Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo‐Independent Regulation of Heat Shock Protein 70 Family Members

Coto‐Llerena, Mairene; Tosti, Nadia; Taha‐Mehlitz, Stephanie; Kancherla, Venkatesh; Paradiso, Viola; Gallon, John; Bianco, Gaia; Garofoli, Andrea; Ghosh, Souvik; Tang, Fengyuan; Ercan, Caner; Matter, Matthias S.; Droeser, Raoul A.; Zavolan, Mihaela; Soysal, Savas D.; Flüe, Markus von; Kollmar, Otto; Terracciano, Luigi; Ng, Charlotte K.Y.; Piscuoglio, Salvatore

doi:10.1002/hep4.1656

Cited by 13 publications

(6 citation statements)

References 53 publications

(71 reference statements)

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“…TEAD4 is a key member of the TEAD family and it binds to different cofactors to regulate the transcription of target genes that involved in cellular cell functions [22]. TEAD4 plays an oncogenic role in many cancers including gastric cancer, hepatocellular carcinoma, lung adenocarcinoma and head neck squamous cell carcinoma by increasing cancer cell proliferation, migration and epithelial-mesenchymal transition (EMT) [46][47][48]. For example, Li et al reported that YAP/TEAD4 interaction mediates transcriptional activity of KIF4A promoter by binding KIF4A promoter, which will promote cell growth of esophageal squamous cell carcinoma (ESCC) cells [49].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway

et al. 2022

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Background Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated. Methods The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated. Results We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia. Conclusions Our findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.

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Section: Discussionmentioning

confidence: 99%

Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway

et al. 2022

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“…NR2F2 and OSM have been shown to be related to metastasis in gastric cancer and breast cancer, respectively (33,34); HSPA6 has been shown to play a critical role in the recurrence of hepatocellular carcinoma (35); AR has been shown to play a crucial role in cancer progression and continues to be a primary therapeutic target in prostate cancer (36). However, these previous studies (33)(34)(35)(36) included limited direct information about the IRGs of primary ESCA. Thus, these genes' immunomodulatory roles in monitoring the progression of primary ESCA and predicting prognosis need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

The prognostic value of an immune-related gene signature and infiltrating tumor immune cells based on bioinformatics analysis in primary esophageal cancer

Du¹,

Pang²,

Li³

et al. 2022

J Gastrointest Oncol

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Background: Immunotherapy is a promising novel treatment for esophageal cancer (ESCA). However, previous studies provide limited direct information about the prognostic significance of immune-related genes (IRGs) in primary ESCA development. This study explored the prognostic value of IRGs and infiltrating tumor immune cells in primary ESCA. Methods: The ribonucleic acid (RNA)-sequencing data and clinical information of primary ESCA were downloaded from The Cancer Genome Atlas (TCGA) database. Which included the clinical factors and prognosis outcomes of the ESCA patients. The IRGs were downloaded from the ImmPORT database. Results: We established the robust IRG prognostic signature of 4 IRGs (i.e., heat shock protein family A member 6, Oncostatin M, androgen receptor, and nuclear receptor subfamily 2 group F member 2) in primary ESCA, and divided the ESCA patients into high-and low-risk groups based on overall survival (OS). The Kaplan-Meier curves showed the high predictive ability of the prognostic signature in the training, testing, and full data sets (P=2.407e-03, P=1.044e-02, and P=2.535e-04, respectively). Multivariate Cox regression analyses were performed with age, grade, tumor stage, tumor type and the risk score as covariables. The risk score supports the use of a prognostic signature as an independent prognostic factor [training data set: hazard ratio (HR) =1.185, 95% confidence interval (95% CI): 1.013-1.388, P=0.034; testing data set: HR =2.056, 95% CI: 1.015-4.166, P=0.045; full data set: HR =1.197, 95% CI: 1.059-1.354, P=0.004]. The area under the curve (AUC) of the receiver operating characteristic curve validated the high predictive accuracy of the IRG signature in the training, testing, and full data set (AUCs =0.808, 0.657, and 0.751, respectively). The infiltration level of the activated mast cells was significantly higher in the high-risk group than the low-risk group; thus, infiltrating mast cells are associated with worse OS in ESCA patients. Conclusions: Our IRG prognostic signature provides a new direction to predict the survival of primaryESCA patients and has the potential ability to establish, promote, and improve personalized treatment procedures based on each patient's risk.

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“…Immunohistochemical staining was performed as previously described ( 22 , 23 ). Briefly, 8 μm-thick sections were cut, dehydrated, and processed on a Bond III (Leica Biosystems Wetzlar, Germany).…”

Section: Methodsmentioning

confidence: 99%

The Genomic Landscape of Serrated Lesion of the Colorectum: Similarities and Differences With Tubular and Tubulovillous Adenomas

et al. 2021

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Serrated lesions of the colorectum are the precursors of 15–30% of colorectal cancers (CRCs). These lesions have a peculiar morphological appearance, and they are more difficult to detect than conventional adenomatous polyps. In this study, we sought to define the genomic landscape of these lesions using high-depth targeted sequencing. Eight sessile serrated lesions without dysplasia (SSL), three sessile serrated lesions with dysplasia (SSL/D), two traditional serrated adenomas (TSA), and three tubular adenomas (TA) were retrieved from the files of the Institute of Pathology of the University Hospital Basel and from the GILAB AG, Allschwil, Switzerland. Samples were microdissected together with the matched normal counterpart, and DNA was extracted for library preparation. Library preparation was performed using the Oncomine Comprehensive Assay targeting 161 common cancer driver genes. Somatic genetic alterations were defined using state-of-the-art bioinformatic analysis. Most SSLs, as well as all SSL/Ds and TSAs, showed the classical BRAF p.V600E mutation. The BRAF-mutant TSAs showed additional alterations in CTNNB1, NF1, TP53, NRAS, PIK3CA, while TA showed a consistently different profile, with mutations in ARID1A (two cases), SMAD4, CDK12, ERBB3, and KRAS. In conclusion, our results provide evidence that SSL/D and TSA are similar in somatic mutations with the BRAF hotspot somatic mutation as a major driver of the disease. On the other hand, TAs show a different constellation of somatic mutations such as ARID1A loss of function.

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Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo‐Independent Regulation of Heat Shock Protein 70 Family Members

Cited by 13 publications

References 53 publications

Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway

Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway

The prognostic value of an immune-related gene signature and infiltrating tumor immune cells based on bioinformatics analysis in primary esophageal cancer

The Genomic Landscape of Serrated Lesion of the Colorectum: Similarities and Differences With Tubular and Tubulovillous Adenomas

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