Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials

Shi, Guo‐Ming; Xu, Yang; Fan, Jia; Zhou, Jian; Yang, Xun; Qiu, Shuang–Jian; Liao, Yong; Wu, Wei‐Zhong; Ji, Yuan; Ke, Ai–Wu; Ding, Zhen–Bin; He, Yizhou Joseph; Wu, Bing; Yang, Guo‐Huan; Qin, Wenxin; Wu, Zhi‐Ying; Zhu, Jiang; Min, Zhihui; Wu, Zhi‐Quan

doi:10.1007/s00432-008-0407-1

Cited by 147 publications

(126 citation statements)

References 33 publications

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“…We examined the in vivo therapeutic effect of lupeol in the chemoresistant HCC nude mouse model using chemoresistant MHCC-LM3 cells. 32 MHCC-LM3 cells were found to be highly chemoresistant, showing approximately 15-fold and approximately four-fold more resistance to doxorubicin and cisplatin, respectively, compared with Huh-7 and PLC-8024 cells by way of MTT assay due to high ABCG2 expression (data not shown). Using this animal model, we examined the effect of lupeol alone as well as in combination with The in vivo therapeutic effect of lupeol was examined in a nude mice model using chemoresistant MHCC-LM3 cells.…”

Section: Combined Lupeol and Chemotherapeutic Drugmentioning

confidence: 94%

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

et al. 2010

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Liver tumor-initiating cells (T-ICs) are capable of self-renewal and tumor initiation and are more chemoresistant to chemotherapeutic drugs. The current therapeutic strategies for targeting stem cell self-renewal pathways therefore represent rational approaches for cancer prevention and treatment. In the present study, we found that Lup-20(29)-en-3b-ol (lupeol), a triterpene found in fruits and vegetables, inhibited the self-renewal ability of liver T-ICs present in both hepatocellular carcinoma (HCC) cell lines and clinical HCC samples, as reflected by hepatosphere formation. Furthermore, lupeol inhibited in vivo tumorigenicity in nude mice and down-regulated CD133 expression, which was previously shown to be a T-IC marker for HCC. In addition, lupeol sensitized HCC cells to chemotherapeutic agents through the phosphatase and tensin homolog (PTEN)-Akt-ABCG2 pathway. PTEN plays a crucial role in the self-renewal and chemoresistance of liver T-ICs; down-regulation of PTEN by a lentiviral-based approach reversed the effect of lupeol on liver T-ICs. Using an in vivo chemoresistant HCC tumor model, lupeol dramatically decreased the tumor volumes of MHCC-LM3 HCC cell line-derived xenografts, and the effect was equivalent to that of combined cisplatin and doxorubicin treatment. Lupeol exerted a synergistic effect without any adverse effects on body weight when combined with chemotherapeutic drugs. Conclusion: Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs. (HEPATOLOGY 2011;53:160-170)

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Section: Combined Lupeol and Chemotherapeutic Drugmentioning

confidence: 94%

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

et al. 2010

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“…A highly metastatic human HCC cell line (HCCLM3), low-metastatic human HCC cell lines (MHCC97-L, PLC/PRF/5, Hep3B, and HepG2; American Type Culture Collection), 6,18,19 and human umbilical vein endothelial cells (HUVECs; American Type Culture Collection) were used in this study. Male, athymic BALB/c nude mice (8 weeks old; Shanghai Institute of Material Medicine, Chinese Academy of Science, Shanghai, China) were raised under specific pathogen-free conditions.…”

Section: Methodsmentioning

confidence: 99%

CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma

et al. 2010

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Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3b (GSK-3b)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151 high in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC. Conclusion: Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3b/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC. (HEPATOLOGY 2010;52:183-196) Abbreviations: AFP, alpha-fetoprotein; AKT, protein kinase B; bFGF, basic fibroblast growth factor; CDC42, cell division control protein 42 homologue; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSK, glycogen synthase kinase; H&E, hematoxylin and eosin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HR, hazard ratio; HUVEC, human umbilical vein endothelial cell; LY294002, 2-morpholin-4-yl-8-phenylchromen-4-one; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; MVD, microvessel density; NA, not adopted; NS, not significant; OS, overall survival; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNM, tumor node metastasis; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; VEGF, vascular endothelial growth factor.From the

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“…15 Monoclonal mouse antihuman CD151 (11G5a; 1:200 dilution; Serotec, Oxford, United Kingdom) was used to detect the expression of CD151. GAPDH (1:5000 dilution; Chemicon, Temecula, Calif) was used as an internal control.…”

Section: Immunoblot Analysismentioning

confidence: 99%

Overexpression of CD151 as an adverse marker for intrahepatic cholangiocarcinoma patients

Huang

Shi

et al. 2010

Cancer

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BACKGROUND:Previous studies have indicated that CD151, a hydrophobic protein, forms a functional complex with the proto‐oncogene that encodes an N‐methyl‐N′‐nitro‐N‐nitroso‐guanidine (MET) protein (c‐Met), and CD151 overexpression reportedly is involved in metastasis/invasion of several tumors. The objective of the current study was to investigate the expression and role of CD151 and/or c‐Met in intrahepatic cholangiocarcinoma (ICC).METHODS:Sixty ICC tissues with matched nontumorous tissues and 20 normal liver tissues were used to analyze CD151 expression at the level of messenger RNA (mRNA) and protein. Then, the expression of CD151 in an ICC cell line was interrupted using a specific lentiviral‐mediated small hairpin RNA (shRNA)‐CD151, and the role of CD151 in the proliferation, metastasis, and invasion of ICC cells was assessed. The expression of CD151/c‐Met was examined further by immunohistochemistry in a tissue microarray (TMA) that included 140 samples of ICC, and the prognostic role of CD151 and/or c‐Met in ICC was evaluated in Kaplan‐Meier and Cox regression analyses.RESULTS:The expression of CD151 in ICC tissues was much higher than that in nontumorous samples and normal liver; and, after the down‐regulation of CD151, HCCC‐9810 cells had decreased capability for metastasis/invasion in vitro. CD151 overexpression was correlated significantly with larger tumors, poor differentiation, multiple nodular, microvascular/bile duct invasion, and lymphatic metastasis (P<.05). The postoperative 2‐year and 5‐year overall survival (OS) rates for patients with low CD151 expression (<50% tumor staining) and/or low c‐Met expression (<20% tumor staining) were higher than the rates for patients with high CD151 expression (≥50% tumor staining) and/or high c‐Met expression (≥20% tumor staining). Multivariate analysis revealed that CD151 overexpression and c‐Met overexpression were independent prognostic markers for ICC.CONCLUSIONS:Overexpression of CD151 was implicated in metastasis/invasion of ICC, and both CD151 overexpression and c‐Met overexpression may be potential molecular therapeutic targets for ICC. Cancer 2010. © 2010 American Cancer Society.

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Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials

Abstract: SP cells purified from HCC cell lines harbors cancer stem cell-like properties, and may be related to the metastatic potentials and therapeutic-resistance of HCC.

Cited by 147 publications

References 33 publications

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma

Overexpression of CD151 as an adverse marker for intrahepatic cholangiocarcinoma patients

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