SLUG and SNAIL as Potential Immunohistochemical Biomarkers for Renal Cancer Staging and Survival

Zivotic, Maja; Kovacevic, Sanjin; Nikolic, Gorana; Mioljevic, Ana; Filipovic, Isidora; Djordjevic, Marija; Jovicic, Vladimir; Topalovic, Nikola; Ilic, Kristina; Radojevic Skodric, Sanja; Dundjerovic, Dusko; Nesovic Ostojic, Jelena

doi:10.3390/ijms241512245

Cited by 3 publications

(1 citation statement)

References 45 publications

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“…Decreased expression of E-cadherin by immunohistochemistry staining was already described in sunitinib resistant tumors [ 39 ]. The survival period is significantly longer in patients whose tumors do not express Slug [ 40 ]. Recently, we have demonstrated an upregulation of AXL and PDL1 that was associated with a significant low survival for RCC patients [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

Buart,

Diop,

Damei

et al. 2023

Cancers

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von Hippel-Lindau (VHL) disease, due to mutations of the tumor suppressor VHL gene, is a rare hereditary syndrome with a high risk of developing clear cell renal cell carcinoma (ccRCC). We asked whether the VHL-C162F mutation interferes with proliferation, migration, healing and forming colony ability by using wild-type VHL (WT VHL) and VHL-C162F reconstituted cells. We then analyzed the in vitro impact of the sunitinib treatment on VHL-C162F cells. We showed that VHL-C162F mutations have no impact on cell morphology, colony formation and migration ability but confer a significant higher healing ability than in WT VHL cells. RNA sequencing analysis revealed that VHL-C162F mutation upregulates genes involved in hypoxia and epithelial mesenchymal transition (EMT) pathways by comparison with VHL WT cells. We next showed a decrease in healing ability in VHL-C162F cells depleting on ZHX2, an oncogenic driver of ccRCC, highlighting the potential involvement of ZHX2 in aggressiveness of the VHL-C162F cells. Moreover, we found that sunitinib treatment inhibits ZHX2 expression and induces a reduced proliferation correlating with downregulation of P-ERK. Sunitinib treatment also conferred a more mesenchymal profile to VHL-C162F cells with significant downregulation of E-cadherin and upregulation of N-cadherin, Slug and AXL. Sunitinib therapy may therefore promote disease progression in VHL-C162F patients.

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Section: Discussionmentioning

confidence: 99%

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

Buart,

Diop,

Damei

et al. 2023

Cancers

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FAP Serves as a Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma

Liao,

Fan,

Weng

et al. 2024

Analytical Cellular Pathology

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Head and neck squamous cell carcinoma (HNSCC) poses significant challenges with poor survival rates and limited therapeutic strategies. Our study, using The Cancer Genome Atlas (TCGA) data, assesses cancer-associated fibroblast (CAF) gene signatures’ clinical relevance. In our analysis across TCGA tumor types, differential gene expression analysis revealed that fibroblast activation protein (FAP) is upregulated in tumor tissues and associated with poorer survival rates in HNSCC. Furthermore, mechanistic studies employing gene-silencing techniques substantiated that FAP knockout led to a significant decrease in cellular proliferation, invasion, and migration in HNSCC cell lines. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, we established that high FAP expression correlates with vital biological processes such as extracellular matrix organization, angiogenesis, and cellular motility. Importantly, FAP was found to regulate these processes by promoting the expression of key proteins involved in epithelial–mesenchymal transition-related pathways. Additionally, our analysis revealed a significant correlation between FAP expression and the expression profiles of immune checkpoint molecules, underscoring its potential role in immune modulation. Collectively, our findings illuminate FAP’s pivotal role in HNSCC pathogenesis and its potential as a prognostic biomarker and therapeutic target. This research lays the groundwork for understanding the multifaceted roles and regulatory mechanisms of CAFs in HNSCC, thereby offering valuable perspectives for the development of targeted therapeutic strategies aimed at improving patient outcomes.

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Cisplatin‑resistant germ cell tumor models: An exploration of the epithelial‑mesenchymal transition regulator SLUG

Cardoso,

Rosa,

Moreno

et al. 2024

Mol Med Rep

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Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10–20% of patients with advanced disease demonstrate resistance to cisplatin-based chemotherapy, and epithelial-mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 ( SLUG ) transcriptional factor, and, to the best of our knowledge, remains unexplored within TGCTs. Therefore, the present study investigated the EMT transcription factor SLUG in TGCTs. In silico analyses were performed to investigate the expression of EMT markers in TGCTs. In addition, a cisplatin-resistant model for TGCTs was developed using the NTERA-2 cell line, and a mouse model was also established. Subsequently, EMT was assessed both in vitro and in vivo within the cisplatin-resistant models using quantitative PCR and western blot analyses. The results of the in silico analysis showed that the different histologies exhibited distinct expression profiles for EMT markers. Seminomas exhibited a lower expression of EMT markers, whereas embryonal carcinomas and mixed GCT demonstrated high expression. Notably, patients with lower SLUG expression had longer median progression-free survival (46.4 months vs. 28.0 months, P=0.022). In the in vitro analysis, EMT-associated genes [fibronectin; vimentin ( VIM ); actin, α2, smooth muscle; collagen type I α1; transforming growth factor-β1; and SLUG ] were upregulated in the cisplatin-resistant NTERA-2 (NTERA-2R) cell line after 72 h of cisplatin treatment. Consistent with this finding, the NTERA-2R mouse model demonstrated a significant upregulation in the expression levels of VIM and SLUG. In conclusion, the present findings suggested that SLUG may serve a crucial role in connecting EMT with the development of cisplatin resistance, and targeting SLUG may be a putative therapeutic strategy to mitigate cisplatin resistance.

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SLUG and SNAIL as Potential Immunohistochemical Biomarkers for Renal Cancer Staging and Survival

Cited by 3 publications

References 45 publications

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

FAP Serves as a Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma

Cisplatin‑resistant germ cell tumor models: An exploration of the epithelial‑mesenchymal transition regulator SLUG

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