TY - JOUR
T1 - A multi-omics study delineates new molecular features and therapeutic targets for esophageal squamous cell carcinoma
AU - Jin, Xing
AU - Liu, Lei
AU - Wu, Jia
AU - Jin, Xiaoxia
AU - Yu, Guanzhen
AU - Jia, Lijun
AU - Wang, Fengying
AU - Shi, Minxin
AU - Lu, Haimin
AU - Liu, Jibin
AU - Liu, Dan
AU - Yang, Jing
AU - Li, Hua
AU - Ni, Yan
AU - Luo, Qin
AU - Jia, Wei
AU - Wang, Wei
AU - Chen, Wen Lian
N1 - Funding information:
This work was supported by the National Natural Science Foundation of China (31970708, 81770147, 81802891, 82002953), National Scientific and Technological Major Special Project of China (2019ZX09201004-002-013), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug Innovation and Development (2017ZX09304001), Research fund of Shanghai Municipal Commission of Health (20174Y0090), Shanghai Rising-Star Program (18QA1404100), Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Youth Talent Program, Shanghai Municipal Key Clinical Specialty (shslczdzk03701), Three-Year Plan of Shanghai Municipality for Further Accelerating The Development of Traditional Chinese Medicine (ZY(2018-2020)-CCCX-1016), Shanghai Chenguang Program (18CG47), Gaofeng Clinical Medicine Grant of Shanghai Municipal Education Commission, Health Commission of Pudong New Area Health and Family Planning Scientific Research Project (PW2019E-1), and Xinling Scholar Program of Shanghai University of Traditional Chinese Medicine.
Publisher copyright:
© 2021 The Authors.
PY - 2021/9
Y1 - 2021/9
N2 - Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with inferior prognosis. Here, we conducted comprehensive transcriptomic, proteomic, phosphoproteomic, and metabolomic characterization of human, treatment-naive ESCC and paired normal adjacent tissues (cohort 1, n = 24) in an effort to identify new molecular vulnerabilities for ESCC and potential therapeutic targets. Integrative analysis revealed a small group of genes that were related to the active posttranscriptional and posttranslational regulation of ESCC. By using proteomic, phosphoproteomic, and metabolomic data, networks of ESCC-related signaling and metabolic pathways that were closely linked to cancer etiology were unraveled. Notably, integrative analysis of proteomic and phosphoproteomic data pinpointed that certain pathways involved in RNA transcription, processing, and metabolism were stimulated in ESCC. Importantly, proteins with close linkage to ESCC prognosis were identified. By enrolling an ESCC patient cohort 2 (n = 41), three top-ranked prognostic proteins X-prolyl aminopeptidase 3 (XPNPEP3), bromodomain PHD finger transcription factor (BPTF), and fibrillarin (FBL) were verified to have increased expression in ESCC. Among these prognostic proteins, only FBL, a well-known nucleolar methyltransferase, was essential for ESCC cell growth in vitro and in vivo. Furthermore, a validation study using an ESCC patient cohort 3 (n = 100) demonstrated that high FBL expression predicted unfavorable patient survival. Finally, common cancer/testis antigens and established cancer drivers and kinases, all of which could direct therapeutic decisions, were characterized. Collectively, our multi-omics analyses delineated new molecular features associated with ESCC pathobiology involving epigenetic, posttranscriptional, posttranslational, and metabolic characteristics, and unveiled new molecular vulnerabilities with therapeutic potential for ESCC.
AB - Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with inferior prognosis. Here, we conducted comprehensive transcriptomic, proteomic, phosphoproteomic, and metabolomic characterization of human, treatment-naive ESCC and paired normal adjacent tissues (cohort 1, n = 24) in an effort to identify new molecular vulnerabilities for ESCC and potential therapeutic targets. Integrative analysis revealed a small group of genes that were related to the active posttranscriptional and posttranslational regulation of ESCC. By using proteomic, phosphoproteomic, and metabolomic data, networks of ESCC-related signaling and metabolic pathways that were closely linked to cancer etiology were unraveled. Notably, integrative analysis of proteomic and phosphoproteomic data pinpointed that certain pathways involved in RNA transcription, processing, and metabolism were stimulated in ESCC. Importantly, proteins with close linkage to ESCC prognosis were identified. By enrolling an ESCC patient cohort 2 (n = 41), three top-ranked prognostic proteins X-prolyl aminopeptidase 3 (XPNPEP3), bromodomain PHD finger transcription factor (BPTF), and fibrillarin (FBL) were verified to have increased expression in ESCC. Among these prognostic proteins, only FBL, a well-known nucleolar methyltransferase, was essential for ESCC cell growth in vitro and in vivo. Furthermore, a validation study using an ESCC patient cohort 3 (n = 100) demonstrated that high FBL expression predicted unfavorable patient survival. Finally, common cancer/testis antigens and established cancer drivers and kinases, all of which could direct therapeutic decisions, were characterized. Collectively, our multi-omics analyses delineated new molecular features associated with ESCC pathobiology involving epigenetic, posttranscriptional, posttranslational, and metabolic characteristics, and unveiled new molecular vulnerabilities with therapeutic potential for ESCC.
KW - esophageal squamous cell carcinoma
KW - fibrillarin
KW - molecular feature
KW - multi-omics
UR - https://onlinelibrary.wiley.com/toc/20011326/2021/11/9
U2 - 10.1002/ctm2.538
DO - 10.1002/ctm2.538
M3 - Journal article
C2 - 34586744
SN - 2001-1326
VL - 11
JO - Clinical and Translational Medicine
JF - Clinical and Translational Medicine
IS - 9
M1 - e538
ER -
