Pathobiological implications of MUC4 in non-small-cell lung cancer.
BACKGROUND
Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC).


METHODS
We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated.


RESULTS
MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042).


CONCLUSIONS
MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Prabin Dhangada
PD
Majhi
Imayavaramban
I
Lakshmanan
Moorthy P
MP
Ponnusamy
Maneesh
M
Jain
Srustidhar
S
Das
Sukhwinder
S
Kaur
Su Tomohiro
ST
Shimizu
William W
WW
West
Sonny L
SL
Johansson
Lynette M
LM
Smith
Fang
F
Yu
Cleo E
CE
Rolle
Poonam
P
Sharma
George B
GB
Carey
Surinder K
SK
Batra
Apar Kishor
AK
Ganti
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D055264:Mucin-4 / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D015996:Survival Rate; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; C524658:MUC4 protein, human; D055264:Mucin-4; D012333:RNA, Messenger