Multi-omics characterization of esophageal squamous cell carcinoma identifies molecular subtypes and therapeutic targets
Dengyun Zhao, … , Zigang Dong, Kangdong Liu
Dengyun Zhao, … , Zigang Dong, Kangdong Liu
Published April 23, 2024
Citation Information: JCI Insight. 2024;9(10):e171916. https://doi.org/10.1172/jci.insight.171916.
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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 4

Elevated expression of TIMMDC1 promotes ESCC growth and is associated with poor prognosis.

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Elevated expression of TIMMDC1 promotes ESCC growth and is associated wi...
(A) Representative IHC staining images of a human ESCC TMA using a specific antibody for TIMMDC1 are shown. Scale bar: 100 μm. (B and C) Protein levels of TIMMDC1 were analyzed in an ESCC TMA, including paired tumor and adjacent nontumor tissues of 66 patients (B) and tumors without paired nontumor tissues for of patients (C). (D) Kaplan-Meier plot comparing the survival probability of patients with high/low TIMMDC1 expression. (E) Transcript expression level of TIMMDC1 was determined in the TCGA-ESCA patient cohort. (F) TIMMDC1 knockdown efficiency was assessed by Western blot. (G and H) Cell proliferation was measured by MTT (n = 6 for each group) (G) and soft agar (n = 12 for each group) assays (H) after knockdown of TIMMDC1. Scale bar: 200 μm. (I) TIMMDC1 overexpression efficiency was assessed by Western blot. (J and K) Cell proliferation was measured by MTT (n = 6 for each group) (J) and soft agar (n = 12 for each group) assays (K) after overexpression of TIMMDC1. Scale bar: 200 μm. (L–O) KYSE30 and KYSE450 cells stably expressing scramble or shTIMMDC1 were s.c. injected into the right flank of each mouse (KYSE30: scramble, n = 10; sh1, n = 10; sh2, n = 7; KYSE450: scramble, n = 10; sh1, n = 8; sh2, n = 7). Tumors were excised at the end of the experiment. (L) Images of xenograft tumors. (M) Xenograft tumor growth curves in mice. (N) Weights of xenograft tumors. (O) Tumor inhibition ratios of TIMMDC1 knockdown. In all statistical plots, data were expressed as the mean ± SD. Two-tailed Student’s t test (B, C, E, J, and K) and 1-way ANOVA (G, H, M, and N) were used to determine statistical significance. *P < 0.05, **P < 0.01, ***P < 0.001. Representative results from at least 3 independent biological replicates (F–K) are shown.