Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells

Abstract

Abstract. The Hedgehog (Hh) pathway has been confirmed a contributor to the carcinogenesis and progression of various tumor types. To investigate the Hh signaling activity in human hepatocellular carcinoma (HCC), we detected the expression levels of Hh pathway components (Shh, Ptch1 and Gli2) in 57 samples of HCC and corresponding adjacent-tumor liver tissues. The Hh pathway was overexpressed in cancer tissues compared with non-cancer tissues and correlated closely with histologic differentiation and portal venous invasion of HCC. To elucidate the relationship between Hh signaling and HCC progression, we performed a further study in vitro. First, the expression levels of the signaling were detected in a subset of hepatoma cell lines and SMMC-7721 cells selected with high level of Hh signaling expression. Next, we employed KAAD-cyclopamine (a specific inhibitor of Hedgehog pathway) to block the Hh pathway in SMMC-7721 cells and assessed the changes of their biological behaviors. The results showed that the blockade of Hh signaling pathway by KAAD-cyclopamine induced reduction of DNA synthesis leading to marked cell growth inhibition and also caused significant attenuation in invasiveness and motility of HCC cells. Collectively, our data demonstrated that the Hh pathway plays an important role in HCC development and invasion. Blockade of the Hh signaling pathway may be a potential target of new therapeutic strategy for HCC.

Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

“…Additional mechanisms of aberrant pathway activation can be ligand-dependent, autocrine activation of the pathway, whereby cancer cells can upregulate the synthesis of the Shh ligand and stimulate Hh/GLI pathway activation. This type of pathway activation is common in prostate cancer, hepatocellular carcinoma, pancreatic cancer, and non-small cell lung cancer [ 236 , 237 , 238 , 239 , 240 ]. The Shh ligand can also be secreted by tumor cells and can participate in paracrine signaling, activating the Hh/GLI signaling pathway in both tumor and stromal cells, often seen in pancreatic and prostate cancers [ 34 , 235 , 241 , 242 ].…”

Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma

“…The SHH signaling pathway (SHH) plays a pivotal role in the proliferation and invasiveness of HCC cells [ 48 , 49 , 50 , 51 , 52 ]. The activation of the SHH signaling pathway occurs after the HH ligand binds to its receptor Patched1 (PTCH1) [ 51 , 52 ].…”

“…Although there is no universal CSC marker that can be used to identify the CSCs of HCC, studies have shown some of the main surface markers that can identify liver CSCs, including epithelial cell adhesion/activating molecule (EpCAM) (CD326), cluster of differentiation 90 (CD90), CD44 and CD133 [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. The reported main molecular signaling pathways attending the pathogenesis of the CSCs of HCC include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch pathways [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ,…”

The Role of Smoothened in Cancer

“…The SMO inhibitor cyclopamine has been shown to reduce DNA synthesis, resulting in inhibition of the cell growth, invasiveness, and motility of HCC cells [ 78 ]. In addition, cyclopamine suppresses cell viability and increases apoptosis after downregulating Bcl-2 in HCC cells [ 73 ].…”