Multi-omics characterization of esophageal squamous cell carcinoma identifies molecular subtypes and therapeutic targets
Dengyun Zhao, Yaping Guo, Huifang Wei, Xuechao Jia, Yafei Zhi, Guiliang He, Wenna Nie, Limeng Huang, Penglei Wang, Kyle Vaughn Laster, Zhicai Liu, Jinwu Wang, Mee-Hyun Lee, Zigang Dong, Kangdong Liu
Dengyun Zhao, Yaping Guo, Huifang Wei, Xuechao Jia, Yafei Zhi, Guiliang He, Wenna Nie, Limeng Huang, Penglei Wang, Kyle Vaughn Laster, Zhicai Liu, Jinwu Wang, Mee-Hyun Lee, Zigang Dong, Kangdong Liu
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Research Article Oncology Therapeutics

Multi-omics characterization of esophageal squamous cell carcinoma identifies molecular subtypes and therapeutic targets

Abstract

Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer and is characterized by an unfavorable prognosis. To elucidate the distinct molecular alterations in ESCC and investigate therapeutic targets, we performed a comprehensive analysis of transcriptomics, proteomics, and phosphoproteomics data derived from 60 paired treatment-naive ESCC and adjacent nontumor tissue samples. Additionally, we conducted a correlation analysis to describe the regulatory relationship between transcriptomic and proteomic processes, revealing alterations in key metabolic pathways. Unsupervised clustering analysis of the proteomics data stratified patients with ESCC into 3 subtypes with different molecular characteristics and clinical outcomes. Notably, subtype III exhibited the worst prognosis and enrichment in proteins associated with malignant processes, including glycolysis and DNA repair pathways. Furthermore, translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1) was validated as a potential prognostic molecule for ESCC. Moreover, integrated kinase-substrate network analysis using the phosphoproteome nominated candidate kinases as potential targets. In vitro and in vivo experiments further confirmed casein kinase II subunit α (CSNK2A1) as a potential kinase target for ESCC. These underlying data represent a valuable resource for researchers that may provide better insights into the biology and treatment of ESCC.

Authors

Dengyun Zhao, Yaping Guo, Huifang Wei, Xuechao Jia, Yafei Zhi, Guiliang He, Wenna Nie, Limeng Huang, Penglei Wang, Kyle Vaughn Laster, Zhicai Liu, Jinwu Wang, Mee-Hyun Lee, Zigang Dong, Kangdong Liu

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Figure 6

Tumor inhibitory effect of CX-4945 in vitro and in vivo.

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Tumor inhibitory effect of CX-4945 in vitro and in vivo. (A and B) MTT (...
(A and B) MTT (n = 6 for each group) (A) and soft agar (n = 12 for each group) (B) assays were performed on KYSE30 and KYSE450 cells following treatment with CX-4945 at concentrations ranging from 0 μM to 20 μM. (C) The growth of organoids was evaluated after treatment with CX-4945 at the same concentration (n = 4 for each group). Scale bar: 100 μm. (D) Western blotting was performed to determine the protein levels of CSNK2A1 and p-CSNK2A1 T360/S362 in ESCC cell lines. (E) The inhibitory effect of CX-4945 on cell proliferation was assessed using MTT assay in ESCC cell lines. (F) Pearson correlation analysis was employed to evaluate the correlation between p-CSNK2A1 T360/S362 levels and inhibition rate of cell proliferation in 7 ESCC cell lines. (G) LEG379 tumors excised from the mice treated with CX-4945 were analyzed (n = 10 for each group). (H–J) PDX tumor growth (H), tumor weights (I), and tumor inhibition ratios (J) of the LEG379 case treated with CX-4945 were determined. (K–N) LEG397 tumors excised from mice treated with CX-4945 were examined (n = 8 for each group) (K), followed by analysis of PDX tumor growth (L), tumor weights (M), and tumor inhibition ratios (N) of the LEG397 case. Additionally, LEG244 tumors obtained from mice treated with lentiviruses encoding shCSNK2A1 were investigated (n = 10 for each group). (O–R) The LEG244 case treated with lentiviruses encoding shCSNK2A1 were examined (O), and PDX tumor growth (P), tumor weights (Q), and tumor inhibition ratios (R) were determined. In all statistical plots, data were expressed as the mean ± SD. One-way ANOVA (A–C, H, I, L, M, P, and Q) was used to determine statistical significance. *P < 0.05, **P < 0.01, ***P < 0.001. Representative results from at least 3 independent biological replicates (A–E) are shown.