Deficiency of epithelial–mesenchymal transition causes child indirect inguinal hernia

Somuncu, Salih; Somuncu, Özge Sezin; Ballica, Basak; Tabandeh, B.

doi:10.1016/j.jpedsurg.2019.06.020

Cited by 9 publications

(10 citation statements)

References 24 publications

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“…Second, given that the cases were selected from past medical histories of the 47 target diseases in BBJ, the details of the inguinal hernias, including direct/ indirect, and medial/lateral were not available. The differences of indirect hernia and direct hernia is not only in the way the hernias occur but also in the underlying pathology as stated by Somuncu et al [78] However, the results of previous GWAS indicated the underlying significant loci across different subtypes of inguinal hernia. [23] Thus, we believe that our conclusions should not be affected by the unavailability of such data.…”

Section: Discussionmentioning

confidence: 93%

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias

Hikino

Koido²,

Tomizuka

et al. 2021

EBioMedicine

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Background: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. Methods: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. Findings: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The transethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 077, standard error = 026) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. Interpretation: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia.

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Section: Discussionmentioning

confidence: 93%

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias

Hikino

Koido²,

Tomizuka

et al. 2021

EBioMedicine

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“…A couple of studies have proven that JAK2/STAT3 signaling plays a key role in modulating keratinocyte differentiation and epithelial carcinogenesis ( 16 – 19 ). Our previous data also suggested that JAK2/STAT3 signaling was involved in the tumorigenesis of HNSCC ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

“…JAK/STAT3 has been observed in numerous tumors and underpins a majority of features of cancer (52), including cell proliferation (53), antiapoptosis (54), angiogenesis (55), metastasis (56), and cancer stem cell maintenance (57). In addition, increasing evidence has proven that JAK/STAT3 signaling plays a key role in modulating keratinocyte differentiation and epithelial carcinogenesis (16)(17)(18)(19). Amano et al demonstrated that suppressing STAT3 activation by JAK inhibitors increases the levels of terminal differentiation and improves skin barrier function (17).…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma

et al. 2021

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ObjectivesRecently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear.MethodsThe lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo.ResultsWGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells.ConclusionOur study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC.

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“…In other words, child IH cells maintained their epithelial stage and did not enter the mesenchymal phase. Subsequent to this study, EMT can be thought as a factor of IIH development in adults while the arrested EMT might be the factor of child IIH [57] (Table 1). The genes effecting IIH development and EMT effects are shown in Figure 2 with respect to the reference studies.…”

Section: Epithelial-mesenchymal Transition In Iihmentioning

confidence: 99%

“…Overall, abnormal deviations of EMT-related genes influence the development of IIH. Thus, the report on both genetic and epigenetic control of EMT in patients with primary IH may help to understand the pathogenesis and bring new therapeutic methods for this disease [57].…”

Section: Epithelial-mesenchymal Transition In Iihmentioning

confidence: 99%

A Comprehensive Review: Molecular and Genetic Background of Indirect Inguinal Hernias

Somuncu

2021

Visc Med

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Background: The occurrence of indirect inguinal hernias (IIH) is 5 times more prevalent than that of direct inguinal hernias (IH) and it is 7 times more common in males, owing to the attendance of the processus vaginalis (PV) throughout testicular descent. Summary: In children, the immense mainstream of IH is indirect. The progress of IIH development in children is instigated with a patent PV, which is mostly treated by simple herniorrhaphy. Syndromes of the collagen, microfibril, elastin, and glycosaminoglycan constituents of the extracellular matrix may attend to the development of IH. Our recent research showed that the lack of epithelial-mesenchymal transition (EMT) in children contributes to the development of IIH, while the scenario is defined as the opposite in adults. However, there is still a lack of knowledge on all of the genetic and molecular causes of the disease. Key Messages: Here we aimed to review the published genetic background of IH, the deficiencies of connective tissue causing the disease, recently defined molecular pathways involved including EMT, and possible recurrence reasons. This comprehensive study can deliver an analytic outline aiding to define patients with IH combined with fundamental genetic diseases.

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Deficiency of epithelial–mesenchymal transition causes child indirect inguinal hernia

Cited by 9 publications

References 24 publications

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias

Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma

A Comprehensive Review: Molecular and Genetic Background of Indirect Inguinal Hernias

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