TY - JOUR
T1 - Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7nAChR-mediated MUC4 upregulation
AU - Momi, N.
AU - Ponnusamy, M. P.
AU - Kaur, S.
AU - Rachagani, S.
AU - Kunigal, S. S.
AU - Chellappan, S.
AU - Ouellette, M. M.
AU - Batra, S. K.
N1 - Funding Information:
We thank Ms Kristi L Berger for editing the manuscript. We acknowledge the invaluable technical support from Mr Erik Moore and Mrs Kavita Mallya. We also thank Janice A Tayor and James R Talaska, the members of the confocal laser scanning microscope core facility at UNMC, for their support. This work was, in part, supported by grants from the National Institutes of Health (RO1 CA133774,RO1 CA131944, RO1 CA78590, UO1 CA111294, P50 CA127297 and U54 CA163120).
PY - 2013/3/14
Y1 - 2013/3/14
N2 - Despite evidence that long-term smoking is the leading risk factor for pancreatic malignancies, the underlying mechanism(s) for cigarette-smoke (CS)-induced pancreatic cancer (PC) pathogenesis has not been well established. Our previous studies revealed an aberrant expression of the MUC4 mucin in PC as compared with the normal pancreas, and its association with cancer progression and metastasis. Interestingly, here we explore a potential link between MUC4 expression and smoking-mediated PC pathogenesis and report that both cigarette smoke extract and nicotine, which is the major component of CS, significantly upregulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via the α7 subunit of nicotinic acetylcholine receptor (nAChR) stimulation and subsequent activation of the JAK2/STAT3 downstream signaling cascade in cooperation with the MEK/ERK1/2 pathway; this effect was blocked by the α7nAChR antagonists, α-bungarotoxin and mecamylamine, and by specific siRNA-mediated STAT3 inhibition. In addition, we demonstrated that nicotine-mediated MUC4 upregulation promotes the PC cell migration through the activation of the downstream effectors, such as HER2, c-Src and FAK; this effect was attenuated by shRNA-mediated MUC4 abrogation, further implying that these nicotine-mediated pathological effects on PC cells are MUC4 dependent. Furthermore, the in vivo studies showed a marked increase in the mean pancreatic tumor weight (low dose (100 mg/m 3 total suspended particulate (TSP)), P=0.014; high dose (247 mg/m 3 TSP), P=0.02) and significant tumor metastasis to various distant organs in the CS-exposed mice, orthotopically implanted with luciferase-transfected PC cells, as compared with the sham controls. Moreover, the CS-exposed mice had elevated levels of serum cotinine (low dose, 155.88±35.96 ng/ml; high dose, 216.25±29.95 ng/ml) and increased MUC4, α7nAChR and pSTAT3 expression in the pancreatic tumor tissues. Altogether, our findings revealed for the first time that CS upregulates the MUC4 mucin in PC via the α7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of PC.
AB - Despite evidence that long-term smoking is the leading risk factor for pancreatic malignancies, the underlying mechanism(s) for cigarette-smoke (CS)-induced pancreatic cancer (PC) pathogenesis has not been well established. Our previous studies revealed an aberrant expression of the MUC4 mucin in PC as compared with the normal pancreas, and its association with cancer progression and metastasis. Interestingly, here we explore a potential link between MUC4 expression and smoking-mediated PC pathogenesis and report that both cigarette smoke extract and nicotine, which is the major component of CS, significantly upregulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via the α7 subunit of nicotinic acetylcholine receptor (nAChR) stimulation and subsequent activation of the JAK2/STAT3 downstream signaling cascade in cooperation with the MEK/ERK1/2 pathway; this effect was blocked by the α7nAChR antagonists, α-bungarotoxin and mecamylamine, and by specific siRNA-mediated STAT3 inhibition. In addition, we demonstrated that nicotine-mediated MUC4 upregulation promotes the PC cell migration through the activation of the downstream effectors, such as HER2, c-Src and FAK; this effect was attenuated by shRNA-mediated MUC4 abrogation, further implying that these nicotine-mediated pathological effects on PC cells are MUC4 dependent. Furthermore, the in vivo studies showed a marked increase in the mean pancreatic tumor weight (low dose (100 mg/m 3 total suspended particulate (TSP)), P=0.014; high dose (247 mg/m 3 TSP), P=0.02) and significant tumor metastasis to various distant organs in the CS-exposed mice, orthotopically implanted with luciferase-transfected PC cells, as compared with the sham controls. Moreover, the CS-exposed mice had elevated levels of serum cotinine (low dose, 155.88±35.96 ng/ml; high dose, 216.25±29.95 ng/ml) and increased MUC4, α7nAChR and pSTAT3 expression in the pancreatic tumor tissues. Altogether, our findings revealed for the first time that CS upregulates the MUC4 mucin in PC via the α7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of PC.
KW - MUC4
KW - cigarette smoke
KW - metastasis and pancreatic cancer
KW - mucin
KW - nicotine
UR - http://www.scopus.com/inward/record.url?scp=84875232362&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875232362&partnerID=8YFLogxK
U2 - 10.1038/onc.2012.163
DO - 10.1038/onc.2012.163
M3 - Article
C2 - 22614008
AN - SCOPUS:84875232362
SN - 0950-9232
VL - 32
SP - 1384
EP - 1395
JO - Oncogene
JF - Oncogene
IS - 11
ER -