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

Journal Reference

Pathol Oncol Res. 2015;21(4):901-8.

Al-Bahrani R1, Nagamori S, Leng R, Petryk A, Sergi C.

Department of Laboratory Medicine and Pathology, University of Alberta, 8440-112 Street, Edmonton, T6G 2B7, AB, Canada.


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 sonic hedgehog has been observed during carcinogenesis, including colorectal carcinoma. Our aim was to investigate the expression pattern of Sonic hedgehog 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 sonic hedgehog and Avidin-Biotin Complex method. We also investigated the co-localization of sonic hedgehog and Bone morphogenetic protein 4 (BMP4) in CCA using indirect double IHC. Moreover, we examined whether sonic hedgehog is expressed in two HCC cell lines HepG2 and HuH-7 and three CCA cell lines OZ, HuCCT1 and HuH28. We found that sonic hedgehog was expressed in 15 out of 21 cases (71.4 %) of HCC and 100 % of CCA cases by immunohistochemistry. Sonic hedgehog expression showed a positive trend in liver tumors (HCC, CCA) with high grade (G2-G3). Sonic hedgehog 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 Sonic hedgehog expression by Western blot analysis. In conclusion, sonic hedgehog 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 sonic hedgehog and BMP4.

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