Overexpression of Epcam and CD133 Correlates with Poor Prognosis in Dual-phenotype Hepatocellular Carcinoma

Abstract

Background: Dual-phenotype hepatocellular carcinoma (DPHCC) is associated with high rate of post-operative recurrence and low rate of survival, which may reflect the post-operative persistence of cancer stem cells (CSCs). Here we explored the potential correlation between DPHCC and expression of CSCs markers. Methods: In this retrospective study, we included 19 patients with DPHCC and 61 patients with non-DPHCC treated in 2015 by liver resection. Paraffin-embedded tumor tissue specimens were analyzed using immunohistochemistry as well as immunofluorescence double-staining. Rates of recurrence-free survival and overall survival were compared between the two groups using the Kaplan-Meier method, and expression of the CSC markers CD133, CD90, and EpCAM were compared using real-time quantitative PCR and western blotting. Results: Overall survival rates were significantly lower for patients with DPHCC than patients with non-DPHCC at 1 year (78.9% vs 93.4%), 2 years (52.6% vs 72.1%), and 3 years (42.1% vs 67.2%) (P = 0.019). Multivariate Cox proportional hazard modeling identified CK19 positivity (P = 0.016) and multiple nodules (P = 0.023) as independent predictors of poor recurrence-free survival. Independent predictors of poor overall survival were CK19 positivity (P = 0.032), Barcelona Clinic Liver Cancer stage C (P = 0.025) and carbohydrate antigen 19-9 (CA19-9) >37 ng/ml (P = 0.016). Expression of CD133 and EpCAM mRNA and protein were significantly higher in DPHCC tissue than non-DPHCC tissue, while CD90 expression was similar between the groups. Conclusions: These results suggest that DPHCC is associated with significantly lower overall survival than non-DPHCC, and that the poor prognosis among DPHCC patients may be related to the presence of CSCs expressing CD133 and EpCAM.

Integrated Genomic and Transcriptomic Analysis reveals key genes for predicting dual-phenotype Hepatocellular Carcinoma Prognosis

“…Different from CHC, dual-phenotype hepatocellular carcinoma (DPHCC) is a new subtype of HCC 7 . Previously, we found that DPHCC had a higher rate of postoperative recurrence and a lower survival rate than non-DPHCC 8 .…”

“…The pathological diagnosis of DPHCC is: (1) Immunohistochemically, more than 15% of the tumor cells, at least one hepatocyte marker (such as Hep Par 1) shows strong positive expression, and mainly diffuse distribution; (2) More than 15% of tumor cells, at least one cholangiocyte marker (such as CK19), and at least one hepatocyte marker (such as Hep par 1) are co-expressed. If the tumor tissue contains any component of HCC and intrahepatic cholangiocarcinoma, no matter whether there is a transition zone between these components or the tissue shows that tumor cells do not express markers of both hepatocytes and cholangiocarcinoma, these patients cannot be diagnosed as DPHCC 7 , 8 . While the incidence rate of DPHCC is much lower than that of CHC 9 , DPHCC is more aggressive and exhibits a worse postoperative prognosis.…”

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

“…As previously mentioned, CD133 expression is negatively correlated with overall survival and recurrence rates in patients with HCC [ 144 , 236 , 237 , 238 ]. HCC patients with higher level of CD133 expression in primary lesion have shorter 5-year survival times and higher relapse rates after surgical resection compared to patients with lower CD133 expression [ 144 , 239 ]. The up-regulated expression levels of CD133 have also been related to the ability to survive under hypoxia or malnutrition by performing autophagy [ 240 ].…”

“…These authors found that the CD133-positive subpopulation showed a distinct high tumorigenicity in an immunodeficiency mouse xenograft model and lower levels of mature hepatocyte-specific markers, such as cytochrome P450 and glutamine synthetase (GS), when compared with CD133-negative counterparts [ 143 ]. Furthermore, Zhang et al found that enhanced cytoplasmic CD133 expression is correlated with poor prognosis HCC patients [ 144 ]. Interestingly, normal stem/progenitor cells and CSCs share many features, including the capacity to self-renew and differentiate into multiple cell types [ 145 ].…”

Percutaneous radiofrequency ablation is superior to hepatic resection in patients with small hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) has a high mortality among all cancers worldwide[ 1 ]. Most patients with HCC have decreased liver function and require treatment to completely excise the lesion and effectively mitigate further damage to the liver[ 2 ].…”