Publications by authors named "Lian-Yue Yang"

48 Publications

Programmed cell death 10 promotes metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma via PP2Ac-mediated YAP activation.

Cell Death Dis 2021 Sep 14;12(9):849. Epub 2021 Sep 14.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Tumour metastasis is the main cause of postoperative tumour recurrence and mortality in patients with hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Accumulating evidence has demonstrated that programmed cell death 10 (PDCD10) plays an important role in many biological processes. However, the role of PDCD10 in HCC progression is still elusive. In this study, we aimed to explore the clinical significance and molecular function of PDCD10 in HCC. PDCD10 is significantly upregulated in HCC, which also correlates with aggressive clinicopathological characteristics and predicts poor prognosis of HCC patients after liver resection. High PDCD10 expression promotes HCC cell proliferation, migration, and invasion in vitro and tumour growth, metastasis in vivo. In addition, PDCD10 could facilitate epithelial-to-mesenchymal transition (EMT) of HCC cells. In terms of the mechanism, PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to the interaction of YAP and dephosphorylation of the YAP protein. This interaction contributes to YAP nuclear translocation and transcriptional activation. PP2Ac is necessary for PDCD10-mediated HCC progression. Knocking down PP2Ac abolished the tumour-promoting role of PDCD10 in the migration, invasion and EMT of HCC. Moreover, a PP2Ac inhibitor (LB100) could restrict tumour growth and metastasis of HCC with high PDCD10 expression. Collectively, PDCD10 promotes EMT and the progression of HCC by interacting with PP2Ac to promote YAP activation, which provides new insight into the mechanism of cancer metastasis. PDCD10 may be a potential prognostic biomarker and therapeutic target for HCC.
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http://dx.doi.org/10.1038/s41419-021-04139-zDOI Listing
September 2021

Serum epidermal growth factor-like domain 7 serves as a novel diagnostic marker for early hepatocellular carcinoma.

BMC Cancer 2021 Jul 3;21(1):772. Epub 2021 Jul 3.

Department of Surgery, Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Background: Epidermal growth factor-like domain 7 (Egfl7), a recently identified secreted protein, was significantly increased in patients with HCC by our previous studies. However, its efficacy in the diagnosis of early HCC remains unknown. In this study, we therefore evaluate the efficacy of serum Egfl7 for early HCC diagnosis and compare it with alpha-fetoprotein (AFP).

Methods: Serum Egfl7 levels in testing cohort (1081 participants) and validation cohort (476 participants) were measured by a sandwich enzyme-linked immunoassay (ELISA). The cut-off value of Egfl7 was determined by Youden's index and the efficacies of Egfl7 and AFP in diagnosing early HCC were estimated by receiver operating characteristic (ROC).

Results: Serum Egfl7 was significantly elevated in patients with early HCC than all non-HCC controls in whatever Testing Cohort or Validation Cohort. In the Testing Cohort, ROC curves showed the optimum cut-off value of Egfl7 was 2610 ng/mL and Egfl7 showed a significantly higher sensitivity than AFP in discriminating early HCC from healthy individuals (77.4% vs. 65.3%, P = 0.0013) but the area under ROC (AUROC) and accuracy of Egfl7 and AFP were similar (0.860 vs. 0.868, P = 0.704; 80.2% vs. 83.8%, P = 0.184). In distinguishing patients with early HCC from patients with chronic liver disease (CLD), the AUROC, sensitivity, specificity and accuracy of Egfl7 were 0.800, 75.2, 71.7 and 73.5%, which were all significantly higher than AFP (0.675, 61.8, 62.0 and 61.9% in order). Egfl7 also showed a significant higher sensitivity and accuracy than AFP (76.6% vs. 64.0%, P = 0.0031; 79.9% vs. 66.1%, P < 0.0001) in differentiating early HCC patients from non-HCC individuals. Additionally, 70.8% of early HCC patients with negative AFP could be diagnosed by Egfl7 and the combined use of Egfl7 and AFP increased the sensitivity to 91.0%. These results were confirmed by a validation cohort.

Conclusion: Egfl7 is a valuable serum marker in the diagnosis of early HCC and could complement the efficacy of AFP, especially in distinguishing early HCC from CLD and identifying patients with AFP-negative early HCC.
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http://dx.doi.org/10.1186/s12885-021-08491-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255001PMC
July 2021

ATE1 Inhibits Liver Cancer Progression through RGS5-Mediated Suppression of Wnt/β-Catenin Signaling.

Mol Cancer Res 2021 Sep 22;19(9):1441-1453. Epub 2021 Jun 22.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Arginyltransferase (ATE1) plays critical roles in many biological functions including cardiovascular development, angiogenesis, adipogenesis, muscle contraction, and metastasis of cancer. However, the role of ATE1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we find that ATE1 plays an essential role in growth and malignancy of liver cancer. ATE1 expression is significantly reduced in human HCC samples compared with normal liver tissue. In addition, low ATE1 expression is correlated with aggressive clinicopathologic features and is an independent poor prognostic factor for overall survival and disease-free survival of patients with HCC. Lentivirus-mediated ATE1 knockdown significantly promoted liver cancer growth, migration, and disease progression and . Opposing results were observed when ATE1 was upregulated. Mechanistically, ATE1 accelerated the degradation of β-catenin and inhibited Wnt signaling by regulating turnover of Regulator of G Protein Signaling 5 (RGS5). Loss- and gain-of-function assays confirmed that RGS5 was a key effector of ATE1-mediated regulation of Wnt signaling. Further studies indicated that RGS5 might be involved in regulating the activity of GSK3-β, a crucial component of the cytoplasmic destruction complex. Treatment with a GSK inhibitor (CHIR99021) cooperated with ablation of ATE1 or RGS5 overexpression to promote Wnt/β-catenin signaling, but overexpression of ATE1 or RGS5 knockdown did not reverse the effect of GSK inhibitor. IMPLICATIONS: ATE1 inhibits liver cancer progression by suppressing Wnt/β-catenin signaling and can serve as a potentially valuable prognostic biomarker for HCC.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0027DOI Listing
September 2021

NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma.

Cancer Sci 2021 Jul 4;112(7):2753-2769. Epub 2021 May 4.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China.

Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease-free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial-mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia-inducible factor-1α (HIF-1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor-promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N-acetyl-l-cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor-promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.
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http://dx.doi.org/10.1111/cas.14925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253267PMC
July 2021

EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics.

Clin Sci (Lond) 2021 Apr;135(7):847-864

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

Metastasis is the main cause of poor postoperative survival of hepatocellular carcinoma (HCC) patients. Cytoskeleton rearrangement is a key event in cancer metastasis. However, the significance of microtubule (MT), one of the core components of cytoskeleton, in this process is only beginning to be revealed. Here, we find that the MT dynamics regulator end-binding protein 2 (EB2) is highly expressed in HCC and predicts poor prognosis of HCC patients. Functional studies show that EB2 overexpression promotes HCC proliferation, invasion and metastasis in vitro and in vivo, while EB2 knockdown has opposite results. Mechanistically, EB2 mediates MTs destabilization, increases Src (Src proto-oncogene non-receptor tyrosine kinase) activity, and thus facilitates extracellular signal-regulated kinase (ERK) signaling activation, which could in turn promote EB2 expression in HCC, eventually resulting in enhanced HCC proliferation, invasion and metastasis. Furthermore, U0126, a specific ERK inhibitor, could effectively inhibit EB2-mediated HCC proliferation and metastasis in vitro and in vivo. In conclusion, EB2 coordinates MT cytoskeleton and intracellular signal transduction, forming an EB2-MT-ERK positive feedback loop, to facilitate HCC proliferation, invasion and metastasis. EB2 could serve as a promising prognostic biomarker and potential therapeutic target for HCC; HCC patients with high EB2 expression may benefit from treatment with ERK inhibitors.
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http://dx.doi.org/10.1042/CS20201500DOI Listing
April 2021

STMN2 mediates nuclear translocation of Smad2/3 and enhances TGFβ signaling by destabilizing microtubules to promote epithelial-mesenchymal transition in hepatocellular carcinoma.

Cancer Lett 2021 05 8;506:128-141. Epub 2021 Mar 8.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. Electronic address:

Metastasis remains the major obstacle of improving the survival of patients with hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is critical to cancer metastasis. Successful induction of EMT requires dramatic cytoskeleton rearrangement. However, the significance of microtubule (MT), one of the core components of cell cytoskeleton, in this process remains largely unknown. Here we revealed that STMN2, an important MT dynamics regulator, is barely expressed in normal live tissues but markedly up-regulated in HCCs, especially in those with early recurrence. High STMN2 expression correlates with aggressive clinicopathological features and predicts poor prognosis of HCC patients. STMN2 overexpression in HCC cells promotes EMT, invasion and metastasis in vitro and in vivo, whereas STMN2 knockdown has opposite results. Mechanistically, STMN2 modulates MTs disassembly, disrupts MT-Smad complex, and facilitates release from MT network, phosphorylation and nuclear translocation of Smad2/3 even independent of TGFβ stimulation, thereby enhancing TGFβ signaling. Collectively, STMN2 orchestrates MT disassembly to facilitate EMT via TGF-β signaling, providing a novel insight into the mechanisms underlying cancer metastasis. STMN2 is a promising prognostic biomarker and potential therapeutic target for HCC.
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http://dx.doi.org/10.1016/j.canlet.2021.03.001DOI Listing
May 2021

HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/β-catenin signaling.

Clin Sci (Lond) 2019 07 25;133(14):1645-1662. Epub 2019 Jul 25.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China

Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial-mesenchymal transition (EMT) and promotes intrahepatic metastasis, lung metastasis and EMT Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.
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http://dx.doi.org/10.1042/CS20190225DOI Listing
July 2019

Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling.

J Exp Clin Cancer Res 2018 Mar 5;37(1):45. Epub 2018 Mar 5.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China.

Background: Castor zinc finger 1 (CASZ1) plays critical roles in various biological processes and pathologic conditions, including cancer. However, the prognostic importance and biologic functions of CASZ1 in hepatocellular carcinoma (HCC) are still unclear.

Methods: qRT-PCR, western blot and immunohistochemistry analyses were used to determine CASZ1 expression in HCC samples and cell lines. The clinical significance of CASZ1 was assessed in two independent study cohorts containing 232 patients with HCC. A series of in vitro and in vivo experiments were performed to explore the role and molecular mechanism of CASZ1 in HCC progression.

Results: Here we report that CASZ1 expression was downregulated in HCC tissues and cell lines. Low CASZ1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes and early recurrence of HCC patients. Moreover, overexpression of CASZ1 in HCCLM3 cells significantly inhibited cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, whereas silencing CASZ1 significantly enhanced the above abilities of PLC/PRF/5 cells. Further mechanism study indicated that these phenotypic changes were mediated by MAPK/ERK signaling pathway and involved altered expression of MMP2, MMP9 and cyclinD1. Finally, we proved that CASZ1 exerted its tumor-suppressive effect by directly interacting with RAF1 and reducing the protein stability of RAF1.

Conclusions: Our study for the first time demonstrated that CASZ1 is a tumor suppressor in HCC, which may serve as a novel prognostic predictor and therapeutic target for HCC patients.
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http://dx.doi.org/10.1186/s13046-018-0720-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836448PMC
March 2018

miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma.

Clin Cancer Res 2017 May 8;23(10):2593-2604. Epub 2016 Nov 8.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms. 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both and The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry. Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models. Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0851DOI Listing
May 2017

JARID2 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition through PTEN/AKT signaling.

Oncotarget 2016 Jun;7(26):40266-40284

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

JARID2 is crucial for maintenance of pluripotency and differentiation of embryonic stem cells. However, little is known about the role of JARID2 in metastasis of hepatocellular carcinoma (HCC). This study found that JARID2 expression was significantly higher in HCC tissues than that in adjacent non-tumor liver tissues (ANLTs), and its expression level correlated with HCC metastasis. High JARID2 expression was significantly correlated with multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05) and indicated poor prognosis of HCC in training and validation cohorts (all P < 0.05) totaling 182 patients. High JARID2 expression was an independent and significant risk factor for disease-free survival (DFS; P = 0.017) and overall survival (OS; P = 0.041) after curative liver resection in training cohort, and also validated as an independent and significant risk factor for DFS (P = 0.033) and OS (P = 0.031) in validation cohort. Moreover, down-regulation of JARID2 dramatically inhibited HCC cell migration, invasion, proliferation in vitro and metastasis in vivo, whereas overexpression of JARID2 significantly increased migration, invasion, proliferation in vitro and metastasis in vivo. Mechanistically, the data showed that JARID2 exerted its function by repressing PTEN expression through increasing H3K27 trimethylation (H3K27me3) at PTEN promoter region, which subsequently resulted in activation of protein kinase B (AKT) and enhanced epithelial-mesenchymal transition (EMT). In conclusion, this study revealed that JARID2 promotes invasion and metastasis of HCC by facilitating EMT through PTEN/AKT signaling.
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http://dx.doi.org/10.18632/oncotarget.9733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130007PMC
June 2016

YMO1 suppresses invasion and metastasis by inhibiting RhoC signaling and predicts favorable prognosis in hepatocellular carcinoma.

Oncotarget 2016 Aug;7(34):55585-55600

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China.

Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity.
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http://dx.doi.org/10.18632/oncotarget.10866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342438PMC
August 2016

MicroRNA-130b promotes proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling.

Tumour Biol 2016 Aug 10;37(8):10609-19. Epub 2016 Feb 10.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths owing to its high rate of postoperative recurrence and metastasis. New research is continuously identifying novel metastasis-associated oncogenes and tumor suppressor genes. miRNAs are noncoding RNAs that regulate protein synthesis post-translationally. miR-130b is one of several miRNAs involved in tumor metastasis. However, the role of miR-130b in HCC remains controversial. Here, we demonstrate that miR-130b is highly expressed in HCC and that it correlates with tumor number, vascular invasion, and TNM stage-important predictors of postoperative recurrence and metastases. Moreover, high levels of miR-130b predicted poor overall and disease-free survival of HCC patients, and in vitro and in vivo research revealed that knockdown or overexpression of miR-130b inhibited and promoted proliferation and metastasis of HCC cells, respectively. We identified PTEN as a direct functional target of miR-130b using miRNA databases and a dual luciferase report assay. Next, using a gain and loss assay and epithelial-mesenchymal transition (EMT) relative assays, we show that miR-130b may promote proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Collectively, our data suggests that miR-130b may have prognostic value in HCC. Additionally, the miR-130b/PTEN/p-AKT/HIF-1α axis identified in this study provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
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http://dx.doi.org/10.1007/s13277-016-4919-zDOI Listing
August 2016

Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition.

Hepatology 2016 Apr 26;63(4):1256-71. Epub 2016 Jan 26.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China.

Unlabelled: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide because of metastasis. Epithelial-mesenchymal transition (EMT) is widely considered to be crucial to the invasion-metastasis cascade during cancer progression. Actin-like 6A (ACTL6A) is initially verified important for cell proliferation, differentiation, and migration. In this study, we find that ACTL6A plays an essential role in metastasis and EMT of HCC. ACTL6A expression is up-regulated in HCC cells and tissues. A high level of ACTL6A in HCCs is correlated with aggressive clinicopathological features and is an independent poor prognostic factor for overall and disease-free survival of HCC patients. Ectopic expression of ACTL6A markedly promotes HCC cells migration, invasion, as well as EMT in vitro and promotes tumor growth and metastasis in the mouse xenograft model. Opposite results are observed when ACTL6A is knocked down. Mechanistically, ACTL6A promotes metastasis and EMT through activating Notch signaling. ACTL6A knockdown has the equal blockage effect as the Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butylester, in HCC cells. Further studies indicate that ACTL6A might manipulate SRY (sex determining region Y)-box 2 (SOX2) expression and then activate Notch1 signaling.

Conclusions: ACTL6A promotes metastasis and EMT by SOX2/Notch1 signaling, indicating a prognostic biomarker candidate and a potential therapeutic target for HCC.
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http://dx.doi.org/10.1002/hep.28417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834727PMC
April 2016

Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma.

Oncotarget 2015 Dec;6(38):40622-41

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling.
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http://dx.doi.org/10.18632/oncotarget.5872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747357PMC
December 2015

MicroRNA-424 inhibits Akt3/E2F3 axis and tumor growth in hepatocellular carcinoma.

Oncotarget 2015 Sep;6(29):27736-50

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

By comparing the expression profiles of miRNAs in different subtypes of HCC, we identified miR-424 as a HCC related miRNA. We found that the expression of miR-424 was significantly decreased in HCC tissues and six liver cancer cell lines. Significantly, its expression levels were correlated with tumor size, multiple nodules, vein invasion, TNM stage and overall survival of HCC. We showed that up-regulated miR-424 suppressed HCC cell proliferation in vivo and in vitro. Multi-pathway reporter arrays suggested that miR-424 suppressed the pRb-E2F pathway. Consistently, Akt3 and E2F3 were identified as the targets of miR-424 as evidenced by that ectopic miR-424 expression suppressed Akt3 and E2F3 expressions. Silencing Akt3 and E2F3 by siRNA pheno-copied the effect of ectopic miR-424 on HCC growth. Whereas, overexpression of Akt3 and E2F3 attenuated the effect of miR-424 on HCC growth. Together, our data demonstrated a tumor suppressor role for miR-424 in HCC development and progression with therapeutic implications. The strong correlation of miR-424 expression with HCC patient survival suggests that miR-424 could be a valuable biomarker for HCC prognosis.
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http://dx.doi.org/10.18632/oncotarget.4811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695022PMC
September 2015

MicroRNA-188-5p suppresses tumor cell proliferation and metastasis by directly targeting FGF5 in hepatocellular carcinoma.

J Hepatol 2015 Oct 18;63(4):874-85. Epub 2015 May 18.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address:

Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the detailed molecular mechanisms underlying HCC progression are still not completely clear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyze the expression and function of a metastasis-associated miRNA named miR-188-5p in HCC.

Methods: miRNA array analysis was performed to search for metastasis-associated miRNAs in HCC. miR-188-5p expressions in tumor tissues and adjacent non-tumorous liver tissues of HCC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analyzed by Western blot and immunohistochemistry. Luciferase reporter assays was used to validate the target of miR-188-5p. The effect of miR-188-5p on HCC progression was studied in vitro and in vivo.

Results: miR-188-5p was significantly decreased in HCC and its expression levels were highly correlated with multiple nodules, microvascular invasion, overall and disease-free survival of HCC. Ectopic expression of miR-188-5p suppressed HCC cell proliferation and metastasis in vitro and in vivo. Fibroblast growth factor 5 (FGF5) was identified as a major target of miR-188-5p. Enforced expression of miR-188-5p inhibited the expression of FGF5 significantly and the restoration of FGF5 expression reversed the inhibitory effects of miR-188-5p on HCC cell proliferation and metastasis.

Conclusions: These findings collectively demonstrate a tumor suppressor role of miR-188-5p in HCC progression via targeting FGF5, suggesting that miR-188-5p could serve as a potential prognostic biomarker and therapeutic target for HCC.
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http://dx.doi.org/10.1016/j.jhep.2015.05.008DOI Listing
October 2015

Mesohepatectomy for centrally located large hepatocellular carcinoma: Indications, techniques, and outcomes.

Surgery 2014 Nov 17;156(5):1177-87. Epub 2014 Oct 17.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: Whether mesohepatectomy should be performed for large hepatocellular carcinoma (HCC) located in the central part of the liver is controversial, and the safety and long-term survival after this operation remain to be investigated.

Methods: Between January 2002 and December 2012, 696 patients with HCC located in the central part of the liver who received liver resection in our hospital were included in this study. These patients were divided into three groups: 158 patients with large HCC (tumor size >5.0 cm) and 192 patients with small HCC (tumor size ≤ 5.0 cm) who received mesohepatectomy were classified as the mesohepatectomy for large HCC (MHG-L) group and the mesohepatectomy for small HCC (MHG-S) groups, respectively, and 346 patients with large HCC who received hemihepatectomy or less were classified as the non-mesohepatectomy for large HCC (NMHG-L) group. The operative indications, techniques, and outcomes of the three groups were analyzed retrospectively.

Results: There were no substantial differences among the three groups in in-hospital mortality or postoperative complication rates. The overall survival and disease-free survival were not different between the MHG-L group and the NMHG-L group or between the MHG-L group and the MHG-S group. Univariable and multivariable analyses of the MHG-L mesohepatectomy group indicated that cirrhosis, tumor number, and vascular invasion were independent risk factors of poor long-term survival of mesohepatectomy. In the MHG-L and NMHG-L groups, solitary large hepatocellular carcinoma had better long-term survival than nodular large hepatocellular carcinoma.

Conclusion: Mesohepatectomy is safe and efficacious for BCLC B/C patients who have centrally located large HCC, especially for solitary tumors, with good survival outcomes.
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http://dx.doi.org/10.1016/j.surg.2014.05.012DOI Listing
November 2014

MicroRNA-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting PH domain and leucine-rich repeat protein phosphatase.

Hepatology 2014 Oct 21;60(4):1251-63. Epub 2014 Aug 21.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, China.

Unlabelled: Hepatocellular carcinoma (HCC) is a highly invasive tumor with frequent intrahepatic or pulmonary metastasis, which is the main reason for high recurrence and poor survival of HCC after liver resection. However, the mechanisms for metastasis remain incompletely clear. Given that microRNAs (miRNAs) are implicated in HCC progression, we explored a potential role of miRNAs in metastasis by performing miRNA expression profiling in three subtypes of HCC with different metastatic potentials. We discovered miR-331-3p as one of most significantly overexpressed miRNAs and highly associated with metastasis of HCC. Increased expression of miR-331-3p was correlated with poor long-term survival of HCC. We provided both in vivo and in vitro evidence demonstrating that miR-331-3p promoted proliferation and metastasis of HCC cells. Using an integrated approach, we uncovered that PH domain and leucine-rich repeat protein phosphatase (PHLPP) was a novel target of miR-331-3p. Indeed, the miR-331-3p-mediated effects were antagonized by reexpression of PHLPP or mimicked by silencing of PHLPP. We further showed that miR-331-3p-mediated inhibition of PHLPP resulted in stimulation of protein kinase B (AKT) and subsequent epithelial mesenchymal transition (EMT). Finally, inhibition of miR-331-3p through a jetPEI-mediated delivery of anti-miR-331-3p vector resulted in marked inhibition of proliferation and metastasis of HCC in xenograft mice.

Conclusion: miR-331-3p promotes proliferation and EMT-mediated metastasis of HCC through suppression of PHLPP-mediated dephosphorylation of AKT. Our work implicates miR-331-3p as a potential prognostic biomarker and a novel therapeutic target.
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http://dx.doi.org/10.1002/hep.27221DOI Listing
October 2014

Dickkopf-1: as a diagnostic and prognostic serum marker for early hepatocellular carcinoma.

Int J Biol Markers 2013 Sep 27;28(3):286-97. Epub 2013 Sep 27.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan - China.

Background And Aims: The aim of the present study was to evaluate serum Dickkopf-1 (Dkk-1) as a marker for early detection of hepatocellular carcinoma (HCC), as well as for prognostic prediction of early HCC after hepatic resection.

Methods: One-hundred and four cases of matched fresh tissue specimens of early HCC and adjacent non-tumorous liver tissue (ANLT) were obtained for RT-PCR, qRT-PCR, western blot and immunohistochemistry assays. Sera were collected from patients with early HCC (n=184), benign liver tumors (n=29), cirrhosis (n=174), non-cirrhotic hepatitis B (n=193), and from healthy individuals (n=202). The levels of Dkk-1 and alpha fetoprotein (AFP) were measured.

Results: The Dkk-1 mRNA and protein levels were both upregulated in early HCC. Serum levels of Dkk-1 in patients with early HCC were significantly higher than in the other 4 groups (p<0.001). Dkk-1 had a better sensitivity and accuracy than AFP (p<0.05). More importantly, 73.1% of the patients negative for AFP could be diagnosed with early HCC using Dkk-1. A combination of Dkk-1 and AFP further improved the diagnostic efficacy. Patients with a high serum Dkk-1 level had poorer overall and relapse-free survivals than those with a low Dkk-1 level (p=0.028 and p=0.045, respectively). These results were shown in a testing cohort and confirmed in a validation cohort of patients. Univariable and multivariable Cox regression analyses showed serum Dkk-1 level to be an independent prognostic factor for overall survival.

Conclusions: Our data show that Dkk-1 is a diagnostic and prognostic serologic marker for early HCC.
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http://dx.doi.org/10.5301/jbm.5000015DOI Listing
September 2013

The expression of Egfl7 in human normal tissues and epithelial tumors.

Int J Biol Markers 2013 Apr 23;28(1):71-83. Epub 2013 Apr 23.

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China.

Background And Aims: To investigate the expression of Egfl7 in normal adult human tissues and human epithelial tumors.


Methods: RT-PCR and Western blot were employed to detect Egfl7 expression in normal adult human tissues and 10 human epithelial tumors including hepatocellular carcinoma (HCC), lung cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, malignant glioma, ovarian cancer and renal cancer. Immunohistochemistry and cytoimmunofluorescence were subsequently used to determine the localization of Egfl7 in human epithelial tumor tissues and cell lines. ELISA was also carried out to examine the serum Egfl7 levels in cancer patients. In addition, correlations between Egfl7 expression and clinicopathological features as well as prognosis of HCC and breast cancer were also analyzed on the basis of immunohistochemistry results.


Results: Egfl7 was differentially expressed in 19 adult human normal tissues and was overexpressed in all 10 human epithelial tumor tissues. The serum Egfl7 level was also significantly elevated in cancer patients. The increased Egfl7 expression in HCC correlated with vein invasion, absence of capsule formation, multiple tumor nodes and poor prognosis. Similarly, upregulation of Egfl7 in breast cancer correlated strongly with TNM stage, lymphatic metastasis, estrogen receptor positivity, Her2 positivity and poor prognosis. 


Conclusions: Egfl7 is significantly upregulated in human epithelial tumor tissues, suggesting Egfl7 to be a potential biomarker for human epithelial tumors, especially HCC and breast cancer.
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http://dx.doi.org/10.5301/JBM.2013.10568DOI Listing
April 2013

Novel roles of Vmp1: inhibition metastasis and proliferation of hepatocellular carcinoma.

Cancer Sci 2012 Dec 30;103(12):2110-9. Epub 2012 Oct 30.

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China.

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Despite extensive efforts, therapies against metastasis of HCC remain underdeveloped. Vacuole membrane protein 1 (Vmp1) was recently identified to be involved in cancer-relevant processes; however, its expression, clinical significance and biological function in HCC progression are still unknown. Therefore, we evaluated the expression of Vmp1 in human HCC specimens. To functionally characterize Vmp1 in HCC, we upregulated its expression in HCCLM3 cells using a plasmid transfection approach, following which both in vitro and in vivo models were used to elucidate its role. A significant downregulation of Vmp1 was found in human HCC tissues and closely correlated with multiple tumor nodes, absence of capsular formation, vein invasion and poor prognosis of HCC. Such expression was verified with HCC cell lines including HepG2, MHCC97-L and HCCLM3, and the Vmp1 expression levels negatively correlated with metastatic potential. Interestingly, upregulation of Vmp1 significantly affects proliferation, migration, invasion and adhesion of HCCLM3 cells. Using a mouse model, we demonstrated that upregulation of Vmp1 was associated with suppression of growth and pulmonary metastases of HCC. Therefore, our data suggest Vmp1 is a novel prognostic marker and potential therapeutic target for metastasis of HCC.
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http://dx.doi.org/10.1111/cas.12025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659295PMC
December 2012

[Increased expression of Abi1 in hepatocellular carcinoma and its correlation with poor prognosis of hepatocellular carcinoma].

Zhonghua Wai Ke Za Zhi 2009 Nov;47(22):1732-5

Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.

Objective: To investigate the expression of Abi1 in hepatocellular carcinoma (HCC) and the correlation between its expression level and clinical pathological characteristics as well as prognosis of HCC.

Methods: Abi1 expression was determined at both mRNA and protein levels in 40 HCC tissues and their corresponding para carcinomatous liver tissues by RT-PCR and immunohistochemistry. The correlations between Abi1 expression levels and pathological characteristics as well as prognosis were also analyzed.

Results: The expression level of Abi1 mRNA in HCC tissues were significantly higher than those in corresponding para carcinomatous liver tissue (P < 0.05), and the expression level of Abi1 mRNA in nodular HCC tissues were also significantly higher than those in solitary large HCC tissues. Immunohistochemistry results showed that Abi1 protein located in cytoplasm of HCC cells and the expression level of Abi1 protein were significant positive correlated with the number of HCC, capsular formation, venous invasion and Edmondson-Steiner grade (P < 0.05). Combined with follow-up data, the results also showed that HCC patients with high Abi1 protein expression had a higher risk of invasion/metastasis and a shorter survival than those with low Abi1 protein expression (P < 0.05).

Conclusions: Expression level of Abi1 is up-regulated in HCC tissues compared with corresponding para carcinomatous liver tissue and the expression level of Abi1 is significantly correlated with the number of tumor, capsular formation, venous invasion, Edmondson-Steiner grade and prognosis of HCC.
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November 2009

[Down-regulated expression of UNC5b related to hepatocellular carcinoma angiogenesis].

Zhonghua Wai Ke Za Zhi 2009 Oct;47(20):1569-73

Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.

Objective: To investigate the relationship between UNC5b gene expression and angiogenesis of hepatocellular carcinoma (HCC).

Methods: In situ hybridization was performed to detect the expression of UNC5b mRNA in HCC samples, paracarcinomatous liver tissues samples and normal liver samples. The relationship between UNC5b mRNA expression and the HCC clinicopathological features were also analyzed. Human umbilical artery endothelial cells were isolated and stimulated with HCC tissues homogenate, vascular endothelial growth factor and basic fibroblast growth factor. Then RT-PCR was employed to detect the expression of UNC5b mRNA in normal HUAEC as well as activated HUAEC.

Results: In situ hybridization results showed that UNC5b mRNA expression was detected majorly in endothelial cells of all normal liver tissues, and partial PCLTs but was weak or even undetectable in endothelial cells of the corresponding HCC tissues. The expression levels of UNC5b gene in PCLTs were significantly correlated with capsular formation of HCC. Furthermore, RT-PCR results showed that the expression levels of UNC5b mRNA in activated HUAEC were significantly higher than those in normal HUAEC.

Conclusions: Down-regulation of UNC5b gene expression is related to angiogenesis of HCC, which may be associated with the progression of HCC.
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October 2009

Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma.

Hepatology 2009 Dec;50(6):1839-50

Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Unlabelled: Epidermal growth factor-like domain 7 (Egfl7) is a recently identified secreted protein that is believed to be primarily expressed in endothelial cells (ECs). Although its expression was reported elevated during tumorigenesis, whether and how Egfl7 contributes to human malignancies remains unknown. In the present study overexpression of Egfl7 was found predominantly in hepatocellular carcinoma (HCC) cells in HCC tissues and closely correlated with poor prognosis of HCC. The expression of Egfl7 in cancer cells was further verified with HCC cell lines including HepG2, MHCC97-L, and HCCLM3, and the Egfl7 expression levels positively correlated with metastatic potential of HCC cell lines was tested. To functionally characterize Egfl7 in HCC, we depleted its expression in HCCLM3 cells by using small interfering RNA. Interestingly, reduction of Egfl7 expression resulted in significant inhibition of migration but not growth of HCCLM3 cells. Biochemical analysis indicated that Egfl7 could facilitate the phosphorylation of focal adhesion kinase (FAK) and therefore promote the migration of HCCLM3 cells. In addition, this effect was almost completely blocked by inhibition of epidermal growth factor receptor (EGFR), indicating that the activation of FAK by Egfl7 is mediated through EGFR. Finally, we used a mouse model to demonstrate that down-regulation of Egfl7 was associated with suppression of intrahepatic and pulmonary metastases of HCC. Collectively, our study shows for the first time that overexpression of Egfl7 in HCC and Egfl7 promotes metastasis of HCC by enhancing cell motility through EGFR-dependent FAK phosphorylation.

Conclusion: Our study suggests Egfl7 as a novel prognostic marker for metastasis of HCC and a potential therapeutic target.
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http://dx.doi.org/10.1002/hep.23197DOI Listing
December 2009

p53-induced RING-H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection.

Cancer 2009 Oct;115(19):4554-63

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha City, People's Republic of China.

Background: Currently, the role of p53-induced RING-H2 protein (PIRH2) in the development of hepatocellular carcinoma (HCC) remains unknown. The objective of this retrospective study was to investigate the expression of PIRH2 and its relation to prognosis in patients with HCC after hepatic resection.

Methods: Reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR, and Western blot analyses were used to detect expression levels of PIRH2 in 30 samples of HCC tissue and paracarcinomatous liver tissue (PCLT) and in 5 samples of normal liver tissue (NL). In addition, immunohistochemical analysis was performed on 122 HCC specimens and follow-up information data from those patients were reviewed.

Results: Both messenger RNA and protein expression levels of PIRH2 were elevated significantly in HCC tissues compared with PCLT and NL tissues. The increased PIRH2 expression was correlated with vein invasion, Edmondson-Steiner grade, TNM stage, and multiple tumor nodes (P<.05). It is noteworthy that the patients with HCC who had high PIRH2 expression had shorter overall survival and disease-free survival than the patients who had low PIRH2 expression (median survival, 280 days vs 372 days; P = .0002; median disease-free survival, 220 days vs 310 days; P = .0016). Multivariate Cox regression analysis revealed that high PIRH2 expression was an independent prognostic factor for patients with HCC (relative risk, 1.792; P = .009).

Conclusions: The current data revealed that increased expression of PIRH2 was correlated with poor survival in patients with HCC, indicating that PIRH2 is a novel prognostic marker for HCC.
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http://dx.doi.org/10.1002/cncr.24494DOI Listing
October 2009

Decreased expression of inhibitor of growth 4 correlated with poor prognosis of hepatocellular carcinoma.

Cancer Epidemiol Biomarkers Prev 2009 Feb;18(2):409-16

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha City, Hunan Province, PR China.

Objective: Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays an important role in tumor growth and angiogenesis. Here, we examined the expression of ING4 in hepatocellular carcinoma (HCC) tissues and analyzed its correlation with the progression of HCC.

Methods: Specimens from 136 HCC patients were determined immunohistochemically for ING4 expression. The correlation of ING4 levels with clinicopathologic variables, prognosis, and metastatic potential was analyzed. Among the 136 cases, 36 paired HCC and paracarcinomatous liver tissue specimens were analyzed for ING4 expression levels by real-time quantitative reverse transcription-PCR and Western blotting. MVD was determined by CD34 immunostaining to test whether it correlated with ING4 protein expression level.

Results: The ING4 mRNA and protein levels were significantly lower in HCC than paracarcinomatous liver tissue from both real-time quantitative reverse transcription-PCR and Western blotting (P = 0.039 and 0.012, respectively). Importantly, the ING4 protein level correlated with the Edmondson-Steiner grade (P = 0.035), vein invasion (P = 0.015), and microvessel density (P = 0.005). Survival and metastasis analysis indicated that HCC patients with lower ING4 expression had poorer overall survival and disease-free survival than those with high expression (P = 0.0001 and 0.0065; respectively). Multivariable Cox regression analysis revealed that the ING4 expression level was an independent factor for prognosis (hazard risk, 9.63; P = 0.001).

Conclusions: ING4 expression is down-regulated in HCC tissues. ING4 expression level correlates with prognosis and metastatic potential, which suggests that ING4 is a candidate prognostic marker of HCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-08-0575DOI Listing
February 2009

Identification of gene expression profiling in hepatocellular carcinoma using cDNA microarrays.

Dig Dis Sci 2009 Dec;54(12):2729-35

Liver Cancer Laboratory, Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, People’s Republic of China.

The aim of this study was systematic investigation of the differentially expressed genes during carcinogenesis in hepatocellular carcinoma (HCC) using cDNA microarray technology. The differentially expressed genes between 22 fresh HCC tissues and para-cancerous liver tissues (PCLT) were displayed using cDNA microarray technology. The result was verified by the reverse transcriptase polymerase chain reaction. Among the 8,464 human genes, 507 (5.99%) genes were expressed differentially at the mRNA levels between HCC and PCLT. Two hundred (2.36%) genes were down-regulated, whereas 307 (3.63%) genes were up-regulated. The mRNA expression levels of RhoC and protocadherin LKC detected by reverse transcription polymerase chain reaction (RT-PCR) were consistent with the microarray experiment. This study describes a gene expression profiling of HCC, which provides an extensive list of potential molecular markers for early diagnosis and molecular targets for the development of drugs to treat patients with primary HCC.
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http://dx.doi.org/10.1007/s10620-008-0667-2DOI Listing
December 2009

Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection.

Ann Surg 2009 Jan;249(1):118-23

Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Objective: To evaluate and compare the clinical and pathologic characteristics and outcomes after hepatic resection of large hepatocellular carcinoma (SLHCC), small HCC (SHCC), and nodular HCC (NHCC).

Summary Background Data: Traditional viewpoint insists that the classification and prognosis of HCC are determined by the size of HCC. As a result, large HCC is often considered as advanced and unresectable. However, we have observed a unique type of HCC-SLHCC, which is large in size but exhibits good clinical, pathologic, and molecular biologic characteristics as well as prognosis.

Methods: From January 1992 to December 2002, a total of 481 consecutive patients were diagnosed with HCC and received hepatic resection. In this series of patients, the clinical and pathologic data, surgical outcome, and long-term survival of patients with SLHCC (group A, n = 260) were analyzed retrospectively and compared with patients who had SHCC (group B, n = 135) or NHCC (group C, n = 86). Postresection prognostic factors of HCC were also evaluated by univariate and multivariate analysis using Cox's proportional hazards model.

Results: The clinical and pathologic characteristics of SLHCC and SHCC were similar except for tumor necrosis and tumor size. Patients of SLHCC had significantly longer operative time, higher intraoperative blood loss, higher intraoperative blood transfusion, and higher postoperative morbidity than SHCC. However, the 2 groups were similar in duration of hospital stay and overall morbidity. Overall survival and disease-free survival in group A and group B were similar and significantly better than those in group C. Multivariate analysis revealed that large amount of intraoperative blood transfusion and vein invasion were independently significant factors for overall survival of patients with HCC.

Conclusion: The clinical and pathologic characteristics and the outcome after hepatic resection of SLHCC are similar to that of SHCC, but significantly better than NHCC. We propose SLHCC as a specific subtype of HCC and hepatic resection as its choice of standard treatment.
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http://dx.doi.org/10.1097/SLA.0b013e3181904988DOI Listing
January 2009

Decreased expression of methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is correlated with a poor prognosis in patients with hepatocellular carcinoma.

Cancer 2008 May;112(9):2002-10

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha City, PR China.

Background: Recent work has demonstrated that methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is critical in the maintenance of chromosome stability and tumor suppression in mice. To investigate its role in human hepatocellular carcinoma (HCC), which currently is unknown, the authors examined the correlation between Mus81 expression and prognosis in patients with HCC.

Methods: Reverse transcriptase-polymersase chain reaction and Western blot analyses were used to determine Mus81 expression levels in 41 paired HCC and paracarcinomatous liver tissue (PCLT) specimens. Immunohistochemistry analysis was also performed on 104 HCC specimens from patients with follow-up information.

Results: Both Mus81 messenger RNA and protein expression levels were decreased significantly in HCC specimens. Moreover, lower Mus81 expression levels were detected in nodular HCC (NHCC) than in solitary large HCC (SLHCC) specimens. Among 104 specimens of HCC, the positive rate of Mus81 was significantly lower than the rate in PCLT (P = .017), and the decreased Mus81expression was correlated significantly with high Edmondson-Steiner grade, multiple tumor nodes, and venous invasion. Patients with HCC who had low Mus81 expression had either poorer disease-free survival or poorer overall survival than patients who had with high Mus81 expression (P = .0027 and P = .0001, respectively). Multivariate Cox regression analysis revealed that low Mus81 expression was an independent prognostic factor for patients with HCC (risk ratio, 5.74; P = .012).

Conclusions: Mus81 expression levels were decreased significantly in HCC specimens, and the decreased levels were correlated with a poor prognosis in patients with HCC, implicating Mus81 as a candidate prognostic marker in HCC.
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http://dx.doi.org/10.1002/cncr.23396DOI Listing
May 2008

Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma.

Dig Dis Sci 2007 Mar;52(3):770-5

Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, P. R. China.

Our previous study identified RhoC as an invasion and metastasis marker in hepatocellular carcinoma patients. Recent document suggested RhoGTPase is required for autocrine motility factor signaling. In this study, we questioned whether there is a correlation between expression of autocrine motility factor receptor and RhoC. Furthermore, we questioned whether elevated expression of autocrine motility factor correlates with metastasis and poor prognosis of HCC. The mRNA expression level of AMFR and RhoC were examined by RT-PCR in 25 cases of HCC and pericarcinomatous liver tissues (PCLT). In addition, the correlation between the expression level of AMFR and clinical pathologic parameters was analyzed. Furthermore, follow-up information was collected to evaluate the prognostic value of AMFR for HCC patients. Our results showed that the expression of AMFR and RhoC significantly increased in HCC compared with PCLT; extrahepatic metastatic lesions expressed significantly higher levels of AMFR and RhoC than corresponding intrahepatic HCC tissues. There is a highly significant correlation of AMFR expression levels with tumor vein invasion, number of tumor nodes, and tumor stage. Anticipatively, positive correlation was observed between mRNA expression of AMFR and RhoC gene. Furthermore, the HCC patients with high-expression of AMFR had significant high recurrence/metastasis and shorter survival than those with low-expression of AMFR. Together, our findings suggested a strong correlation between the expression of AMFR and RhoC and also a correlation between overexpression of them and invasion and metastasis of HCC. Furthermore, our data indicated AMFR as a potential prognosis for HCC.
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http://dx.doi.org/10.1007/s10620-006-9479-4DOI Listing
March 2007
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