Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence

Abstract

Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan-Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.

Rationale for targeting the Wnt signalling modulator Dickkopf‐1 for oncology

“…In both breast cancer and hepatocellular carcinoma xenograft models, DKK1 increased tumour growth and promoted angiogenesis, suggesting that DKK1 has pro‐angiogenic activity (Smadja et al , ; Tung et al , ). In support of this, knockdown of DKK1 decreased tumour growth and angiogenesis in hepatocellular carcinoma (Huang et al , ). In addition to affecting primary tumour growth, DKK1 has also been linked to the development of metastasis in bone, breast, liver, lung and prostate cancer models, possibly related to the prominent role of DKK1 in stimulating migration and invasion observed in vitro (Thudi et al , ; Tao et al , ; Huang et al , ; Goldstein et al , ; Malladi et al , ; Pang et al , ).…”

Current biomarkers for hepatocellular carcinoma: Surveillance, diagnosis and prediction of prognosis

“…Recently, a modification of this model, the BALAD-2 score, was validated in an international setting and confirmed to reliably predict the prognosis of patients with HCC [81] . Other circulating biomarkers that mirror current knowledge on pathways involved in hepatocarcinogenesis and shown to be of prognostic value are, amongst others, IGF1 [82] , DKK1 [83,84] , GPC-3 and HSP 70 [85] although prospective validation studies are still to come. In patients with advanced HCC, baseline angiopoietin 2 (Ang2), and VEGF concentration in the plasma also independently predict survival [76] .…”

High Level of Serum Protein DKK1 Predicts Poor Prognosis for Patients with Hepatocellular Carcinoma After Hepatectomy

“…Therefore, we can foresee that HCC patients with high levels of preoperative serum DKK1 or both DKK1 and AFP may have poor prognosis after tumor resection, and then an adjuvant effective treatment should be considered. Previously, we demonstrated by tissue microarray that DKK1 could predict prognosis for HCC patients after tumor resection or orthotopic liver transplantation [25,26]. A recent metaanalysis concluded that DKK1 might be a novel common prognostic marker for human tumors, though most of these studies involved for analysis were based on immunohistochemistry results [27].…”

“…Of interest, a recent study reported that ectopic expression of DKK1 could stimulate β-catenin expression [38]. DKK1 was also found to be preferentially expressed in metastatic HCC cell lines and HCC patients with recurrence, and could promote migration and invasion in vivo and in vitro through RhoA and JNK or MMP7 [25][26][38][39]. Nevertheless, more mechanisms of DKK1 in HCC still need to be further investigated.…”