Pancreatic Ductal Deletion of Hnf1b Disrupts Exocrine Homeostasis, Leads to Pancreatitis, and Facilitates Tumorigenesis

Quilichini, Evans; Fabre, Mélanie; Dirami, Thassadite; Stedman, Aline; Vas, Matías De; Ozguc, Ozge; Pasek, Raymond C.; Cereghini, Silvia; Morillon, Lucie; Guerra, Carmen; Couvelard, Anne; Gannon, Maureen; Haumaitre, Cécile

doi:10.1016/j.jcmgh.2019.06.005

Cited by 29 publications

(40 citation statements)

References 82 publications

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“…74 Inactivation of HNF1B by Cre-Sox9 recombination was found to cause chronic pancreatitis with dilation of ducts, acinar-to-ductal metaplasia and lipomatosis. 75 Inactivated HNF1B in mouse ductal cells was seen to decrease the expression of Prox1, Pkhd1, Spp1 and Cys1, which play an important role in maintaining tubule structure. This led to chronic pancreatitis and formation of neoplasia through KRAS activation in mature acinar cells.…”

Section: Hnf1b Interactions and Target Genesmentioning

confidence: 97%

Hepatocyte nuclear factor 1 beta: A perspective in cancer

2021

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Hepatocyte nuclear factors (HNFs) exist as an assembly of transcription factors that have a vital role in the expression regulation of genes pertaining to the liver. 1 Conversely, these transcription factors are not restricted to hepatocytes, their expression has been observed in other tissues. 2 There are four major families of HNFs namely HNF1, HNF3, HNF4 and HNF6. The HNF1 family members; HNF1-α/A and HNF-1β/B comprise a POU-homeodomain and bind to DNA as homodimers or heterodimers. 3 Hepatocyte nuclear factor 1B (HNF1B, TCF2) located on chromosome 17q12, 4 belongs to the family of Pit-1, Oct-1/2, UNC-86 (POU) homeodomain-comprising transcription factors (Figure 1). The POU domain is bipartite (POU H and POU S) and is comprised of two subunits separated by a short 15-55 amino acid (aa) non-conserved region. The protein contains three predominant functional

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Section: Hnf1b Interactions and Target Genesmentioning

confidence: 97%

Hepatocyte nuclear factor 1 beta: A perspective in cancer

2021

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“…In the exocrine pancreas, one regulatory module, containing NR5A2, was shared between acinar and ductal cells, although with a tendency for increased regulon activity in ductal cells (Figure 2D/H) . Other exocrine regulons included ONECUT1, REST and HNF1B with reported roles in exocrine development (Nissim et al , 2016; Kropp, Zhu and Gannon, 2019) and the adult exocrine pancreas (Quilichini et al , 2019; Bray et al , 2020) (Figure 2D) . In summary, this analysis confirms the expected separation of exocrine and endocrine cells with distinct gene regulatory programs, and identifies known and novel candidate regulators of pancreas cell states.…”

Section: Resultsmentioning

confidence: 93%

“…Top ranked regulons in ductal cells included well known regulators of ductal and exocrine cell identity such as POU2F3, NR5A2 and HNF1B (Nissim et al , 2016; Yamashita et al , 2017; Quilichini et al , 2019) (Figure 3E/F) . In addition, we observed CDX2 and PPARD as highly specific ductal regulons (Figure 3F/G) .…”

Section: Resultsmentioning

confidence: 99%

Predicting the Key Regulators of Cell Identity in Human Adult Pancreas

Vanheer¹,

Schiavo

Haele

et al. 2020

Preprint

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SUMMARYCellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology.HIGHLIGHTS-Reconstruction of gene regulatory networks for human adult pancreatic cell types-An interactive resource to explore and visualize gene expression and regulatory states-Predicting putative transcription factors driving pancreatic cell identity-HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively

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“…HNF1B is a member of the HNF family, participates in regulating the metabolism of lipids, carbohydrates and proteins, and plays an important role in regulating hepatocyte differentiation and liver development 20 . Recent studies have shown that HNF1B has a significant correlation with the occurrence and development of various tumors, such as prostate cancer and pancreatic cancer 21 , 22 . In this study, we found that the expression of HNF1B was upregulated at different levels in BLCA, CHOL, KIRP, LIHC, STAD, THCA, and UCEC and downregulated in COAD, GBM, KICH, KIRC, and LUSC.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of HNF1B mRNA in Human Cancers Based on Data Mining

Nie¹,

Wang²,

Wang³

et al. 2020

Int. J. Med. Sci.

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Cancer incidence is rapidly growing, and cancer is the leading cause of death worldwide in the 21st century. Hepatocyte nuclear factor 1B (HNF1B) is a transcription factor that involves the growth and development of multiple organs. The aim of this study was to explore the significance of HNF1B in human cancer by an integrative analysis of online databases. The UALCAN database, cBio cancer genomics portal, Cancer Regulome tools, Kaplan-Meier plotter and Tumor IMmune Estimation Resource (TIMER) website were used to perform the corresponding analysis. The results showed that HNF1B is dysregulated in various cancers and associated with the differential overall survival of cancer patients. HNF1B showed many mutation forms and high mutation levels in different cancer types. In addition, we found that HNF1B interacted with different genes in multiple aspects. Moreover, HNF1B expression is associated with many immune cell infiltration levels and influences the prognostic prediction of immune cells in some kinds of cancers. In conclusion, HNF1B plays a significant role in cancer and may be a potential target for cancer immunotherapy.

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Pancreatic Ductal Deletion of Hnf1b Disrupts Exocrine Homeostasis, Leads to Pancreatitis, and Facilitates Tumorigenesis

Abstract: This study shows how Hnf1b inactivation in pancreatic ductal cells leads to chronic pancreatitis, neoplasia, and potentiates pancreatic intraepithelial neoplasia formation. This shows a cause of pancreatitis and identifies Hnf1b as a potential tumor suppressor for pancreatic cancer.

Cited by 29 publications

References 82 publications

Hepatocyte nuclear factor 1 beta: A perspective in cancer

Hepatocyte nuclear factor 1 beta: A perspective in cancer

Predicting the Key Regulators of Cell Identity in Human Adult Pancreas

Integrative Analysis of HNF1B mRNA in Human Cancers Based on Data Mining

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