Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Kayed, Hany; Kleeff, Jörg; Keleg, Shereen; Guo, Junchau; Ketterer, Knut; Berberat, Pascal O.; Giese, Nathalia A.; Espósito, Irene; Giese, Thomas; Büchler, Markus W.; Frieß, Helmut

doi:10.1002/ijc.20194

Cited by 99 publications

(95 citation statements)

References 43 publications

(47 reference statements)

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“…IHH is significantly upregulated in primary pancreatic cancer (56). CpG hyper-methylation of HHIP1 promoter was detected in 13 out of 17 pancreatic cancer cell lines, and in 35 out of 75 primary pancreatic cancer (50).…”

Section: Hedgehog Signaling In Gastrointestinal Cancermentioning

confidence: 96%

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

Katoh¹,

Katoh²

2006

Int J Mol Med

125

164

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Section: Hedgehog Signaling In Gastrointestinal Cancermentioning

confidence: 96%

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

Katoh¹,

Katoh²

2006

Int J Mol Med

125

164

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“…Real-time PCR was performed using the LightCycler FastStart DNA SYBR Green kit. The number of specific transcripts was normalised to housekeeping genes (cyclophilin B and HPRT) and presented as adjusted transcripts/ml cDNA, as described previously (Kayed et al, 2004).…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

“…For induction experiments, cells were seeded in 10 cm cell culture plates in 10% FCS growth medium and allowed to attach for 12 h. Growth medium was replaced by serumreduced medium (1% FCS), and supplemented with recombinant TGF-b1 (500 pM), BMP2 (100 ng ml À1 ), FGF2 (10 ng ml À1 ), Shh (500 ng ml À1 ), Ihh (500 ng ml À1 ) (R&D Systems GmbH) and TNF-a (100 ng ml À1 ) (Promega Biosciences Inc., Mannheim, Germany) for 48 h. The doses were determined to ensure the efficacy and absent toxicity of each factor (Nakamura et al, 1997;Kleeff et al, 2000;Li et al, 2003;Kayed et al, 2004;Guo et al, 2006). Afterwards, cell culture supernatants, cell lysates, and mRNA were isolated as described.…”

Section: Cell Culturementioning

confidence: 99%

“…In addition, a number of growth factors that have the potential to regulate Runx2 expression also play a role in pancreatic carcinogenesis, such as TGF-b1 (Friess et al, 1993a, b;Yamanaka et al, 1993), BMP2 (Kleeff et al, 1999), and IHH (Kayed et al, 2004). Therefore, in the present study the localisation, transcriptional activity, and regulation of Runx2 expression in human pancreatic ductal adenocarcinoma (PDAC) was analysed.…”

mentioning

confidence: 93%

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Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

et al. 2007

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Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-b1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (Po0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-b1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-b1 and BMP2 in an auto-and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment.

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“…16,17 Immunohistochemistry. Paraffin-embedded tissue sections (2-3 mm thick) were immunostained using the DAKO Envision TM+ system (DAKO Corporation, Carpinteria, CA).…”

confidence: 99%

Basic transcription factor 3 (BTF3) regulates transcription of tumor-associated genes in pancreatic cancer cells

Kusumawidjaja

Kayed

Giese

et al. 2007

Cancer Biology & Therapy

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Basic transcription factor 3 (BTF3) acts as a transcription factor and modulator of apoptosis, and is differentially expressed in colorectal cancer and glioblastomas. In the present study, the expression of BTF3, as well as its role in apoptosis and gene transcription, was analyzed in pancreatic ductal adenocarcinoma (PDAC). QRT-PCR, immunohistochemistry, immunoblotting, and immunofluorescence analyses were carried out to investigate BTF3 mRNA/protein expression and localization. BTF3 silencing in pancreatic cancer cells was performed using specific siRNA molecules. Functional analyses were carried out using cell growth assays, apoptosis assays, and DNA array analysis. BTF3 and BTF3a exhibited 1.3-fold and 4.6-fold increased median mRNA levels in PDAC tissues, compared to normal pancreatic tissues. BTF3 localized mainly in the cytoplasm and nuclei of tubular complexes and pancreatic cancer cells. Pancreatic cancer cell lines expressed the mRNA and protein of BTF3a (27 kDa) and BTF3b (22 kDa) isoforms. BTF3 silencing using specific siRNA molecules did not influence apoptosis induced by chemotherapy or radiotherapy. In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFk-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.

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Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Cited by 99 publications

References 43 publications

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

Basic transcription factor 3 (BTF3) regulates transcription of tumor-associated genes in pancreatic cancer cells

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