CEACAM6 promotes gastric cancer invasion and metastasis by inducing epithelial-mesenchymal transition via PI3K/AKT signaling pathway

Mingde Zang; Baogui Zhang; Yunqiang Zhang; Jianfang Li; Liping Su; Zhenggang Zhu; Qinlong Gu; Bingya Liu; Min Yan

doi:10.1371/journal.pone.0112908

CEACAM6 promotes gastric cancer invasion and metastasis by inducing epithelial-mesenchymal transition via PI3K/AKT signaling pathway

PLoS One. 2014 Nov 14;9(11):e112908. doi: 10.1371/journal.pone.0112908. eCollection 2014.

Authors

Mingde Zang¹, Baogui Zhang¹, Yunqiang Zhang¹, Jianfang Li¹, Liping Su¹, Zhenggang Zhu¹, Qinlong Gu¹, Bingya Liu¹, Min Yan¹

Affiliation

¹ Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Abstract

Overexpressed CEACAM6 in tumor tissues plays important roles in invasion, metastasis and anoikis resistance in a variety of human cancers. We recently reported that CEACAM6 expression is upregulated in Gastric cancer (GC) tissues and promoted GC metastasis. Here, we report that CEACAM6 promotes peritoneal metastases in vivo and is negatively correlated with E-cadherin expression in GC tissues. Overexpressed CEACAM6 induced epithelial-mesenchymal transition (EMT) in GC, as measured by increases in the EMT markers N-cadherin, Vimentin and Slug while E-cadherin expression was decreased in CEACAM6-overexpressing GC cells; opposing results were observed in CEACAM6-silenced cells. Furthermore, E-cadherin expression was negatively correlated with depth of tumor invasion, lymph node metastasis and TNM stage in GC tissues. Additionally, CEACAM6 elevated matrix metalloproteinase-9 (MMP-9) activity in GC, and anti-MMP-9 antibody could reverse the increasing invasion and migration induced by CEACAM6. CEACAM6 also increased the levels of phosphorylated AKT, which is involved in the progression of a variety of human tumors. We further observed that LY294002, a PI3K inhibitor, could reverse CEACAM6-induced EMT via mesenchymal-epithelial transition. These findings suggest that CEACAM6 enhances invasion and metastasis in GC by promoting EMT via the PI3K/AKT signaling pathway.

Publication types

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

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Antigens, CD / genetics
Antigens, CD / metabolism*
Cadherins / metabolism
Cell Adhesion Molecules / antagonists & inhibitors
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism*
Cell Line, Tumor
Cell Movement
Chromones / pharmacology
Cytoskeleton / metabolism
Epithelial-Mesenchymal Transition / drug effects
Female
GPI-Linked Proteins / antagonists & inhibitors
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Humans
Lymphatic Metastasis
Male
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Morpholines / pharmacology
Neoplasm Invasiveness
Peritoneal Neoplasms / pathology
Peritoneal Neoplasms / secondary
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology*
Vimentin / metabolism

Substances

Antigens, CD
CEACAM6 protein, human
Cadherins
Cell Adhesion Molecules
Chromones
GPI-Linked Proteins
Morpholines
Phosphoinositide-3 Kinase Inhibitors
Vimentin
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Proto-Oncogene Proteins c-akt
Matrix Metalloproteinase 9

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81172324, No. 91229106, No. 81272749, and No. 81372231), and Key Project of Shanghai Education Committee (No. 12ZZ105 and No.12ZZ102) and Science and Technology Commission of Shanghai Municipality (No. 13ZR1425600). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.