Systemic treatment of advanced esophageal squamous cell carcinoma: chemotherapy, molecular-targeting therapy and immunotherapy

Hirano, Hidekazu; Kato, Ken

doi:10.1093/jjco/hyz034

Cited by 119 publications

(95 citation statements)

References 60 publications

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“…Although the incidence of ESCC has shown a downward trend in recent years, the morbidity and mortality of the disease remain high worldwide [2]. At present, the comprehensive treatment ESCC consists of surgery and definitive chemoradiotherapy, supplemented with cisplatin and 5-fluorouracil (5-FU) (CF) [3].…”

Section: Introductionmentioning

confidence: 99%

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

et al. 2020

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Background: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors originated from digestive system around the world and the treatment was limited by the unclear mechanism. DNA polymerase epsilon 2, accessory subunit (POLE2) is involved in DNA replication, repair, and cell cycle control, whose association with ESCC is still not clear. Methods: In this study, the expression level of POLE2 in ESCC tissues was detected by IHC. The POLE2 knockdown cell line was constructed, identified by qPCR and western blot and used for detecting cellular functions and constructing xenotransplantation mice model. MTT Assay, colony formation assay, flow cytometry, wound-healing assay and Transwell assay were used to detected cell proliferation, apoptosis and migration. Results: We firstly identified that the expression of POLE2 was overexpressed in ESCC. Moreover, the high expression of POLE2 can predict the tumor deterioration and poor prognosis of ESCC patients. Additionally, downregulation of POLE2 was involved in ESCC progression by promoting proliferation, migration, and inhibiting apoptosis in vitro. In vivo studies proved that POLE2 was positively correlated with ESCC tumor formation, which was consistent with the results in vitro. We also illuminated that POLE2 knockdown upregulated pro-apoptotic proteins (Bax, Caspase3, CD40L, FasL, IGFBP-5 and P21) and downregulated anti-apoptotic proteins (CLAP-2, IGF-I and sTNF-R2). In addition, POLE2 was involved in ESCC via targeting PI3K/Akt, Cyclin D1 signaling pathway. Conclusions: Therefore, POLE2 was proved to be involved in the development of ESCC, which may be a potential therapeutic target and bring new breakthroughs in the treatment of ESCC.

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Section: Introductionmentioning

confidence: 99%

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

et al. 2020

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“…Due to the lack of effective therapeutic strategies, it is imperative to develop a therapeutic target to improve the survival rate. Although current molecular targeted therapies have shown promise for the treatment of ESCC, patient prognosis remains poor (8). The aim of the present study was to identify novel biomarkers and therapeutic targets for ESCC using bioinformatics analysis.…”

Section: Discussionmentioning

confidence: 99%

“…have a 5-year survival of 20-25% (8,9). Although a number of genes are related to the development of ESCC, early diagnosis, treatment and prognosis assessment of ESCC are difficult (10).…”

Section: Minichromosome Maintenance 6 Complex Component Identified Bymentioning

confidence: 99%

Minichromosome maintenance 6 complex component identified by bioinformatics analysis and experimental validation in esophageal squamous cell carcinoma

Ren

Xiong

et al. 2020

Oncol Rep

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Esophageal squamous cell carcinoma (ESCC), the main subtype of esophageal cancer (EC), is a common lethal type of cancer with a high mortality rate. The aim of the present study was to select key relevant genes and identify potential mechanisms involved in the development of ESCC based on bioinformatics analysis. Minichromosome maintenance 6 complex component (MCM6) has been identified to be upregulated in multiple malignancies; however, its contributions to ESCC remain unclear. For the purposes of the present study, four datasets were downloaded from the Gene Expression Omnibus (GSE63941, GSE26886, GSE17351 and GSE77861), and the intersection of the differentially expressed genes was obtained using a Venn diagram. The protein-protein interaction was then constructed, and the modules were verified by Cytoscape, in which the key genes have a high connectivity degree with other genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway were subsequently filtered out to analyze the development of ESCC. MCM6, an upregulated gene, was selected and connected with most of the other genes, for further research validation. The expression levels of MCM6 were then assessed using the Oncomine, GEPIA and UALCAN databases and validated in both ESCC tissues samples and cell lines by immunohistochemistry and RT-qPCR. Cell counting kit-8 (CCK-8), flow cytometry, wound healing and Transwell assays were used to determine the proliferation, apoptosis, cell cycle, migration and invasion of ESCC cells. A total of 24 genes were identified by a series of bioinformatics analyses and the results revealed that the genes were associated with DNA replication and cell cycle. Experimental validation revealed that MCM6 expression was significantly elevated in both ESCC tissues and cell lines. The results were consistent with those of bioinformatics analysis. Furthermore, the knockdown of MCM6 inhibited cell proliferation, migration and invasion and promoted cell apoptosis, and made cells arrested in S stage. In summary, the findings of bioinformatics analysis provided a novel hypothesis for ESCC progression. In particular, the aberrantly elevated expression of MCM6 is a potential biomarker for ESCC diagnosis and treatment.

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“…Although great advances have been made in the detection and treatment of ESCC in the past decade, the outcomes of many patients still remain grim [58][59][60]; better preventive methods and therapeutic strategies are urgently needed for a better clinical prospect of ESCC patients. Our ndings suggest that the temperature (54 °C) of thermal stimuli activating TRPV2 channel and driving the progress of ESCC is much lower than the dietary temperatures among many populations, therefore, to advise the communities to stay away from high-temperature food could be an option.…”

Section: Discussionmentioning

confidence: 99%

Thermal stress involved in TRPV2 promotes tumorigenesis through the pathway of PI3K/Akt/mTOR in esophageal squamous cell carcinoma

Huang¹,

Li²,

Tian³

et al. 2020

Preprint

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BackgroundEsophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide. Although the exposure of esophageal mucosa to heat stimuli has long been recognized as an important risk for the initiation and development of ESCC, its underlying mechanisms remain uncharacterized. MethodsWestern blotting and immunofluorescence were used to detect the expression and localization of transient receptor potential vanilloid receptor 2 (TRPV2) in the ESCC cells. The cancerous behaviors of the ESCC cells were evaluated by a single-cell culturing assay, a wound healing assay, a 3D culturing assay and a tube formation assay respectively. In vivo tumorigenicity and metastasis of the ESCC cells were examined via xenograft nude mouse models. Western blotting and IHC were performed to determine the expression profiles of TRPV2 in the ESCC patient tissues. TRPV2 knocked-out ESCC cell line was established using CRISPR-Cas9 gene editing technique.ResultsHere, we found that the expression of TRPV2, one of the thermally sensitive TRP family members, was upregulated in both ESCC cells and clinical samples. We further showed that activation of TRPV2 by recurrent acute thermal stress (54°C, a temperature unexpectedly much lower than those in many dietary modalities) or O1821 (20 μM), a TRPV2 agonist, promoted cancerous behaviors in ESCC cells. The proangiogenic capacity of the heat-challenged ESCC cells was also found to be enhanced profoundly in the tube formation assay; both tumor formation and metastasis that originated from the cells were substantially promoted in nude mouse models upon the activation of TRPV2. These effects were inhibited significantly by tranilast (120 μM), a TRPV2 inhibitor, and abolished by TRPV2 knock-out using CRISPR-Cas9 gene editing. Conversely, overexpression of TRPV2 by transfection of TRPV2 DNA into NE2 cells, could switch the cells to tumorigenesis upon activation of TRPV2. Mechanistically, the driving role of TRPV2 in the progression of ESCC is mainly regulated by the PI3K/Akt/mTOR signaling pathway. Application of a pan-PI3K/mTOR inhibitor and/or a PTEN activator resulted in markedly reduced ESCC cell proliferation. ConclusionsOur study first proved that TRPV2 plays an important role in the tumorigenesis of ESCC upon thermal stress. We revealed that TRPV2-PI3K/Akt/mTOR is a novel and promising target for the prevention and treatment of ESCC.

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Systemic treatment of advanced esophageal squamous cell carcinoma: chemotherapy, molecular-targeting therapy and immunotherapy

Cited by 119 publications

References 60 publications

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

POLE2 knockdown reduce tumorigenesis in esophageal squamous cells

Minichromosome maintenance 6 complex component identified by bioinformatics analysis and experimental validation in esophageal squamous cell carcinoma

Thermal stress involved in TRPV2 promotes tumorigenesis through the pathway of PI3K/Akt/mTOR in esophageal squamous cell carcinoma

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