inhibited IH-induced M2 polarization of TAMs and prevented IH-induced adverse tumor outcomes in a mouse model of sleep apnea 10. OSA-related CIH altered CD8 + T-cells in combination with changes in the tumor microenvironment that enhanced malignant tumor properties 11. Studies...

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“…This transcription factor regulates the related biological processes by binding to the 5 -flanking sequence of the coding region with various affinities. HOXA4 is associated with various cancer types and its downregulation leads to inhibition of growth and invasion of lung cancer cells (Cheng et al, 2018). Based on molecular analyses, the HOXA4 (c.920A>C:p.H307P) mutation may acquire pathogenicity by disrupting the DNA binding process during the early embryonic period and thus inhibit development of auricle cartilage.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

et al. 2020

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Objective: We used data from twins and their families to probe the genetic factors contributing to microtia-atresia, in particular, early post-twinning variations that potentially account for the discordant phenotypes of monozygotic twin pairs. Methods: Six families of monozygotic twins discordant for congenital microtia-atresia were recruited for study. The six patients shared a consistent clinical phenotype of unilateral microtia-atresia. Whole-exome sequencing (WES) was performed for all six twin pairs and their parents. Family segregation and multiple bioinformatics methods were applied to identify suspicious mutations in all families. Recurring mutations commonly detected in at least two families were highlighted. All variants were validated via Sanger sequencing. Gene Ontology (GO) analysis was performed to identify candidate gene sets and related pathways. Copy number variation (CNV), linkage analysis, association analysis and machine learning methods were additionally applied to isolate candidate mutations, and comparative genomics and structural modeling tools used to evaluate their potential roles in onset of microtia-atresia. Results: Our analyses revealed 61 genes with suspected mutations associated with microtia-atresia. Five (HOXA4, MUC6, CHST15, TBX10, and AMER1) contained 7 de novo mutations that appeared in at least two families, which have been previously reported as pathogenic for other diseases. Among these, HOXA4 (c.920A>C, p.H307P) was determined as the most likely pathogenic variant for microtia-atresia. GO analysis revealed four gene sets involving 11 pathways potentially related to underlying pathogenesis of the disease. CNVs in three genes (UGT2B17, OVOS, and KATNAL2) were detected in at least two families. Linkage analysis disclosed 13 extra markers for the disease, of which two (FGFR1 and EYA1) were validated via machine learning analysis as plausible candidate genes for the disease.

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HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

Cited by 32 publications

References 43 publications

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

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