Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting

Liu, Wei; Xie, Lei; He, Yaohui; Wu, Zhi‐Yong; Liu, Lu-Xin; Bai, Xuefeng; Deng, Dan-Xia; Xu, Xiu‐E; Liao, Lian‐Di; Lin, Wan-Wan; Heng, Jing-Hua; Xu, Xin; Liu, Peng; Huang, Qinjun; Li, Chengyu; Zhang, Zhi-Da; Wang, Wei; Zhang, Guorui; Gao, Xiang; Wang, Shaohong; Li, Chunquan; Xu, Li‐Yan; Li, Wen; Li, En‐Min

doi:10.1038/s41467-021-25202-5

Cited by 70 publications

(57 citation statements)

References 89 publications

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“…UCSC genome browser views for representative genes that are differentially expressed in normal and ESCC samples were shown (Additional file 1 : Figure S1A-S1D). Hallmark gene sets analysis results revealed that genes involved in epithelial mesenchymal transition, interferon gamma response, and E2F targets are the top three most enriched in genes up-regulated in tumors, and genes involved in estrogen response early, fatty acid metabolism, and xenobiotic metabolism are the top three most enriched in genes down-regulated in tumors, which are in consistent with our recent proteomic analysis (Additional file 1 : Figure S1E, S1F) [ 44 ].…”

Section: Resultssupporting

confidence: 89%

Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis

et al. 2022

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Background Esophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown. Methods Transcriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results Transcriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo. Conclusions An oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

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Section: Resultssupporting

confidence: 89%

Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis

et al. 2022

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“…Mutation, copy number variation, and transcriptome data of ESCC from TCGA database were downloaded from the UCSC Xena datahub ( https://xenabrowser.net/datapages/ ). The proteomic data and corresponding clinical data for 124 ESCC samples were obtained from Liu et al‘s study( Liu et al, 2021 ). In total, four published immunotherapy datasets were collected to support the predictive value of ICD-score in immune checkpoint blockade treatment, including three SKCM cohorts and 1 urothelial carcinoma.…”

Section: Methodsmentioning

confidence: 99%

Stratification From Heterogeneity of the Cell-Death Signal Enables Prognosis Prediction and Immune Microenvironment Characterization in Esophageal Squamous Cell Carcinoma

Zhang

Chen

2022

Front. Cell Dev. Biol.

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Esophageal squamous cell carcinoma (ESCC) is the primary subtype of esophageal cancer (EC) characterized by a high incidence rate and extremely poor prognosis worldwide. Previous studies suggested that the specific cell death signal was linked to different immune subtypes in multiple cancers, while a comprehensive investigation on ESCC is to be performed yet. In the current study, we dissected different cell death signals in ESCC tumors and then integrated that functional information to stratify ESCC patients into different immunogenic cell death (ICD) subtypes. By systematically analyzing the transcriptomes of 857 patients and proteomic profile of 124 patients, we found that the signals of necroptosis, pyroptosis, and ferroptosis are positively associated with activated immunity in ESCC. We identified two ICD pattern terms, namely, ICD-high and ICD-low subtypes that positively correlated to both progression-free survival and overall survival. In addition, cell fraction deconvolution analysis revealed that more infiltrated leukocytes were enriched in ICD-high types, especially antigen-presenting cells, such as dendritic cells and macrophages. With the XGBoost algorithm, we further developed a 14-gene signature which can simplify the subtyping for allocating new samples, by which we validated the prognosis value of the signature and proved that the ICD score scheme could serve as a promising biomarker for stratifying patients with immunotherapy in several immune checkpoint blockade treatment cohorts. Collectively, we successfully constructed the ICD scheme, which enables predicting of the prognosis or immunotherapy efficacy in ESCC patients and uncovered the critical interplay between cell death signals and immune status in ESCC.

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“…Of note, several further drugs have been approved for the treatment of other diseases, such as valdecoxib (ranked 4th) which targets PTGS2 and is used for the treatment of rheumatoid arthritis ( 36 ). Furthermore, it has been reported that certain molecules may inhibit ESCC cells in vitro or in animal models, such as curcumin ( 37 , 38 ) and menadione ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome‑based drug repositioning identifies TPCA‑1 as a potential selective inhibitor of esophagus squamous carcinoma cell viability

Zou

Xiao

et al. 2022

Int J Mol Med

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Esophageal squamous cell carcinoma (ESCC) is a cancer type with limited treatment options. The present study aimed to screen for small molecules that may inhibit ESCC cell viability. The small-molecule-perturbed signatures were extrapolated from the library of integrated network-based cellular signatures (LINCS) database. Since LINCS does not include small-molecule-perturbed signatures of ESCC cells, it was hypothesized that non-ESCC cell lines that display transcriptome profiles similar to those of ESCC may have similar small-molecule-perturbated responses to ESCC cells and that identifying small molecules that inhibit the viability of these non-ESCC cells may also inhibit the viability of ESCC cells. The transcriptomes of >1,000 cancer cell lines from the Cancer Cell Line Encyclopedia database were analyzed and 70 non-ESCC cell lines exhibiting similar transcriptome profiles to those of ESCC cells were identified. Among them, six cell lines with transcriptome signatures upon drug perturbation were available in the LINCS, which were used as reference signatures. A total of 20 ESCC datasets were analyzed and 522 downregulated and 461 upregulated differentially expressed genes (DEGs) that were consistently altered across >50% of the datasets were identified. These DEGs together with the reference signatures were then used as inputs of the ZhangScore method to score small molecules that may reverse transcriptome alterations of ESCC. Among the top-ranked 50 molecules identified by the ZhangScore, four candidates that may inhibit ESCC cell viability were experimentally verified. Furthermore, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), an inhibitor of the NF-κB pathway, was able to preferentially inhibit the viability of ESCC cells compared with non-tumorigenic epithelial Het-1A cells. Mechanistically, TPCA-1 induced ESCC KYSE-450 cell apoptosis by inhibiting the phosphorylation of inhibitor of NF-κB kinase subunit β, leading to IκBα stabilization and NF-κB signaling pathway inhibition. Collectively, these results demonstrated that LINCS-based drug repositioning may facilitate drug discovery and that TPCA-1 may be a promising candidate molecule in the treatment of ESCC.

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Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting

Cited by 70 publications

References 89 publications

Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis

Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis

Stratification From Heterogeneity of the Cell-Death Signal Enables Prognosis Prediction and Immune Microenvironment Characterization in Esophageal Squamous Cell Carcinoma

Transcriptome‑based drug repositioning identifies TPCA‑1 as a potential selective inhibitor of esophagus squamous carcinoma cell viability

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