Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression

Gail L. Matters, John F. Harms, Christopher O. McGovern, Calpurnia Jayakumar, Keisha Crepin, Zachary P. Smith, Melissa C. Nelson, Heather Stock, Craig W. Fenn, James Kaiser, Mark Kester, Jill P. Smith

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

OBJECTIVES: This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer. METHODS: Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors. RESULTS: Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. CONCLUSIONS: These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)e151-e161
JournalPancreas
Volume38
Issue number5
DOIs
StatePublished - Jul 1 2009

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Gastrins
Gene Expression Regulation
Pancreatic Neoplasms
Down-Regulation
Growth
Small Interfering RNA
Neoplasms
Messenger RNA
Transfection
Clone Cells
Peptides
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Nude Mice
Caspase 3
Fluorescent Antibody Technique
Complementary DNA
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

Cite this

Matters, G. L., Harms, J. F., McGovern, C. O., Jayakumar, C., Crepin, K., Smith, Z. P., ... Smith, J. P. (2009). Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas, 38(5), e151-e161. https://doi.org/10.1097/MPA.0b013e3181a66fdc
Matters, Gail L. ; Harms, John F. ; McGovern, Christopher O. ; Jayakumar, Calpurnia ; Crepin, Keisha ; Smith, Zachary P. ; Nelson, Melissa C. ; Stock, Heather ; Fenn, Craig W. ; Kaiser, James ; Kester, Mark ; Smith, Jill P. / Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. In: Pancreas. 2009 ; Vol. 38, No. 5. pp. e151-e161.
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abstract = "OBJECTIVES: This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer. METHODS: Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors. RESULTS: Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90{\%} reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. CONCLUSIONS: These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.",
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Matters, GL, Harms, JF, McGovern, CO, Jayakumar, C, Crepin, K, Smith, ZP, Nelson, MC, Stock, H, Fenn, CW, Kaiser, J, Kester, M & Smith, JP 2009, 'Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression', Pancreas, vol. 38, no. 5, pp. e151-e161. https://doi.org/10.1097/MPA.0b013e3181a66fdc

Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. / Matters, Gail L.; Harms, John F.; McGovern, Christopher O.; Jayakumar, Calpurnia; Crepin, Keisha; Smith, Zachary P.; Nelson, Melissa C.; Stock, Heather; Fenn, Craig W.; Kaiser, James; Kester, Mark; Smith, Jill P.

In: Pancreas, Vol. 38, No. 5, 01.07.2009, p. e151-e161.

Research output: Contribution to journalArticle

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T1 - Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression

AU - Matters, Gail L.

AU - Harms, John F.

AU - McGovern, Christopher O.

AU - Jayakumar, Calpurnia

AU - Crepin, Keisha

AU - Smith, Zachary P.

AU - Nelson, Melissa C.

AU - Stock, Heather

AU - Fenn, Craig W.

AU - Kaiser, James

AU - Kester, Mark

AU - Smith, Jill P.

PY - 2009/7/1

Y1 - 2009/7/1

N2 - OBJECTIVES: This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer. METHODS: Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors. RESULTS: Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. CONCLUSIONS: These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.

AB - OBJECTIVES: This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer. METHODS: Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors. RESULTS: Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. CONCLUSIONS: These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.

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