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. 2013 Apr 19;32(1):22.
doi: 10.1186/1756-9966-32-22.

Clinical significance and gene expression study of human hepatic stellate cells in HBV related-hepatocellular carcinoma

Rui Liao  1 , Han Wu, Yong Yi, Jia-Xing Wang, Xiao-Yan Cai, Hong-Wei He, Yun-Feng Cheng, Jian Zhou, Jia Fan, Jian Sun, Shuang-Jian Qiu
Affiliations

Clinical significance and gene expression study of human hepatic stellate cells in HBV related-hepatocellular carcinoma

Rui Liao et al. J Exp Clin Cancer Res. .

Abstract

Background: Peritumoral activated hepatic stellate cells (HSCs) are versatile myofibroblast-like cells closely related with hepatocellular carcinoma (HCC) progression. So far, comprehensive comparison of gene expression of human HSCs during hepatocarcinogenesis is scanty. Therefore, we identified the phenotypic and genomic characteristics of peritumoral HSCs to explore the valuable information on the prognosis and therapeutic targets of HBV related HCC.

Methods: A tissue microarray containing 224 HBV related HCC patients was used to evaluate the expression of phenotype markers of HSCs including α-SMA, glial fibrillary acidic protein (GFAP), desmin, vinculin and vimentin. HSCs and cancer associated myofibroblasts (CAMFs) were isolated from normal, peritumoral human livers and cancer tissues, respectively. Flow cytometry and gene microarray analysis were performed to evaluate the phenotypic changes and gene expression in HCC, respectively.

Results: Peritumoral α-SMA positive HSCs showed the prognostic value in time to recurrence (TTR) and overall survival (OS) of HCC patients, especially in early recurrence and AFP-normal HCC patients. Expression of GFAP positive HSCs cell lines LX-2 was significantly decreased after stimulation with tumor conditioned medium. Compared with quiescent HSCs, peritumoral HSCs and intratumoral CAMFs expressed considerable up- and down-regulated genes associated with biological process, cellular component, molecular function and signaling pathways involved in fibrogenesis, inflammation and progress of cancer.

Conclusions: Peritumoral activated HSCs displayed prognostic value in HBV related-HCC, and their genomic characteristics could present rational biomarkers for HCC risk and promising therapeutic targets.

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Figures

Figure 1
Figure 1
Images of immunostained cells, HE stain and survival curves for univariate analyses. a-l showed vinculin, vimentin and α-SMA staining cells in intratumoral (a, b, e, f, i and j) and peritumoral areas (c, d, g, h, k and l), respectively (x 200). a, c, e, g, i and k were negative controls. m and n showed HE stain in intratumoral (m) and peritumoral areas (n), respectively (x 200). High density of peritumoral α-SMA was related to decreased OS (o) and TTR (p).
Figure 2
Figure 2
The frequency of GFAP+ hepatic stellate cells (HSCs) after stimulation with tumor conditioned medium (TCM) from hepatocellular carcinoma (HCC) cell lines MHCC97L, HCCLM3 and HCCLM6 which was determined by flow cytometry. The relative quantitation was also shown. *P <0.01 compared with HSCs exposed to TCM from HCC cell lines.
Figure 3
Figure 3
Gene expression patterns between peritumoral activated hepatic stellate cells (pHSCs), intratumoral cancer associated myofibroblasts (CAMFs), culture-activated HSCs (aHSCs) and quiescence HSCs (qHSCs), respectively. Each panel of 3 separate cell sample per group (1, 2, and 3) showed hierarchical clustering based on different expression genes represented as a heat map. The Venn plot showed overlapping patterns of probe sets with ≥2-fold up-regulated or down-regulated genes (P < 0.05) in pHSCs (P), CAMFs (T) and aHSCs (A) compared with aHSCs (Q). The number shown in the shared areas represented the common entities.
Figure 4
Figure 4
Pathway analysis showed functional networks identified between peritumoral (P) activated hepatic stellate cells (HSCs) and intratumoral myofibroblasts (T). Selected significant canonical pathways associated with PPAR signaling (a, P vs T upregulation) and P53 (b, P vs T downregulation) were shown, respectively. Yellow, orange and green marked nodes represented down-regulated genes, up-regulated genes and no significance, respectively.
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