Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Hu, Wen‐Yu; Xin, Yanguo; Zhao, Yinan; Ji, Hu

doi:10.1620/tjem.244.177

Cited by 15 publications

(10 citation statements)

References 86 publications

(114 reference statements)

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“…Short stature homeobox 2 ( SHOX2 ) is highly orthologous to murine Shox2 and human SHOX ( Blaschke et al, 1998 ; De Baere et al, 1998 ; Marchini et al, 2016 ; Hu et al, 2018 ). According to current studies on Shox2 , SHOX , and SHOX2, SHOX2 is considered to play a critical role in idiopathic short stature and various types of cardiac arrhythmias ( Mortensen et al, 2012 ; Marchini et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Zeng

Tai

et al. 2021

Front. Mol. Biosci.

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Background: Detection of SHOX2 methylation has been used to assist in the early diagnosis of lung cancer in many hospitals as SHOX2 may be important in the tumorigenesis of lung cancer. However, there are few studies on the mRNA expression, methylation, and molecular mechanism of SHOX2 in lung cancer. We aimed to explore the role of SHOX2 in lung adenocarcinoma (LUAD).Methods: First, we examined the differential expression of SHOX2 mRNA and methylation in cancerous and normal tissues using databases. Second, we analyzed the relationship between SHOX2 expression and common clinical parameters in LUAD patients. Third, we further explored the methylated level and its specific location of SHOX2 and the mainly factors of SHOX2 gene expression. Finally, we screened the correlatively expressed genes to analyze the pathways from the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes using DAVID.Results: We found that the mRNA expression of SHOX2 was higher in multiple cancers, including LUAD and lung squamous cell carcinoma (LUSC), than in normal tissues. Among LUAD patients, SHOX2 expression was higher in patients of middle–young age, with smoking history, in advanced stages, and with nodal distant metastasis. In addition, our results showed that patients with high expression of SHOX2 are prone to recurrence, poor differentiation, and poor prognosis. Thus, we identified that SHOX2 might be an oncogene for LUAD progression. The main factor influencing the high expression of SHOX2 mRNA may be DNA methylation, followed by copy number variation (CNV), but not by gene mutations in LUAD. Unexpectedly, we found that SHOX2 undergoes hypomethylation in the gene body instead of hypermethylation in the promoter. Additionally, SHOX2 has cross talk in the PI3K–Akt signaling pathway and ECM–receptor interaction.Conclusion:SHOX2 is highly expressed in most cancers. SHOX2 gene expression might be mainly regulated by methylation of its gene body in LUAD, and its high expression or hypomethylation indicates poor differentiation and poor prognosis. SHOX2 could be involved in PI3K–Akt and other important cancer-related signaling pathways to promote tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Zeng

Tai

et al. 2021

Front. Mol. Biosci.

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“…Our tissue-specific validation approach also indicates new roles for Shox during different embryonic developmental processes, including neuronal development and cardiogenesis, similar to/reminiscent of its paralog Shox2 ( Yu et al, 2007 ; Vickerman et al, 2011 ; Liu et al, 2012 ; Ha and Dougherty, 2018 ; Hu et al, 2018 ). Shox2-regulated targets, such as Bmp4 and Nppb , are involved in various biological processes such as heart and limb development ( Yu et al, 2007 ; Puskaric et al, 2010 ; Aza-Carmona et al, 2014 ; Hoffmann et al, 2017 ).…”

Section: Discussionmentioning

confidence: 76%

Identification and Tissue-Specific Characterization of Novel SHOX-Regulated Genes in Zebrafish Highlights SOX Family Members Among Other Genes

et al. 2021

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SHOX deficiency causes a spectrum of clinical phenotypes related to skeletal dysplasia and short stature, including Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome, and idiopathic short stature. SHOX controls chondrocyte proliferation and differentiation, bone maturation, and cellular growth arrest and apoptosis via transcriptional regulation of its direct target genes NPPB, FGFR3, and CTGF. However, our understanding of SHOX-related pathways is still incomplete. To elucidate the underlying molecular mechanisms and to better understand the broad phenotypic spectrum of SHOX deficiency, we aimed to identify novel SHOX targets. We analyzed differentially expressed genes in SHOX-overexpressing human fibroblasts (NHDF), and confirmed the known SHOX target genes NPPB and FGFR among the most strongly regulated genes, together with 143 novel candidates. Altogether, 23 genes were selected for further validation, first by whole-body characterization in developing shox-deficient zebrafish embryos, followed by tissue-specific expression analysis in three shox-expressing zebrafish tissues: head (including brain, pharyngeal arches, eye, and olfactory epithelium), heart, and pectoral fins. Most genes were physiologically relevant in the pectoral fins, while only few genes were also significantly regulated in head and heart tissue. Interestingly, multiple sox family members (sox5, sox6, sox8, and sox18) were significantly dysregulated in shox-deficient pectoral fins together with other genes (nppa, nppc, cdkn1a, cdkn1ca, cyp26b1, and cy26c1), highlighting an important role for these genes in shox-related growth disorders. Network-based analysis integrating data from the Ingenuity pathways revealed that most of these genes act in a common network. Our results provide novel insights into the genetic pathways and molecular events leading to the clinical manifestation of SHOX deficiency.

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“…For reduced heart rate, we argued that disrupted shox2 expression may lead to developmental defects, as previous research showed the relationship between shox2 mutant and bradycardic arrhythmia, one of whose symptoms is reduced heart rate [24]. Again, the assumption made behind this hypothesis was that the abnormal function was due to developmental failure, as the short stature homeobox 2 (shox2) transcription factor is crucial in the formation and differentiation of the sinoatrial node (SAN) [24].…”

Section: Discussionmentioning

confidence: 99%

Piezo Type Mechanosensitive Ion Channel Component 1 is Required for Heart Development in Zebrafish

Liu¹,

Fang²,

Chen³

et al. 2021

Preprint

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PIEZO1 is a non-selective cation channel protein that converts mechanical stimuli into electrochemical signals through mechanical force transmission. In recent years, more and more attention has been paid to its relationship with cardiovascular development and related diseases. However, PIEZO1 is difficult to be used as a therapeutic target due to incomplete study of its related phenotype and mechanism. Starting with the phenotypes of zebrafish at different stages of development, piezo1 knockout zebrafish features decreased heart rate in embryonic stage, increased heart size in 72dpf larvae, as well as ventricular enlargement, passivation and increased immune infiltration in adult stage. Further characterization revealed the relationship between PIEZO1 and AcanA protein at embryonic stage, and hand2 protein at adult stage. Through further RNA-seq analysis, ptpn21 downregulation, shox2 upregulation, itga4 upregulation were used to explain ventricular enlargement, heart rate decrease and immune infiltration increase respectively. Overall, this study provides a theoretical basis for elucidating the mechanism of PIEZO1 in regulating cardiac development.

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Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Cited by 15 publications

References 86 publications

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Identification and Tissue-Specific Characterization of Novel SHOX-Regulated Genes in Zebrafish Highlights SOX Family Members Among Other Genes

Piezo Type Mechanosensitive Ion Channel Component 1 is Required for Heart Development in Zebrafish

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