Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A

Jason W. Hoskins, Jinping Jia, Marta Flandez, Hemang Parikh, Wenming Xiao, Irene Collins, Mickey A. Emmanuel, Abdisamad Ibrahim, John Powell, Lizhi Zhang, Nuria Malats, William R. Bamlet, Gloria M Petersen, Francisco X. Real, Laufey T. Amundadottir

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

Original languageEnglish (US)
Pages (from-to)2670-2678
Number of pages9
JournalCarcinogenesis
Volume35
Issue number12
DOIs
StatePublished - Dec 1 2014

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Gene Expression Profiling
Pancreatic Neoplasms
Clone Cells
Neoplasms
G1 Phase Cell Cycle Checkpoints
RNA Sequence Analysis
Gene Expression
Cell Line
cdc Genes
Gene Regulatory Networks
Epigenomics
Genes
Pancreas
Carcinogenesis
Adenocarcinoma
Homeostasis
Down-Regulation
Apoptosis
Messenger RNA
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hoskins, J. W., Jia, J., Flandez, M., Parikh, H., Xiao, W., Collins, I., ... Amundadottir, L. T. (2014). Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis, 35(12), 2670-2678. https://doi.org/10.1093/carcin/bgu193

Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. / Hoskins, Jason W.; Jia, Jinping; Flandez, Marta; Parikh, Hemang; Xiao, Wenming; Collins, Irene; Emmanuel, Mickey A.; Ibrahim, Abdisamad; Powell, John; Zhang, Lizhi; Malats, Nuria; Bamlet, William R.; Petersen, Gloria M; Real, Francisco X.; Amundadottir, Laufey T.

In: Carcinogenesis, Vol. 35, No. 12, 01.12.2014, p. 2670-2678.

Research output: Contribution to journalArticle

Hoskins, JW, Jia, J, Flandez, M, Parikh, H, Xiao, W, Collins, I, Emmanuel, MA, Ibrahim, A, Powell, J, Zhang, L, Malats, N, Bamlet, WR, Petersen, GM, Real, FX & Amundadottir, LT 2014, 'Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A', Carcinogenesis, vol. 35, no. 12, pp. 2670-2678. https://doi.org/10.1093/carcin/bgu193
Hoskins JW, Jia J, Flandez M, Parikh H, Xiao W, Collins I et al. Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis. 2014 Dec 1;35(12):2670-2678. https://doi.org/10.1093/carcin/bgu193
Hoskins, Jason W. ; Jia, Jinping ; Flandez, Marta ; Parikh, Hemang ; Xiao, Wenming ; Collins, Irene ; Emmanuel, Mickey A. ; Ibrahim, Abdisamad ; Powell, John ; Zhang, Lizhi ; Malats, Nuria ; Bamlet, William R. ; Petersen, Gloria M ; Real, Francisco X. ; Amundadottir, Laufey T. / Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. In: Carcinogenesis. 2014 ; Vol. 35, No. 12. pp. 2670-2678.
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