Hepatocyte nuclear factor 1 alpha influences pancreatic cancer growth and metastasis

Abstract

Hepatocyte nuclear factor 1 homeobox alpha (HNF1α) is a transcription factor involved in endodermal organogenesis and pancreatic precursor cell differentiation and development. Earlier studies have reported a role for HNF1α in pancreatic ductal adenocarcinoma (PDAC) but it is controversial. The mechanism by which it impacts PDAC is yet to be explored in depth. In this study, using the online databases we observed that HNF1α is upregulated in PDAC, which was also confirmed by our immunohistochemical analysis of PDAC tissue microarray. Silencing HNF1α reduced the proliferative, migratory, invasive and colony forming capabilities of pancreatic cancer cells. Key markers involved in these processes (pPI3K, pAKT, pERK, Bcl2, Zeb, Snail, Slug) were significantly changed in response to alterations in HNF1α expression. On the other hand, overexpression of HNF1α did not induce any significant change in the aggressiveness of pancreatic cancer cells. Our results demonstrate that reduced expression of HNF1α leads to inhibition of pancreatic cancer growth and progression, which indicates that it could be a potential oncogene and target for PDAC.

SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner

“…During the development of pancreas, SOX9 plays a key role as one of the transcription factors whose coordinated interactions in early precursor cells drive the pancreatic organogenesis process [ 19 ]. Some developmental transcription factors are differentially expressed in pancreatic tumors as well, and they take part in the formation of unique tumor phenotypes [ 34 , 35 , 36 , 37 ]. Therefore, we performed Western blot analysis of the HNF1A, GATA4, GATA6, FOXA1, and FOXA2 proteins in pancreatic cancer cell lines with downregulated SOX9 expression for the purpose of investigating the potential functional link between SOX9 and the expression of these protein master regulators of pancreatic development ( Figure 2 G,H and Figure S3G ).…”

Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis

“…Immunofluorescence was performed as described earlier [30,31]. In brief, HPAC cells were transfected with either SOD2 siRNA (siSOD2) or SOD2 plasmid DNA (ov-SOD2).…”

“…A portion of each of the tissues was fixed in 10% formalin for histopathological analysis and immunohistochemistry. The remainder of the tissue sample was flash-frozen in liquid nitrogen to be used for molecular analysis [29,31].…”

Deregulation of Transcription Factor Networks Driving Cell Plasticity and Metastasis in Pancreatic Cancer

“…HNF1α downregulates apoptosis inhibitors and modulates the expression of cell cycle genes. However, whether HNF1α acts through the AKT/mTOR pathway requires additional investigation, since silencing of HNF1A activates AKT/mTOR signaling, but may also result in reduced expression of PI3K, AKT and mTOR ( Hoskins et al, 2014 ; Luo et al, 2015 ; Subramani et al, 2020 ). Other studies indicate that HNF1A is an oncogene necessary for the regulation of cancer stem cell (CSC) populations in PDAC, promotes anchorage-independent growth, proliferation, as well as invasive and migratory capacities ( Abel et al, 2018 ; Subramani et al, 2020 ).…”

“…However, whether HNF1α acts through the AKT/mTOR pathway requires additional investigation, since silencing of HNF1A activates AKT/mTOR signaling, but may also result in reduced expression of PI3K, AKT and mTOR ( Hoskins et al, 2014 ; Luo et al, 2015 ; Subramani et al, 2020 ). Other studies indicate that HNF1A is an oncogene necessary for the regulation of cancer stem cell (CSC) populations in PDAC, promotes anchorage-independent growth, proliferation, as well as invasive and migratory capacities ( Abel et al, 2018 ; Subramani et al, 2020 ). These contradictory findings could be explained by the hypothesis that cellular plasticity and thus the ability to induce partial-EMT is indeed necessary to acquire stemness, whereas reversal to an epithelial phenotype is crucial for metastatic outgrowth at secondary sites.…”