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Gastroenterology. 2019 May;156(6):1761-1774. doi: 10.1053/j.gastro.2019.01.263. Epub 2019 Feb 12.

Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer.

Author information

1
Division of Gastroenterology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Division of Gastroenterology, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio.
2
Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
3
Division of Gastroenterology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
4
Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
5
Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
6
Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
7
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
8
Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.
9
Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
10
Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
11
Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Electronic address: kkg5@case.edu.

Abstract

BACKGROUND & AIMS:

Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression.

METHODS:

We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice.

RESULTS:

Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells.

CONCLUSIONS:

In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.

KEYWORDS:

InFlo; LY2157299; PARADIGM; SP600125

PMID:
30768984
PMCID:
PMC6701681
[Available on 2020-05-01]
DOI:
10.1053/j.gastro.2019.01.263
[Indexed for MEDLINE]

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