Published online Feb 28, 2019. doi: 10.3748/wjg.v25.i8.923
Peer-review started: September 28, 2018
First decision: October 23, 2018
Revised: December 25, 2018
Accepted: December 27, 2018
Article in press: December 28, 2018
Published online: February 28, 2019
Processing time: 152 Days and 10.9 Hours
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC patients suffer from a high mortality-to-incidence ratio and low cure rate since we still have no specific and effective treatment. Although tremendous advances have been made in the investigation of HCC, the specific mechanisms of the progression of this disease are still only partially established. Hence, more research is needed to elucidate the underlying potential mechanisms to develop effective strategies for HCC.
To determine the role of developing brain homeobox 2 (Dbx2) gene in promoting the development of HCC.
Dbx2 expression in clinical specimens and HCC cell lines was detected by Western blot (WB) and immunohistochemistry. Gain and loss of Dbx2 function assays were performed in vitro and in vivo. Cell viability assays were used to investigate cell growth, flow cytometry was employed to assess cell cycle and apoptosis, and trans-well assays were conducted to evaluate cell migration, invasion, and metastasis. The expression of key molecules in the sonic hedgehog (Shh) signaling was determined by WB.
Compared to matched adjacent non-tumorous tissues, Dbx2 was overexpressed in 5 HCC cell lines and 76 surgically resected HCC tissues. Dbx2 overexpression was correlated with large tumor size. Both gain and loss of function assays indicated that Dbx2 promoted HCC cell proliferation by facilitating the transition from G1 to S phase, attenuating apoptosis and promoted HCC proliferation, migration, and invasion in vitro and in vivo. Mechanistically, Dbx2 modulated Shh signaling by enhancing FTCH1 and GLi1 expression in HCC cells that overexpressed Dbx2, which was reversed in HCC cells with Dbx2 knockdown.
Our results indicate that Dbx2 is significantly upregulated in HCC tissues and plays significant roles in proliferation and metastasis of HCC cells by activating the Shh pathway.
Core tip: Developing brain homeobox 2 (Dbx2) plays an important role in cell differentiation and is frequently upregulated in tumor tissues, while its function in hepatocellular carcinoma (HCC) has not been reported. Our results indicate that Dbx2 is obviously upregulated in HCC tissues and strongly correlated with tumor size. Subsequently, both gain and loss of function assays indicated that Dbx2 promoted HCC migration, invasion, and proliferation by facilitating the transition from G1 to S phase and attenuating apoptosis in vitro and in vivo. Mechanistically, Dbx2 modulates sonic hedgehog signaling by enhancing FTCH1 and GLi1 expression in HCC cells.