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Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation

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...

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Autores principales: Momi, Navneet, Ponnusamy, Moorthy P., Kaur, Sukhwinder, Rachagani, Satyanarayana, Kunigal, Sateesh S, Chellappan, Srikumar, Ouellette, Michel M, Batra, Surinder K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427417/
https://www.ncbi.nlm.nih.gov/pubmed/22614008
http://dx.doi.org/10.1038/onc.2012.163
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author Momi, Navneet
Ponnusamy, Moorthy P.
Kaur, Sukhwinder
Rachagani, Satyanarayana
Kunigal, Sateesh S
Chellappan, Srikumar
Ouellette, Michel M
Batra, Surinder K
author_facet Momi, Navneet
Ponnusamy, Moorthy P.
Kaur, Sukhwinder
Rachagani, Satyanarayana
Kunigal, Sateesh S
Chellappan, Srikumar
Ouellette, Michel M
Batra, Surinder K
author_sort Momi, Navneet
collection PubMed
description 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 to 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 (CSE) and nicotine, which is the major component of CS, significantly up-regulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via 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. Additionally, we demonstrated that nicotine-mediated MUC4 up-regulation 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 demonstrated a dramatic increase in the mean pancreatic tumor weight [low-dose (100 mg/m(3) 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 to 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 up-regulates the MUC4 mucin in PC via α7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of pancreatic cancer.
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spelling pubmed-34274172013-09-14 Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation Momi, Navneet Ponnusamy, Moorthy P. Kaur, Sukhwinder Rachagani, Satyanarayana Kunigal, Sateesh S Chellappan, Srikumar Ouellette, Michel M Batra, Surinder K Oncogene Article 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 to 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 (CSE) and nicotine, which is the major component of CS, significantly up-regulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via 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. Additionally, we demonstrated that nicotine-mediated MUC4 up-regulation 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 demonstrated a dramatic increase in the mean pancreatic tumor weight [low-dose (100 mg/m(3) 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 to 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 up-regulates the MUC4 mucin in PC via α7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of pancreatic cancer. 2012-05-21 2013-03-14 /pmc/articles/PMC3427417/ /pubmed/22614008 http://dx.doi.org/10.1038/onc.2012.163 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Momi, Navneet
Ponnusamy, Moorthy P.
Kaur, Sukhwinder
Rachagani, Satyanarayana
Kunigal, Sateesh S
Chellappan, Srikumar
Ouellette, Michel M
Batra, Surinder K
Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title_full Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title_fullStr Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title_full_unstemmed Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title_short Nicotine/Cigarette-smoke Promotes Metastasis of Pancreatic Cancer Through α7nAChR-mediated MUC4 Up-regulation
title_sort nicotine/cigarette-smoke promotes metastasis of pancreatic cancer through α7nachr-mediated muc4 up-regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427417/
https://www.ncbi.nlm.nih.gov/pubmed/22614008
http://dx.doi.org/10.1038/onc.2012.163
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