PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis

Xiaorong Zhou; Barrett L Updegraff; Yabin Guo; Michael Peyton; Luc Girard; Jill E Larsen; Xian-Jin Xie; Yunyun Zhou; Tae Hyun Hwang; Yang Xie; Jaime Rodriguez-Canales; Pamela Villalobos; Carmen Behrens; Ignacio I Wistuba; John D Minna; Kathryn A O'Donnell

doi:10.1158/0008-5472.CAN-16-1267-T

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PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis

Journal article

Open access

Peer reviewed

PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis

Xiaorong Zhou, Barrett L Updegraff, Yabin Guo, Michael Peyton, Luc Girard, Jill E Larsen, Xian-Jin Xie, Yunyun Zhou, Tae Hyun Hwang, Yang Xie, …

Cancer research (Chicago, Ill.), Vol.77(1), pp.187-197

01/01/2017

DOI: 10.1158/0008-5472.CAN-16-1267-T

PMCID: PMC5410365

PMID: 27821484

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Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the efficacy of membrane proteins as therapeutic targets in human malignancies, we examined cell-surface receptors that may act as drivers of lung tumorigenesis. Here, we report that the PROTOCADHERIN PCDH7 is overexpressed frequently in NSCLC tumors where this event is associated with poor clinical outcome. PCDH7 overexpression synergized with EGFR and KRAS to induce MAPK signaling and tumorigenesis. Conversely, PCDH7 depletion suppressed ERK activation, sensitized cells to MEK inhibitors, and reduced tumor growth. PCDH7 potentiated ERK signaling by facilitating interaction of protein phosphatase PP2A with its potent inhibitor, the SET oncoprotein. By establishing an oncogenic role for PCDH7 in lung tumorigenesis, our results provide a rationale to develop novel PCDH7 targeting therapies that act at the cell surface of NSCLC cells to compromise their growth. Cancer Res; 77(1); 187-97. ©2016 AACR.

MAP Kinase Signaling System - physiology

Immunoprecipitation

Cadherins - metabolism

Tissue Array Analysis

Humans

Lung Neoplasms - metabolism

Histone Chaperones - metabolism

Lung Neoplasms - pathology

Receptor, Epidermal Growth Factor - metabolism

Heterografts

Polymerase Chain Reaction

Proto-Oncogene Proteins p21(ras) - metabolism

Carcinoma, Non-Small-Cell Lung - pathology

Carcinoma, Non-Small-Cell Lung - metabolism

Proportional Hazards Models

Cell Transformation, Neoplastic - metabolism

Blotting, Western

Transcription Factors - metabolism

Animals

Protein Phosphatase 2 - metabolism

Survival Analysis

Cell Line, Tumor

Mice, Inbred NOD

Signal Transduction - physiology

Mice

Cell Transformation, Neoplastic - pathology

Details

Title: Subtitle: PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis
Creators: Xiaorong Zhou - Department of Immunology, Nantong University School of Medicine, Nantong, China
Barrett L Updegraff - Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas
Yabin Guo - Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas
Michael Peyton - Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
Luc Girard - Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas
Jill E Larsen - Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland
Xian-Jin Xie - Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
Yunyun Zhou - Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas
Tae Hyun Hwang - Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas
Yang Xie - Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas
Jaime Rodriguez-Canales - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Pamela Villalobos - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Carmen Behrens - Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Ignacio I Wistuba - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
John D Minna - Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
Kathryn A O'Donnell - Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.77(1), pp.187-197
DOI: 10.1158/0008-5472.CAN-16-1267-T
PMID: 27821484
PMCID: PMC5410365
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: P30 CA142543 / NCI NIH HHS P50 CA070907 / NCI NIH HHS T32 GM008203 / NIGMS NIH HHS U01 CA176284 / NCI NIH HHS
Language: English
Date published: 01/01/2017
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917658002771

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