Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: Potential implications for diagnosis and therapy

Satyanarayana Rachagani, María P. Torres, Sushil Kumar, Dhanya Haridas, Michael Baine, Muzafar A Macha, Sukwinder Kaur, Moorthy Palanimuthu Ponnusamy, Parama Dey, Parthasarathy Seshacharyulu, Sonny L. Johansson, Maneesh Jain, Kay Uwe Wagner, Surinder Kumar Batra

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods. In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (KrasG12D;Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. Results: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN- (p<0.0062), CXCL1 (p<0.00014) and CXCL2 (p<0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. Conclusions: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.

Original languageEnglish (US)
Article number68
JournalJournal of Hematology and Oncology
Volume5
DOIs
StatePublished - Oct 30 2012

Fingerprint

Mucins
Pancreatic Neoplasms
Therapeutics
Pancreas
Neoplasms
Adenocarcinoma
Mucin-1
Knockout Mice
Real-Time Polymerase Chain Reaction
Immunohistochemistry
Macrophages
Cytokines
Neoplasm Metastasis
Inflammation
Messenger RNA
Mutation

Keywords

  • Inflammatory cytokines
  • Kras mouse model
  • Mucins

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

Cite this

Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model : Potential implications for diagnosis and therapy. / Rachagani, Satyanarayana; Torres, María P.; Kumar, Sushil; Haridas, Dhanya; Baine, Michael; Macha, Muzafar A; Kaur, Sukwinder; Palanimuthu Ponnusamy, Moorthy; Dey, Parama; Seshacharyulu, Parthasarathy; Johansson, Sonny L.; Jain, Maneesh; Wagner, Kay Uwe; Batra, Surinder Kumar.

In: Journal of Hematology and Oncology, Vol. 5, 68, 30.10.2012.

Research output: Contribution to journalArticle

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abstract = "Background: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods. In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (KrasG12D;Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. Results: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN- (p<0.0062), CXCL1 (p<0.00014) and CXCL2 (p<0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. Conclusions: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.",
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T2 - Potential implications for diagnosis and therapy

AU - Rachagani, Satyanarayana

AU - Torres, María P.

AU - Kumar, Sushil

AU - Haridas, Dhanya

AU - Baine, Michael

AU - Macha, Muzafar A

AU - Kaur, Sukwinder

AU - Palanimuthu Ponnusamy, Moorthy

AU - Dey, Parama

AU - Seshacharyulu, Parthasarathy

AU - Johansson, Sonny L.

AU - Jain, Maneesh

AU - Wagner, Kay Uwe

AU - Batra, Surinder Kumar

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N2 - Background: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods. In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (KrasG12D;Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. Results: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN- (p<0.0062), CXCL1 (p<0.00014) and CXCL2 (p<0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. Conclusions: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.

AB - Background: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods. In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (KrasG12D;Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. Results: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN- (p<0.0062), CXCL1 (p<0.00014) and CXCL2 (p<0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. Conclusions: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.

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