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Differential Expression of Sonic Hedgehog Protein in Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

Abstract

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) are the two most common primary liver malignancies in adult patients. The molecular mechanisms underlying the pathogenesis of HCC and CCA are still poorly understood. Sonic hedgehog (SHH) signaling plays an essential role during mammalian development, i.e., promoting organ growth, tissue differentiation, and cell polarity. The upregulation of SHH has been observed during carcinogenesis, including colorectal carcinoma. Our aim was to investigate the expression pattern of SHH in HCC and CCA. We investigated 40 malignant tumors of the liver, including 21 HCC and 19 of intrahepatic CCA cases by immunohistochemistry (IHC) using a polyclonal antibody against SHH and Avidin-Biotin Complex method. We also investigated the co-localization of SHH and Bone morphogenetic protein 4 (BMP4) in CCA using indirect double IHC. Moreover, we examined whether SHH is expressed in two HCC cell lines HepG2 and HuH-7 and three CCA cell lines OZ, HuCCT1 and HuH28. We found that SHH was expressed in 15 out of 21 cases (71.4 %) of HCC and 100 % of CCA cases by immunohistochemistry. SHH expression showed a positive trend in liver tumors (HCC, CCA) with high grade (G2-G3). SHH localized to the epithelial cells, while BMP4 was expressed in the stromal cells in CCA by double IHC. However, both HCC and CCA cell lines showed SHH expression by Western blot analysis. In conclusion, SHH seems to be an interesting marker of de-differentiation in liver tumors and the simultaneous epithelial-mesenchymal expression may be an intriguing prompt to investigate cross-talks between SHH and BMP4.

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Acknowledgments

We are grateful to the following funding agencies and institutions: University of Alberta Internal Funds (Canada) and the Saudi Cultural Bureau, Ottawa, ON, Canada, supported RA-B (MSc Lab Med & Pathology graduate student). The sponsors had no role in study design, data collection, data analysis, and data interpretation or in writing of the report. CS is the B105 lab director and principal investigator, designed the project and was responsible for the interpretation of data, obtaining sponsorship funding, and coordination of the study. RA-B wrote the first draft of the manuscript. RA-B was responsible for data gathering and interpretation. All authors reviewed the final draft of the manuscript.

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No conflicts of interest were declared.

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Correspondence to Consolato Sergi.

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Al-Bahrani, R., Nagamori, S., Leng, R. et al. Differential Expression of Sonic Hedgehog Protein in Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Pathol. Oncol. Res. 21, 901–908 (2015). https://doi.org/10.1007/s12253-015-9918-7

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  • DOI: https://doi.org/10.1007/s12253-015-9918-7

Keywords

  • Hepatocellular carcinoma
  • Cholangiocarcinoma
  • Sonic hedgehog
  • Bone morphogenetic protein 4
  • Immunohistochemistry