p63-Mediated activation of the β-catenin/c-Myc signaling pathway stimulates esophageal squamous carcinoma cell invasion and metastasis

Kwang Bok Lee; Shuai Ye; Man Hee Park; Byung Hyun Park; Ju-Seog Lee; Soo Mi Kim

doi:10.1016/j.canlet.2014.07.016

p63-Mediated activation of the β-catenin/c-Myc signaling pathway stimulates esophageal squamous carcinoma cell invasion and metastasis

Cancer Lett. 2014 Oct 10;353(1):124-32. doi: 10.1016/j.canlet.2014.07.016. Epub 2014 Jul 18.

Authors

Kwang Bok Lee¹, Shuai Ye¹, Man Hee Park², Byung Hyun Park³, Ju-Seog Lee⁴, Soo Mi Kim⁵

Affiliations

¹ Department of Orthopedic Surgery, Chonbuk National University Medical School and Hospital, Jeonju 561-181, Republic of Korea.
² Catholic University of Pusan, Busan 609-757, Republic of Korea.
³ Department of Biochemistry, Chonbuk National University Medical School, Jeonju 561-181, Republic of Korea.
⁴ Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
⁵ Department of Physiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 561-181, Republic of Korea. Electronic address: soomikim@jbnu.ac.kr.

PMID: 25045846
DOI: 10.1016/j.canlet.2014.07.016

Abstract

The development of esophageal squamous carcinomas (ESC) results from numerous genetic alterations. Our previous study demonstrated that p63 is highly expressed in human ESC cells and stimulates their growth; however, the mechanism by which p63 regulates ESC cell adhesion and invasion remains unclear. In the present study, we further elucidated the underlying molecular mechanisms by which p63 regulates metastasis in ESC cells. Knockdown of p63 significantly diminished the invasion of ESC cell lines TE-8 and TE-12, whereas overexpression of p63 significantly increased the migration rates of BE3 and OE33 cells. The mRNA and protein levels of vimentin, twist, SUSD2, and uPA were significantly decreased in p63-knockdown ESC cells, while overexpression of p63 induced an increase in vimentin, SUSD2, and uPA. In addition, knockdown of p63 in ESC cells significantly reduced levels of β-catenin and c-Myc, while overexpression of p63 increased β-catenin, but reduced p-β-catenin level. Therefore, p63 regulates the migration and invasion of ESC cells through activation of the β-catenin/c-Myc pathway. Our results suggest that targeting p63 may constitute a potential therapeutic strategy for ESC.

Keywords: Esophageal squamous carcinoma cell; Twist; c-Myc; p63; β-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology
Cell Line, Tumor
Cell Movement*
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / pathology
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Neoplasm Invasiveness
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism*
RNA Interference
RNA, Messenger / metabolism
Signal Transduction*
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
Urokinase-Type Plasminogen Activator / genetics
Urokinase-Type Plasminogen Activator / metabolism
Vimentin / genetics
Vimentin / metabolism
beta Catenin / genetics
beta Catenin / metabolism*

Substances

CTNNB1 protein, human
MYC protein, human
Membrane Glycoproteins
Nuclear Proteins
Proto-Oncogene Proteins c-myc
RNA, Messenger
SUSD2 protein, human
TP63 protein, human
TWIST1 protein, human
Transcription Factors
Tumor Suppressor Proteins
Twist-Related Protein 1
Vimentin
beta Catenin
Urokinase-Type Plasminogen Activator