Bmi1 Severs as a Potential Tumor-Initiating Cell Marker and Therapeutic Target in Esophageal Squamous Cell Carcinoma

Wang, X; Li, Kang; Cheng, Maosheng; Wang, Ganping; Han, Hui; Chen, Fangfang; Liao, Wenjing; Chen, Zhi; Chen, Jianwen; Bao, Yongzhan; Peng, Liang; Chen, Demeng

doi:10.1155/2020/8877577

Cited by 9 publications

(5 citation statements)

References 38 publications

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“…As previously described, mice were treated with 50 µg/ mL 4NQO (Sigma, N8141) to induce ESCC formation. 36 Briefly, 6-week-old male mice were orally administered with 4NQO dissolved in drinking water for 16 weeks to induce the formation and development of ESCC. Subsequently, the mice were returned to normal water for 10 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…To quantify the IHC staining results on patients with ESCC, the IHC staining intensity was assigned scores: 0 (negative), 1 (weak), 2 (medium), or 3 (strong), and IHC score was calculated by multiplying the percentage of positive cells (P) by the intensity (I), using the formula: Q=P×I; with a maximum score of 300. 36 The IHC score was calculated based on the percentage of positive cells within ESCC mouse model.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs

Xiong,

Chen,

Liu

et al. 2024

J Immunother Cancer

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BackgroundCD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic.MethodsWe investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276wKO) and K14cre; CD276 conditional knockout (CD276cKO) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion.ResultsIn this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs’ formation and reducing NK cells in vivo.ConclusionsThis study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs

Xiong,

Chen,

Liu

et al. 2024

J Immunother Cancer

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“…IHC and H&E staining procedure had been described previously 38 . All the primary antibodies including METTL13 (GeneTex, GTX120626-S), Snail (Cell Signaling Technology, 3879T), and Ki67 (Affinity, AF0198) were used at dilution in 1:100.…”

Section: Methodsmentioning

confidence: 99%

Methyltransferase like 13 mediates the translation of Snail in head and neck squamous cell carcinoma

Wang

Wan

et al. 2021

Int J Oral Sci

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Methyltransferase like 13 (METTL13), a kind of methyltransferase, is implicated in protein binding and synthesis. The upregulation of METTL13 has been reported in a variety of tumors. However, little was known about its potential function in head and neck squamous cell carcinoma (HNSCC) so far. In this study, we found that METTL13 was significantly upregulated in HNSCC at both mRNA and protein level. Increased METTL13 was negatively associated with clinical prognosis. And METTL13 markedly affected HNSCC cellular phenotypes in vivo and vitro. Further mechanism study revealed that METTL13 could regulate EMT signaling pathway by mediating enhancing translation efficiency of Snail, the key transcription factor in EMT, hence regulating the progression of EMT. Furthermore, Snail was verified to mediate METTL13-induced HNSCC cell malignant phenotypes. Altogether, our study had revealed the oncogenic role of METTL13 in HNSCC, and provided a potential therapeutic strategy.

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“…At the molecular level, multiple studies have demonstrated that BMI1 can collaborate with the PRC2 protein EZH2, a well-known histone methyltransferase, to suppress gene transcription, likely through the enhancement of trimethylation of H3 at lysine 27 (H3K27me3) 16 – 18 . This epigenetic modification has been shown to play a crucial role in the regulation of self-renewal in both normal stem cells and TICs, also referred to as cancer stem cells 13 , 19 . Indeed, Chen et al showed that BMI1 high TIC promoted tumor invasive growth and lymph node metastasis in squamous cell carcinoma 14 .…”

Section: Introductionmentioning

confidence: 99%

Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation

Xu,

Qin,

et al. 2023

Nat Commun

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Bile duct tumor thrombosis (BDTT) is a complication mostly observed in patients with advanced hepatocellular carcinoma (HCC), causing jaundice and associated with poor clinical outcome. However, its underlying molecular mechanism is unclear. Here, we develop spontaneous preclinical HCC animal models with BDTT to identify the role of BMI1 expressing tumor initiating cells (BMI1high TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1high TICs, which possess strong tumorigenicity and increased trans-intrahepatic biliary epithelial migration ability by secreting lysosomal cathepsin B (CTSB). Orthotopic liver implantation of BMI1high TICs into mice generates tumors and triggers CTSB mediated bile duct invasion to form tumor thrombus, while CTSB inhibitor treatment prohibits BDTT and extends mouse survival. Clinically, the elevated serum CTSB level determines BDTT incidence in HCC patients. Mechanistically, BMI1 epigenetically up-regulates CTSB secretion in TICs by repressing miR-218-1-3p expression. These findings identify a potential diagnostic and therapeutic target for HCC patients with BDTT.

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Bmi1 Severs as a Potential Tumor-Initiating Cell Marker and Therapeutic Target in Esophageal Squamous Cell Carcinoma

Cited by 9 publications

References 38 publications

CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs

CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs

Methyltransferase like 13 mediates the translation of Snail in head and neck squamous cell carcinoma

Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation

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