TY - JOUR
T1 - MUC4 mucin-induced epithelial to mesenchymal transition
T2 - A novel mechanism for metastasis of human ovarian cancer cells
AU - Ponnusamy, M. P.
AU - Lakshmanan, I.
AU - Jain, M.
AU - Das, S.
AU - Chakraborty, S.
AU - Dey, P.
AU - Batra, S. K.
N1 - Funding Information:
This work are supported by the grants from the National Institutes of Health (CA78590, CA111294, CA127297, CA133774 and CA131944), Department of Defense (BC074639) and the Susan G Komen Foundation (KG070826). We thank Ms Kristi L Berger for editing the paper. The authors acknowledge the invaluable technical support from Mr Erik Moore and Mrs Kavita Mallya. We also thank Janice A Tayor and James R Talaska of the confocal laser scanning microscope core facility at the UNMC for their support.
PY - 2010/10/21
Y1 - 2010/10/21
N2 - The acquisition of invasiveness in ovarian cancer (OC) is accompanied by the process of epithelial-to-mesenchymal transition (EMT). The MUC4 mucin is overexpressed in ovarian tumors and has a role in the invasiveness of OC cells. The present study was aimed at evaluating the potential involvement of MUC4 in the metastasis of OC cells by inducing EMT. Ectopic overexpression of MUC4 in OC cells (SKOV3-MUC4) resulted in morphological alterations along with a decreased expression of epithelial markers (E-cadherin and cytokeratin (CK)-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) compared with the control cells (SKOV3-vector). Also, pro-EMT transcription factors TWIST1, TWIST2 and SNAIL showed an upregulation in SKOV3-MUC4 cells. We further investigated the pathways upstream of N-cadherin, such as focal adhesion kinase (FAK), MKK7, JNK1/2 and c-Jun, which were also activated in the SKOV3-MUC4 cells compared with SKOV3-vector cells. Inhibition of phospho-FAK (pFAK) and pJNK1/2 decreased N-cadherin expression in the MUC4-overexpressing cells, which further led to a significant decrease in cellular motility. Knockdown of N-cadherin decreased the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), AKT and matrix metalloproteinase 9 (MMP9), and inhibited the motility in the SKOV3-MUC4 cells. Upon in vivo tumorigenesis and metastasis analysis, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distance organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm). Taken together, our study reveals a novel role for MUC4 in inducing EMT through the upregulation of N-cadherin and promoting metastasis of OC cells.
AB - The acquisition of invasiveness in ovarian cancer (OC) is accompanied by the process of epithelial-to-mesenchymal transition (EMT). The MUC4 mucin is overexpressed in ovarian tumors and has a role in the invasiveness of OC cells. The present study was aimed at evaluating the potential involvement of MUC4 in the metastasis of OC cells by inducing EMT. Ectopic overexpression of MUC4 in OC cells (SKOV3-MUC4) resulted in morphological alterations along with a decreased expression of epithelial markers (E-cadherin and cytokeratin (CK)-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) compared with the control cells (SKOV3-vector). Also, pro-EMT transcription factors TWIST1, TWIST2 and SNAIL showed an upregulation in SKOV3-MUC4 cells. We further investigated the pathways upstream of N-cadherin, such as focal adhesion kinase (FAK), MKK7, JNK1/2 and c-Jun, which were also activated in the SKOV3-MUC4 cells compared with SKOV3-vector cells. Inhibition of phospho-FAK (pFAK) and pJNK1/2 decreased N-cadherin expression in the MUC4-overexpressing cells, which further led to a significant decrease in cellular motility. Knockdown of N-cadherin decreased the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), AKT and matrix metalloproteinase 9 (MMP9), and inhibited the motility in the SKOV3-MUC4 cells. Upon in vivo tumorigenesis and metastasis analysis, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distance organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm). Taken together, our study reveals a novel role for MUC4 in inducing EMT through the upregulation of N-cadherin and promoting metastasis of OC cells.
KW - E-cadherin
KW - EMT
KW - MUC4
KW - N-cadherin
KW - metastasis and ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=77958451128&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77958451128&partnerID=8YFLogxK
U2 - 10.1038/onc.2010.309
DO - 10.1038/onc.2010.309
M3 - Article
C2 - 20697346
AN - SCOPUS:77958451128
SN - 0950-9232
VL - 29
SP - 5741
EP - 5754
JO - Oncogene
JF - Oncogene
IS - 42
ER -