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Huang D, Yang B, Yao Y, Liao M, Zhang Y, Zeng Y, Zhang F, Wang N, Tong G. Autophagic Inhibition of Caveolin-1 by Compound Phyllanthus urinaria L. Activates Ubiquitination and Proteasome Degradation of β-catenin to Suppress Metastasis of Hepatitis B-Associated Hepatocellular Carcinoma. Front Pharmacol 2021; 12:659325. [PMID: 34168559 PMCID: PMC8217966 DOI: 10.3389/fphar.2021.659325] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/24/2021] [Indexed: 12/29/2022] Open
Abstract
Compound Phyllanthus urinaria L. (CP) is a traditional Chinese medicine (TCM) formula for cancer treatment in the clinic, particularly during progression of hepatitis B-associated hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted metastasis of HBV-associated HCC by stabilizing β-catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and subsequently attenuated the metastasis-promoting effect of Cav-1. In addition, the anti-cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the tumor growth and metastasis of HBV-associated HCC in both mice liver cancer xenograft and zebrafish xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-catenin axis to control the late-phase of cancer progression.
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Affiliation(s)
- Danping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bowen Yang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaoyao Yao
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mianmian Liao
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Zhang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yihao Zeng
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxue Zhang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng Wang
- The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangdong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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Yang M, Xu Z, Wang Q, Zhang AQ, Min J. A hyposensitive anticancer drug induces higher surface expression and release of heat shock proteins in a human hepatocellular carcinoma cell line. Mol Med Rep 2015; 12:2879-85. [PMID: 25955691 DOI: 10.3892/mmr.2015.3727] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 03/24/2015] [Indexed: 11/05/2022] Open
Abstract
Heat shock proteins (HSPs) respond to multiple stresses and have been implicated as essential immune chaperones that regulate innate and adaptive immunity. The exposure of HSPs containing tumour peptide complex to immune surveillance elements may elicit a specific anti-tumour response. The present study examined the potential of anticancer drugs to induce apoptosis of HepG2 cells and elicit the expression of HSP proteins, including HSP70 and gp96, on the membrane or their release to the extracellular environment, leading to HSP exposure. In the present study, etoposide and carboplatin were classified by an adenosine triphosphate assay as representatives of hypersensitive and hyposensitive anticancer drugs, respectively. Flow cytometry, immunofluorescence, ELIZA and reverse transcription quantitative polymerase chain reaction were all used to detect changes in the HSPs. The results demonstrated that etoposide and carboplatin induced apoptosis of HepG2 cells. In addition, following treatment with etoposide or carboplatin, HSP70/gp96 expression increased, demonstrating a 'transfer expression' pattern: The cytosol expression decreased while the surface expression increased. These alterations progressed steadily with notable alterations following treatment with etoposide for 24 h or carboplatin for 72 h. Additionally, at the end of treatment, release of HSP70/gp96 to the extracellular environment increased. Notably, following treatment with the hyposensitive anticancer drug carboplatin for 72 h, the surface expression of gp96 in HepG2 cells was significantly increased. These results suggest that when combined with cancer cell apoptosis, anticancer drugs induce the membrane expression and release of HSP70/gp96 in hepatocellular carcinoma (HCC) cells, which may represent a crucial event in the immune anti-tumour response. Notably, treatment with the hyposensitive anticancer drug for a longer time period resulted in greater surface expression and release of gp96, which suggests a potential use for hyposensitive anticancer drugs in HSP-based dendritic cell vaccine preparation and chemoimmunotherapy for HCC patients.
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Affiliation(s)
- Mei Yang
- Breast Disease Center, Guangdong Women and Children Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510010, P.R. China
| | - Zhe Xu
- Department of Ophthalmology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Qi Wang
- Breast Disease Center, Guangdong Women and Children Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510010, P.R. China
| | - An-Qin Zhang
- Breast Disease Center, Guangdong Women and Children Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510010, P.R. China
| | - Jun Min
- Department of Hepatobiliary Surgery, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
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Lei JY, Yan LN, Wang WT. Transplantation vs resection for hepatocellular carcinoma with compensated liver function after downstaging therapy. World J Gastroenterol 2013; 19:4400-4408. [PMID: 23885153 PMCID: PMC3718910 DOI: 10.3748/wjg.v19.i27.4400] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 04/27/2013] [Accepted: 06/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: Our study aimed to compare the results of liver transplantation (LT) and liver resection (LR) in patients with hepatocellular carcinoma (HCC) that met the Milan criteria after successful downstaging therapy.
METHODS: From February 2004 to August 2010, a consecutive series of 102 patients were diagnosed with advanced-stage HCC that met the modified UCSF down-staging protocol inclusion criteria. All of the patients accepted various down-staging therapies. The types and numbers of treatments were tailored to each patient according to the tumor characteristics, location, liver function and response. After various downstaging therapies, 66 patients had tumor characteristics that met the Milan criteria; 31 patients accepted LT in our center, and 35 patients accepted LR. The baseline characteristics, down-staging protocols, postoperative complications, overall survival and tumor free survival rate, and tumor recurrence rate were compared between the two groups. Kaplan-Meier analyses were used to estimate the long-term overall survival and tumor-free survival rate. Meanwhile, a Cox proportional hazards model was used for the multivariate analyses of overall survival and disease-free survival rate.
RESULTS: No significant difference was observed between the LT and LR groups with respect to the down-staging protocol, target tumor characteristics, and baseline patient characteristics. Fifteen patients suffered various complications after LT, and 8 patients had complications after LR. The overall complication rate for the LT group was 48.4%, which was significantly higher than the LR group (22.9%) (P = 0.031). The overall in-hospital mortality in hospital for the LT group was 12.9% vs 2.9% for the LR group (P = 0.172). The overall patient survival rates at 1-, 3- and 5-years were 87.1%, 80.6% and 77.4%, respectively, after LT and 91.4%, 77.1% and 68.6%, respectively, after LR (P = 0.498). The overall 1-, 3- and 5-year tumor recurrence-free rates were also comparable (P = 0.656). Poorer tumor differentiation (P = 0.041) and a higher post-downstage alpha-fetoprotein (AFP) level (> 400 ng/mL) (P = 0.015) were the two independent risk factors for tumor recurrence in the LT and LR patients who accepted successful down-staging therapy.
CONCLUSION: Due to the higher postoperative morbidity and similar survival and tumor recurrence-free rates, LR might offer better or similar outcome over LT, but a larger number and further randomized studies may be needed in the future for drawing any positive conclusions.
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Kaibori M, Kubo S, Nagano H, Hayashi M, Haji S, Nakai T, Ishizaki M, Matsui K, Uenishi T, Takemura S, Wada H, Marubashi S, Komeda K, Hirokawa F, Nakata Y, Uchiyama K, Kwon AH. Clinicopathological Features of Recurrence in Patients After 10-year Disease-free Survival Following Curative Hepatic Resection of Hepatocellular Carcinoma. World J Surg 2013; 37:820-8. [DOI: 10.1007/s00268-013-1902-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Zhou XD, Tang ZY, Ma ZC, Fan J, Wu ZQ, Qin LX, Zhou J, Yu Y, Sun HC, Qiu SJ. Twenty-year survivors after resection for hepatocellular carcinoma-analysis of 53 cases. J Cancer Res Clin Oncol 2009. [PMID: 19294419 DOI: 10.1007/s00432-009-0546-z.epub] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE To clarify the clinicopathologic features of patients surviving > or =20 years after resection for hepatocellular carcinoma (HCC). METHODS Between 1961 and 1987, a total of 396 patients underwent hepatic resection for HCC; 53 (13.4%) patients survived > or =20 years, and 343 (86.6%) patients survived <20 years. A comparative study between the two groups was made. RESULTS By March of 2007, 67.6% (36/53) patients are still alive, disease free; 5.7% (3/53) patients died of tumor recurrence or metastasis; 11.3% (6/53) patients died of liver failure; 5.7% (5/53) patients were lost during follow-up. The longest patient survived 43 years and 2 months. Five young patients got married after resection and have had babies. One patient with a tumor measuring 17 x 13 x 9 cm (largest tumor in this series) survived for 37 years after resection, still alive, free of disease. Reresection for recurrence was done in nine patients, mean survival being 26 years and 11 months. Reresection for solitary pulmonary metastasis was carried out in three patients, mean survival being 29 years and 2 months. In comparison with patients surviving <20 years, patients surviving > or =20 years were significantly younger (P = 0.031), had a higher incidence of asymptomatic tumors (56.6 vs. 34.4%, P = 0.002); lower gamma-glutamyl transpeptidase level (< or =50 U/L, 64.2 vs. 25.9%, P < 0.000), lower proportion of liver cirrhosis (66.0 vs. 83.6%, P = 0.002); higher percentage of small tumors (< or =5 cm, 62.3 vs. 29.9%, P < 0.000), single nodule tumors (90.6 vs. 62.9%, P < 0.000), and well-encapsulated tumors (86.8 vs. 43.6%, P < 0.000); lower proportion of tumor emboli in the portal vein (3.8 vs. 22.5%, P = 0.002), better differentiation of tumor cells (Edmondson grade I, 21.6 vs. 9.1%, P = 0.036), and higher curative resection rate (100 vs. 64.1%, P < 0.000). CONCLUSIONS Early detection and curative resection are the principal factors improving long-term survival. Long-term follow-up after resection of HCC is very important, and should continue for the remainder of the patient's life. Reresection for recurrence and metastasis is important approach to improve prognosis.
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Affiliation(s)
- Xin-Da Zhou
- Liver Cancer Institute, Zhong Shan Hospital, Fudan University, 136 Yi Xue Yuan Road, 200032 Shanghai, China.
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Twenty-year survivors after resection for hepatocellular carcinoma-analysis of 53 cases. J Cancer Res Clin Oncol 2009; 135:1067-72. [DOI: 10.1007/s00432-009-0546-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 01/08/2009] [Indexed: 01/12/2023]
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The effect of targeted magnetic nanopaticles on hepatoma and the expression of bcl-2/bax protein. ACTA ACUST UNITED AC 2008; 28:443-6. [PMID: 18704308 DOI: 10.1007/s11596-008-0415-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Indexed: 01/31/2023]
Abstract
The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving 5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D, consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5) group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope (TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method. The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E (P<0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P<0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.
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Yang J, Qin LX, Ye SL, Liu YK, Li Y, Gao DM, Chen J, Tang ZY. The abnormalities of chromosome 8 in two hepatocellular carcinoma cell clones with the same genetic background and different metastatic potential. J Cancer Res Clin Oncol 2003; 129:303-8. [PMID: 12750998 DOI: 10.1007/s00432-003-0436-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2002] [Accepted: 01/28/2003] [Indexed: 12/24/2022]
Abstract
PURPOSE Two hepatocellular carcinoma (HCC) cell clones named MHCC97-H and MHCC97-L with different metastatic potential have recently been established from the same parent cell line MHCC97 in our institute. The cytogenetic alterations of these two clones were investigated in this study to explore the possible clues to the mechanism involved in HCC metastasis. METHODS Their chromosomal aberrations were analyzed with comparative genomic hybridization (CGH), chromosome-specific painting, and two-color fluorescence in situ hybridization (FISH). RESULTS The aberrations were found in a total of 17 chromosomes, and six kinds of the aberrations including gains of 1q, 7q, 8q, 20, and the losses of 8p23, 21q were found both in the two cell clones and their parent cell line MHCC97. Using modified CGH, with the DNA of MHCC97-L as control to test the MHCC97-H clone, the loss of 8p23 and the gain of 1q31-32, 8q21.3-22, 13q22, 17q22 were highlighted, and the most significant finding was on chromosome 8. Dual color FISH combining a pericentromeric probe and a BAC probe mapping at 8q23.1 was then performed to verify this result, and the signal ratios of the BAC to centromere were 1.43 in MHCC97-H and 1.45 in MHCC97-L, confirming the over-representations at 8q in both cells. Another interesting finding in the dual-color metaphase FISH was the intrachromosomal translocation of 8q to 8p (looked like an isochromosome 8) and non-reciprocal translocation of part of 8q to 4q, which was further clarified and proved by the FISH with whole chromosome 8 painting probe. CONCLUSIONS The high copies amplification on 8q, the formation of isochromosome 8, non-reciprocal translocation of partial 8q to 4q, and loss of 8p occurred at the same time and are the characteristic chromosomal aberrations of the two cell clones. The chromosome 8p, especially 8p23, might harbor some novel genes related to the HCC metastasis.
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Affiliation(s)
- Jiong Yang
- Liver Cancer Institute & Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, 200032, Shanghai, China
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Yuen MF, Hon C, Hui CK, Siu CW, Lai CL. Recombinant interferon alfa 2b therapy in a patient with metastatic hepatocellular carcinoma. J Clin Gastroenterol 2002; 35:272-5. [PMID: 12192207 DOI: 10.1097/00004836-200209000-00015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
At present, there is no effective treatment of metastatic hepatocellular carcinoma (HCC). Systemic interferon alfa (IFN-alpha) was found to be of some use in patients with inoperable HCC in two randomized trials. We report a case in which metastatic HCC was cured by systemic IFN-alpha 2b in combination with surgery. A patient developed two bilateral pulmonary metastatic HCC nodules 5 months after the resection of the primary HCC. He was treated with systemic IFN-alpha 2b. One lesion completely disappeared. The other lesion showed an initial response but became resistant to the IFN-alpha 2b therapy after reduction in dosage because of the side effects. This was resected in view of the absence of new metastases after 9 months of IFN-alpha 2b therapy. He remained free from recurrence at 59 months of follow-up. A rare, but reversible, complication of retinal cotton wool spots caused by IFN-alpha 2b occurred in this patient. IFN-alpha 2b is partially effective in treating metastatic HCC. The time for its administration can also serve as an observation period, which is vital in deciding whether definitive surgical treatment of any residual lesions is indicated.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Tang ZY, Sun FX, Tian J, Ye SL, Liu YK, Liu KD, Xue Q, Chen J, Xia JL, Qin LX, Sun SL, Wang L, Zhou J, Li Y, Ma ZC, Zhou XD, Wu ZQ, Lin ZY, Yang BH. Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential. World J Gastroenterol 2001; 7:597-601. [PMID: 11819839 PMCID: PMC4695559 DOI: 10.3748/wjg.v7.i5.597] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Metastatic human HCC model is needed for the studies on mechanism and interven tion of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of hu man HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metasta sis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesio nmolecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis, antisense approach, metallopro teinase inhibitor, differentiation inducer, etc. It is concluded that the establ ishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vivo and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence.
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Affiliation(s)
- Z Y Tang
- Liver Cancer Institute of Fudan University (previous Liver Cancer Institute of Shanghai Medical University)136 Yixueyuan Road, Zhongshan Hospital, Shanghai 200032,China.
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Cui J, Zhou XD, Liu YK, Tang ZY, Zile MH. Abnormal β-catenin gene expression with invasiveness of primary hepatocellular carcinoma in China. World J Gastroenterol 2001; 7:542-6. [PMID: 11819825 PMCID: PMC4688669 DOI: 10.3748/wjg.v7.i4.542] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the abnormal expression of β-catenin gene and its relationship with invasiveness of primary hepatocellular carcinoma among Chinese people.
METHODS: Thirty-four hepatocellular carcinoma (HCC) specimens and adjacent paracancerous tissues, 4 normal liver tissues were immunohistochemically stained to study subcellular distribution of β-catenin. Semiquantitive analysis of expression of β-catenin gene exon 3 mRNA was examined by RT-PCR and in situ hybridization. The relationship between expressions of both β-catenin protein, mRNA and clinicopathological characteristics of HCC was also analyzed.
RESULTS: Immunohistochemistry showed that all normal liver tissues and para-cancerous tissues examined displayed membranous type staining for β-catenin protein, occasionally with weak expression in the cytoplasm. While 21 cases (61.8%) of HCC examined showed accumulated type in cytoplasms or nuclei. The accumuled type Labling Index (LI) of cancer tissue and para-cancarous tissue was (59.9 ± 26.3) and (18.3 ± 9.7) respectively (P < 0.01). Higher accumulated type LI was closely related with invasiveness of HCC. Results of RT-PCR showed the β-catenin gene exon 3 mRNA Expression Index (EI) of 34 HCCs was higher than that of para-cancerous tissue and normal liver tissue. Using in situ hybridization, the signal corresponding to β-catenin gene exon 3 mRNA was particularly strong in cytoplasm of HCC when compared with those of para-cancerous and normal liver tissues. Over expression of β-catenin exon 3 was also found to be correlated with high metastatic potential of HCC.
CONCLUSION: Abnormal expression of β-catenin gene may contribute importantly to the invasiveness of HCC among Chinese people.
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Affiliation(s)
- J Cui
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
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Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, Wu ZQ, Fan J, Qin LX, Zheng BH. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 2001; 91:1479-86. [PMID: 11301395 DOI: 10.1002/1097-0142(20010415)91:8<1479::aid-cncr1155>3.0.co;2-0] [Citation(s) in RCA: 225] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Recently, the implementation of screening programs using alpha-fetoprotein (AFP) and ultrasonography in high risk populations has identified increasing numbers of patients with small hepatocellular carcinoma (small HCC). The aim of this study was to summarize the authors' experience in patients who underwent hepatectomy for small HCC and the factors that influence or improve long term survival. METHODS The study included 1000 patients who underwent hepatectomy for small HCC (< or = 5 cm) and compared them with 1366 patients who underwent hepatectomy for large HCC (> 5 cm) during the same period. A Cox proportional-hazards model was used for multivariate analysis of prognostic factors. RESULTS Comparison between patients with small HCC (n = 1000 patients) and patients with large HCC (n = 1366 patients) revealed that those with small HCC had a higher resection rate (93.6% [1000 of 1068 patients] vs. 55.7% [1366 of 2451 patients]; P < 0.01), a higher curative resection rate (80.5% [805 of 1000 patients] vs. 60.7% [829 of 1366 patients]; P < 0.01), a lower operative mortality rate (1.5% [15 of 1000 patients] vs. 3.7% [50 of 1366 patients]; P < 0.01), better differentiation of tumor cells (Edmondson Grade 3-4; 14.9% vs. 20.1%; P < 0.01), a higher incidence of single nodule tumors (82.6% vs. 64.4%; P < 0.01), a higher proportion of well encapsulated tumors (73.3% vs. 46.3%; P < 0.01), a lower incidence of tumor emboli in the portal vein (4.9% vs. 20.8%; P < 0.01), and higher survival rates after undergoing resection (5 years: 62.7% vs. 37.1%; P < 0.01; 10 years: 46.3% vs. 29.2%; P < 0.01). No significant difference was found between survival after undergoing minor resection (n = 949 patients) or lobectomy (n = 51 patients) in patients with small HCC (P > 0.05). Reresection for subclinical recurrence or solitary pulmonary metastasis after small HCC resection was undertaken in 84 patients. CONCLUSIONS Resection is still the modality of first choice for the treatment of patients with small HCC. Minor resection instead of lobectomy was the key to increasing resectability and decreasing operative mortality, and reresection for subclinical recurrence or solitary pulmonary metastasis was important approach to prolonging survival further.
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Affiliation(s)
- X D Zhou
- Liver Cancer Institute, Zhong Shan Hospital, Shanghai Medical University, Shanghai, People's Republic of China.
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Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31:330-5. [PMID: 10655254 DOI: 10.1002/hep.510310211] [Citation(s) in RCA: 292] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The prognosis for patients with hepatocellular carcinoma (HCC) is poor because of the low chance of curative treatment. To increase the chance of intervention and to improve survival, early detection of subclinical HCC (SCHCC) by alpha-fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many countries. Three hundred six Chinese patients with HCC diagnosed between January 1995 and December 1997 were recruited. They were categorized into two groups: 142 patients (group 1) had SCHCC diagnosed by screening (AFP and/or USG), and 164 patients (group 2) presented with symptomatic HCC. The tumor size was significantly smaller in group 1 compared with that of group 2 (3.5 cm vs. 8.1 cm; P <.0001). A significantly higher proportion of patients had bilobar involvement, multifocal HCC, diffuse-type HCC, portal vein infiltration, and distant metastasis in group 2 when compared with group 1. Operability and feasibility of treatment by transcatheter intra-arterial chemoembolization (TACE) in group 1 patients (26.8% and 45.1%, respectively) were significantly better than in group 2 patients (7.9% and 32.3%, P <.0001 and P =.03, respectively). The cumulative survival rate was significantly higher in group 1 than in group 2 (P <.0001). For those who had surgical resection and those who had TACE, group 1 patients had a higher cumulative survival rate compared with that of group 2 patients (P =.04 and P =.0003, respectively). Screening for HCC by AFP and/or USG can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whether it can improve survival requires a further prospective, randomized study.
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Affiliation(s)
- M F Yuen
- Department of Medicine, Queen Mary Hospital, Hong Kong
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14
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Sun JJ, Zhou XD, Liu YK, Zhou G. Phase tissue intercellular adhesion molecule-1 expression in nude mice human liver cancer metastasis model. World J Gastroenterol 1998; 4:314-316. [PMID: 11819307 PMCID: PMC4761548 DOI: 10.3748/wjg.v4.i4.314] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the phase cancer tissue intercellular adhesion molecule-1 (ICAM-1) expression of human cancer metastasis model in nude mice, and to analyze the relationship between ICAM-1 expression and the metastasis and recurrence of hepatocellular cancinoma (HCC).
METHODS: HCC tissues from liver cancer metastasis model in nude mice (LCI-D20) was orthotopically implanted, and ICAM-1 expression in HCC tissues at different growing time were detected by immunodot blot. Tumor size, intrahepatic and extrahepatic metastasis foci were observed by naked eyes and under light microscope.
RESULTS: ICAM-1 was positively correlated to the tumor growing time (r = 0.88, P < 0.01) and tumor size r = 0.5, P < 0.05). It was higher in metastatic HCC than in nonmetastatic HCC (8.24 ± 0.95 vs 3.03 ± 0.51, P < 0.01). ICAM-1 content in cancer tissues increased suddenly after metastasis occurred and then maintained in a high level. ICAM-1 was also higher in multimetastasis group than in monometastasis group (10.05 ± 1.17 vs 5.48 ± 0.49, P < 0.05).
CONCLUSION: Tissue ICAM-1 could predict not only the metastasis of human liver cancer metastasis model in nude mice early and sensitively, but also the metastasis degree. So tissue ICAM-1 may be a potential index indicating the status of metastasis of HCC patients.
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Sun JJ, Zhou XD, Zhou G, Liu YK. Expression of intercellular adhesive molecule-1 in liver cancer tissues andliver cancer metastasis. World J Gastroenterol 1998; 4:202-205. [PMID: 11819275 PMCID: PMC4723456 DOI: 10.3748/wjg.v4.i3.202] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the relationship between intercellular adhesive molecule-1 (ICAM-1) and liver cancer metastasis and to search for factors to predict metastasis of liver cancer.
METHODS: ICAM-1 expression in fresh tissues of normal liver and hepatocellular cancer (HCC) was examined by immunoperoxidase staining. The expression of ICAM-1 in human hepatoma, tumor surrounding tissues and normal livers were semiquantitatively analyzed by Dot immuno blot. Tissue ICAM-1 expression at mRNA level was detected by Northern blot.
RESULTS: All 6 cases of normal liver samples were negative in anti-ICAM-1 immunohistochemical staining, 80.0% (36/45) of HCC presented various ICAM-1 expression. The number of positive cells was a little higher in large tumors, tumors with intact capsule and metastasis, but there was no significant difference. Two cases with cancer embolus also had high ICAM-1 expression. ICAM-1 concentration in HCC (13.43 ± 0.09) was higher than that in tumor surrounding tissues (5.89 ± 0.17, P < 0.01) and normal livers (4.27 ± 0.21, P < 0.01). It was also higher in metastasis group (20.24 ± 0.30) than in nonmetastasis group (10.23 ± 0.12, P < 0.05). Northern blot analysis revealed that ICAM-1 expression at mRNA level was also higher in HCC and cancer embolus than that in tumor surrounding tissues and normal livers.
CONCLUSION: Tissue ICAM-1 could indicate the growth and metastasis of HCC, and may be an index that can predict liver cancer metastasis.
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Yao M, Zhou XD, Zha XL, Shi DR, Fu J, He JY, Lu HF, Tang ZY. Expression of the integrin alpha5 subunit and its mediated cell adhesion in hepatocellular carcinoma. J Cancer Res Clin Oncol 1997; 123:435-40. [PMID: 9292706 DOI: 10.1007/bf01372547] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Tumor invasion and metastasis are complex processes, requiring the ability of tumor cells to interact with proteins of the extracellular matrix through cell-adhesion molecules on the cell surface. Integrins are heterodimeric membrane glycoproteins, consisting of alpha and beta subunits, which enable cells to recognize adhesive substrates in the extracellular matrix. The roles of the integrin alpha5beta1 in tumor invasion are highlighted by finding that some tumor cells have lost or reduced alpha5beta1 expression. It therefore functions as a negative signaling regulator. Expression of alpha5beta1 and its mediation of cell adhesion in hepatocellular carcinoma (HCC) have not been elucidated. In surgical specimens of HCC we found, by immunohistochemistry and Northern blot analysis, that the alpha5-positive rates in cancerous tissues were lower than the corresponding rates in non-cancerous tissues. Reduced expression of the integrin alpha5 occurred more frequently in HCC with more malignant phenotypes, such as poor differentiation, large size (more than 10-cm in diameter), absence of capsule and high invasion. Reverse transcription/polymerase chain reaction, a more sensitive assay, was used to detect the alpha5 mRNA level in LCID20, a highly metastatic model of human HCC, and LCID35, a low-metastasis model. The results showed that integrin alpha5 was negative in the former and positive in the latter. Cell adhesion assays showed the maximal percentage inhibition of anti-alpha5 mAb on SMMC 7721 cell adhesion to fibronectin to be 68.9 +/- 4.9% at the saturation concentrations of each antibody (200 microg/ml). If anti-alpha5 mAb was combined with anti-beta1 mAb, the inhibition was 74.1 +/- 11.1%. It is concluded that reduced expression of the integrin alpha5 subunit is correlated with more malignant phenotypes of human HCC. Any change in the adhesion of hepatocellular carcinoma cells to fibronectin is mainly dependent upon the function of the integrin alpha5beta1.
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MESH Headings
- Antigens, CD/biosynthesis
- Antigens, CD/metabolism
- Antigens, CD/physiology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Adhesion/physiology
- Fibronectins/metabolism
- Humans
- Integrin alpha5
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Neoplasm Metastasis
- Phenotype
- Polymerase Chain Reaction
- RNA, Messenger/metabolism
- Receptors, Fibronectin/biosynthesis
- Receptors, Fibronectin/metabolism
- Receptors, Fibronectin/physiology
- Tumor Cells, Cultured
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Affiliation(s)
- M Yao
- Liver Cancer Institute, Zhong Shan Hospital, Shanghai Medical University, P.R. China
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Zhou XD, Tang ZY, Yu YQ, Yang BH, Lin ZY, Lu JZ, Ma ZC. Long-term results of surgery for small primary liver cancer in 514 adults. J Cancer Res Clin Oncol 1996; 122:59-62. [PMID: 8543594 DOI: 10.1007/bf01203074] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
During 1958-1993, 2030 patients with pathologically proven primary liver cancer (PLC) were retrospectively reviewed. Comparison between small PLC (< or = 5 cm, n = 514) and large PLC (> 5 cm, n = 1516) revealed that small PLC had a higher resection rate (92.4% versus 49.1%), lower operative mortality (1.7% versus 5.2%), a higher percentage of single tumour nodules (78.0% versus 53.4%), a higher percentage of well encapsulated tumour (74.5% versus 35.8%) and higher survival rates after resection (5-year, 63.8% versus 36.6%; 10-year, 46.8% versus 28.5%). No significant difference was found between survival following limited resection (n = 440) and lobectomy (n = 34) in patients with small PLC. Re-resection of any subclinical recurrence or solitary pulmonary metastasis after small PLC resection was done in 70 cases. These results indicate that resection is still the modality of choice for treatment of small PLC; limited resection instead of lobectomy was the key to increasing resectability and decreasing operative mortality; re-resection of subclinical recurrence was important to prolong survival further.
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Affiliation(s)
- X D Zhou
- Liver Cancer Institute, Zhong Shan Hospital, Shanghai Medical University, P.R. China
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