<scp>H</scp>edgehog pathway as a potential treatment target in human cholangiocarcinoma

Riedlinger, Dorothee; Bahra, Marcus; Boas-Knoop, Sabine; Lippert, Steffen; Bradtmöller, Maren; Guse, Katrin; Seehofer, Daniel; Bova, Roberta; Sauer, Igor M.; Neuhaus, P.; Koch, Arend; Kamphues, Carsten

doi:10.1002/jhbp.107

Cited by 44 publications

(30 citation statements)

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“…Gli-1/2 translocate to the nucleus, where they bind to the Gli-binding consensus element in target genes resulting in their activation. 11 Overexpression and aberrant activation of Hh signaling molecules have been demonstrated in 50-70% of hepatoblastomas, primary HCC and cholangiocyte carcinomas, 12,13 and the Smo antagonists, cyclopamine and GDC-0449 have been used to block the growth of hepatoma cell-derived xenografts in animal experiments. 12,14 However, no study is available focusing on whether overexpression of Hh molecules or enhancing Hh signaling activity is responsible for the highly metastatic behavior of HCC.…”

Section: Introductionmentioning

confidence: 99%

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

et al. 2015

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Section: Introductionmentioning

confidence: 99%

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

et al. 2015

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“…Hedgehog signaling plays a critical role in growth of digestive tract tumors (Berman et al 2003), and the subsequent reports showed the activation of Hedgehog signaling in hepatocellular carcinoma (Huang et al 2006;Al-Bahrani et al 2015;Dugum et al 2016) and cholangiocarcinoma (Kiesslich et al 2014;Riedlinger et al 2014). In fact, we have shown that GLI1 immunoreactivity was detected in 55% of hepatocellular carcinoma (21/38 specimens) and 86% of cholangiocarcinoma (6/7 specimens) (see Tables 2 and 5).…”

Section: Potential Role Of Hedgehog Signaling For Regulation Of Mitf mentioning

confidence: 54%

“…In the presence of a Hedgehog ligand, Smoothened enhances nuclear translocation of gliomaassociated transcription factors, such as glioma-associated oncogene 1 (GLI1) (Varjosalo and Taipale 2008), thereby mediating the Hedgehog signal. Moreover, GLI1 is expressed in the normal bile duct (Kiesslich et al 2014) and is overexpressed in hepatocellular carcinoma (Dugum et al 2016) and cholangiocarcinoma (Kiesslich et al 2014;Riedlinger et al 2014), suggesting that the Hedgehog signaling pathway may be activated in hepatic cancer cells. Considering the cyclopamine-mediated induction of MITF in hepatic cancer cell lines (Samatiwat et al 2016), we have hypothesized that the Hedgehog signaling may influence MITF expression in the liver.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma

Nooron

Ohba

Takeda

et al. 2017

Tohoku J. Exp. Med.

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Cholangiocarcinoma represents the second most common primary liver tumor after hepatocellular carcinoma. Mahanine, a carbazole alkaloid derived from Murraya koenigii (Linn.) Spreng, has been used as folk medicine in Thailand, where the liver fluke-associated cholangiocarcinoma is common. The expression of microphthalmia-associated transcription factor (MITF) is maintained at immunohistochemically undetectable levels in hepatocytes and cholangiocytes. To explore the regulation of MITF expression in the liver, we immunohistochemically analyzed the MITF expression using hepatocellular carcinoma and cholangiocarcinoma specimens of the human liver cancer tissue array. MITF immunoreactivity was detected in subsets of hepatocellular carcinoma (6 out of 38 specimens; 16%) and cholangiocarcinoma (2/7 specimens; 29%). Moreover, immunoreactivity for glioma-associated oncogene 1 (GLI1), a transcription factor of the Hedgehog signaling pathway, was detected in 55% of hepatocellular carcinoma (21/38 specimens) and 86% of cholangiocarcinoma (6/7 specimens). Importantly, MITF was detectable only in the GLI1-positive hepatocellular carcinoma and cholangiocarcinoma, and MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. Subsequently, the effect of mahanine was analyzed in HepG2 human hepatocellular carcinoma and HuCCT1 and KKU-100 human cholangiocarcinoma cells. Mahanine (25 µM) showed the potent cytotoxicity in these hepatic cancer cell lines, which was associated with increased expression levels of MITF, as judged by Western blot analysis. MITF is overexpressed in subsets of hepatocellular carcinoma and cholangiocarcinoma, and detectable MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. MITF expression levels may be determined in hepatic cancer cells by the balance between the Hedgehog signaling and the cellular stress.

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“…45 The hedgehog pathway as well as notchexpression and potential curcumin-treatment have recently been defined as candidates. 46,47 Zhu and associates demonstrated that the IL-6/Stat3-miR-17-92 cluster-PTEN signaling axis plays a decisive role in CCA tumor development and progression. 48 Fibroblast growth factor receptor 2 fusions and ERRFI gene mutations as well as up-regulation of HER-2 signaling have been identified as relevant genomic targets in some patients.…”

Section: Status Quomentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Liver transplant is not a standard therapy for cholangiocarcinoma; complete surgical resection of the tumor is currently the treatment of choice. Palliative options offer only short-term survival.After initial recurrence rates after liver transplant for cholangiocarcinoma in the 1990s were unacceptably high, cholangiocarcinoma has been regarded widely as a contraindication to liver transplant. Ubiquitous organ shortage further supports this conviction. Careful patient selection and a rigorous perioperative treatment by radiochemotherapy have produced some impressive survival data in specialized transplant centers in recent years. Although the graft shortage is aggravating in the Western world, the issue of liver transplant as a treatment for irresectable cholangiocarcinoma is being discussed.This review article provides an update and overview on the current status of liver transplant as a potential option for patients with irresectable cholangiocarcinoma.

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Hedgehog pathway as a potential treatment target in human cholangiocarcinoma

Abstract: The results of our study suggest that the Hh pathway plays a relevant role at least in a subset of human CCC. Inhibition of this pathway may represent a possible treatment option for CCC patients in which the Hh pathway is activated.

Cited by 44 publications

References 29 publications

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma

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