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Li J, Cheng X, Meng Y, Wang M. Comparison of clinical characteristics and outcomes in patients with hepatocellular carcinoma based on serum alpha-fetoprotein status. Eur J Gastroenterol Hepatol 2025; 37:619-626. [PMID: 39976057 DOI: 10.1097/meg.0000000000002933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BACKGROUND Alpha-fetoprotein (AFP) is the most commonly used and crucial tumor marker in clinical diagnosis and prognosis guidance for hepatocellular carcinoma (HCC). However, approximately 30% of HCC patients do not exhibit abnormal serum AFP levels at the time of diagnosis. This study aims to investigate the clinical characteristics and prognosis differences between AFP-negative and AFP-positive patients with HCC. METHODS Clinical data on patients diagnosed between 2010 and 2015 from the Surveillance, Epidemiology, and End Results Program were collected and analyzed. All patients with HCC were reported as AFP-negative or AFP-positive based on AFP test results. Overall survival (OS) and cancer-specific survival (CSS) were compared between the AFP-negative and AFP-positive patients. Logistic regression analysis and multivariable Cox regression analysis were performed to identify the association of AFP with tumor size, lymph node metastasis, distant metastasis, and CSS. RESULTS Of 7090 patients, 2074 (29.3%) and 5016 (70.7%) were AFP-negative and AFP-positive patients, respectively. The 5-year OS and CSS rates in AFP-negative patients were significantly better than AFP-positive patients (36.4 vs. 20.7% and 46.7 vs. 27.2%, both P < 0.001). Logistic regression analysis revealed that the AFP level was an independent risk factor of tumor size [odds ratio (OR), 1.821; 95% confidence interval (CI), 1.625-2.040; P < 0.001], N stage (OR, 1.922; 95% CI, 1.528-2.417; P < 0.001) and M stage (OR, 2.435; 95% CI, 1.980-2.995; P < 0.001). On multivariable Cox-regression analyses, AFP-positive was associated with decreased CSS (hazard ratio, 1.452; 95% CI, 1.355-1.557; P < 0.001). CONCLUSION Abnormal serum AFP was significantly associated with worse prognosis, larger tumor size, more lymph node metastasis, and distant metastasis. Patients with AFP-positive may need more individualized treatment decision and further optimization of HCC management strategies.
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Affiliation(s)
- Jing Li
- Department of Radiation Oncology, Third Affiliated Hospital of Naval Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China
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Song BG, Sinn DH, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW, Kim JM, Joh JW, Choi GS. Changes in Tumor Markers and Their Implications in Selecting Liver Transplantation for Patients With Hepatocellular Carcinoma. Transplant Proc 2020; 52:881-888. [PMID: 32115240 DOI: 10.1016/j.transproceed.2020.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 01/22/2020] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND AIM It has been suggested that tumor markers can provide additional information over tumor size and number-based liver transplantation (LT) criteria. We aimed to assess if changes in tumor markers are associated with the risk of tumor recurrence after LT for hepatocellular carcinoma (HCC) who received loco-regional therapies (LRTs). METHODS A total of 129 patients who received LT with pre-LT LRTs for HCC were analyzed. Milan criteria and tumor markers, alpha-fetoprotein, and protein induced by vitamin K antagonist II, at diagnosis and at transplant were assessed. The primary outcome was tumor recurrence. RESULTS When patients were stratified by radiologic criteria, cumulative recurrence rates at 3 years for patients who were not down-staged (outside Milan to outside Milan), progressed (within Milan to outside Milan), down-staged (outside Milan to within Milan), and bridged (within Milan to within Milan) were 66.7%, 58.3%, 18.7%, and 8.5%, respectively (P < .001). Among patients who were transplanted within Milan criteria at transplant (n = 113), cumulative recurrence rates at 3 years were highest for those with persistently high tumor markers (high to high, 21.7%), followed by those with increase in tumor markers (low to high, 11.1%), those with normalization of tumor markers (high to low, 5.6%), and those with persistently low tumor markers (low to low, 0%), respectively, after LRTs (P = .035). CONCLUSIONS Changes of tumor markers can provide additional information on the risk of recurrence after LT among HCC patients who received LRTs, indicating that they could be used to refine current LT selection criteria.
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Affiliation(s)
- Byeong Geun Song
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Nishida N, Kita R, Miyoshi K, Koda M, Iwai M, Suriawinata AA. Liver Tumors II: Malignant Tumors of the Liver. DIAGNOSIS OF LIVER DISEASE 2019:235-267. [DOI: 10.1007/978-981-13-6806-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shen JY, Li C, Wen TF, Yan LN, Li B, Wang WT, Yang JY, Xu MQ. Alpha fetoprotein changes predict hepatocellular carcinoma survival beyond the Milan criteria after hepatectomy. J Surg Res 2016; 209:102-111. [PMID: 28032546 DOI: 10.1016/j.jss.2016.10.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/15/2016] [Accepted: 10/05/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Assessing the outcomes of surgeries for hepatocellular carcinoma (HCC) patients who exceed the Milan criteria is necessary. Some studies have demonstrated that preoperative or postoperative alpha fetoprotein (AFP) can predict HCC patients' prognoses. METHODS A total of 280 HCC patients who were positive for AFP and received curative resection were retrospectively analyzed. The patients were classified into three groups according to their preoperative and postoperative AFP levels (group A: normalized AFP; group B: AFP decreases >50%, but continued abnormality; and group C: AFP decreases <50%). Disease-free survival and overall survival rates were analyzed using the Kaplan-Meier method. The factors associated with AFP changes were evaluated by logistic regression. RESULTS AFP dynamic changes were independently associated with disease-free survival and overall survival rates. Group A had better 3- and 5-y survivals than groups B or C (58.7% and 39.5% versus 31.3% and 14.9% versus 17.1% and 8.8%, P < 0.001). Preoperative AFP, tumor differentiation, tumor diameter, microvascular invasion, and satellite nodules remained significant risk factors that were associated with AFP changes. Furthermore, in group A, the disappearances of AFP within and beyond 8 wk resulted in similar overall survival rates (P > 0.05). Among those with HCC recurrence, the patients treated with resurgery or radiofrequency ablation achieved the best recurrence to death survivals. Those treated with transcatheter arterial chemoembolization achieved the next best survivals. CONCLUSIONS AFP changes predicted the prognoses of patients with HCC beyond the predictions of the Milan criteria. Preoperative AFP (>400 ng/mL), tumor differentiation, tumor diameter, and satellite nodules were the risk factors related to AFP normalization. The regular follow-up and early detection of recurrent HCCs that are suitable for curative therapies, such as resurgery and radiofrequency ablation, might improve the prognoses. Other therapies, such as transcatheter arterial chemoembolization, might also be effective.
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Affiliation(s)
- Jun-Yi Shen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chuan Li
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tian-Fu Wen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Lv-Nan Yan
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Li
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wen-Tao Wang
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Yin Yang
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ming-Qing Xu
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
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Liu G, Wang K, Li J, Xia Y, Lu L, Wan X, Yan Z, Shi L, Lau WY, Wu M, Shen F. Changes in serum alpha fetoprotein in patients with recurrent hepatocellular carcinoma following hepatectomy. J Gastroenterol Hepatol 2015; 30:1405-1411. [PMID: 25801981 DOI: 10.1111/jgh.12953] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM To study the change in serum alpha fetoprotein (AFP) of patients with recurrent hepatocellular carcinoma (HCC) after curative resection and to analyze its effect on the survival. METHODS We prospectively collected 981 consecutive patients with post-resectional recurrent HCC between 2005 and 2010 at the Eastern Hepatobiliary Surgery Hospital. According to the change of AFP from the initial stage to recurrent stage, the patients were divided into stable-L (20 ng/mL to 20 ng/mL, n = 296), stable-M (20-400 ng/mL to 20-400 ng/mL, n = 102), stable-H (400 ng/mL to 400 ng/mL, n = 212), decreasing (n = 287), and increasing (n = 84) groups. The overall survival (OS) and recurrence to death survival (RTDS) were analyzed using Kaplan-Meier method. Multivariate analysis was performed by Cox proportional hazards regression. RESULTS The stable-H/increasing and stable-L/decreasing groups had the lowest and highest 5-year OS and RTDS rates (10.8%/18.8% vs 56.3%/55.0%; 3.4%/5.1% vs 37.7%/33.2%; both P < 0.001), while the stable-M group had the lower rates, which were 29.8% and 23.6% (for OS and RTDS: vs stable-L, P < 0.001 and 0.002; vs deceasing, P = 0.001 and 0.012; vs increasing, P = 0.113 and 0.011; vs stable-H, both P < 0.001). Cox regression analysis showed that AFP inconsistency was an independent factor affecting RTDS (decreasing vs stable-L, hazard ratio: 1.10, 95% confidence interval: 0.79-1.54, P = 0.575; increasing vs stable-L, 2.93, 2.06-4.16, P < 0.001). CONCLUSIONS The AFP inconsistency was an important prognostic factor for recurrent HCC.
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Affiliation(s)
- Guanghua Liu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Department of Interventional Radiology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Li
- Department of Clinical Database, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lihua Lu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xuying Wan
- Department of Clinical Database, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhenlin Yan
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lehua Shi
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Mengchao Wu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Li W, Cai HX, Ge XM, Li K, Xu WD, Shi WH. Prognostic significance of BMP7 as an oncogene in hepatocellular carcinoma. Tumour Biol 2012. [PMID: 23179403 DOI: 10.1007/s13277-012-0594-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
This study aims to evaluate the association between BMP7 tissue expression and patient prognosis in hepatocellular carcinoma (HCC). The expression of BMP7 mRNA in HCC was characterized using real-time PCR and 30 pairs of fresh frozen HCC tissues and corresponding noncancerous tissues. BMP7 protein expression in HCC was confirmed using immunohistochemistry on a tissue microarray chip. Finally, BMP7 expression was correlated with conventional clinicopathological features of HCC and patient outcome. The expression of BMP7 mRNA and protein in HCC cells was much higher than in normal hepatic cells. Our results showed that the high expression of BMP7 in HCC was related to tumor size (p < 0.001), histological differentiation (p = 0.041), serum AFP (p = 0.007), and tumor stage (p < 0.001). Kaplan-Meier survival analysis showed that a high-expression level of BMP7 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that BMP7 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that a high-expression level of BMP7 serves as a biomarker for poor prognosis for HCC. Thus, we speculate that BMP7 may be a potential target of antiangiogenic therapy for HCC.
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Affiliation(s)
- Wei Li
- Department of Liver and Biliary Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222002, Jiangsu Province, China
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High expression of AP-4 predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy. Tumour Biol 2012; 34:271-6. [PMID: 23055200 DOI: 10.1007/s13277-012-0547-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 09/26/2012] [Indexed: 12/12/2022] Open
Abstract
The aim of this study was to evaluate the association between activating enhancer binding protein 4 (AP-4) tissue expression and patient prognosis in hepatocellular carcinoma (HCC). The levels of AP-4 mRNA and protein in tumor and para-tumor tissue were evaluated in 30 HCC cases by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Additionally, AP-4 protein expression in 112 HCC was analyzed by immunohistochemistry. The correlation of AP-4 expression and patients' clinicopathological parameters was evaluated. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. By RT-PCR and Western blot, the levels of AP-4 mRNA and protein were significantly higher in HCC, compared to that in para-tumor tissue (p < 0.001). Immunohistochemical staining revealed that AP-4 was highly expressed in 53.6 % of the HCC patients. The AP-4 expression level was closely associated with serum alpha fetoprotein elevation, tumor size, histological differentiation, tumor recurrence, tumor metastasis, and tumor stage. Kaplan-Meier survival analysis showed that a high expression level of AP-4 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that AP-4 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that a high expression level of AP-4 serves as a biomarker for poor prognosis for HCC. Thus, we speculate that AP-4 may be a potential target of antiangiogenic therapy for HCC.
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Langeswaran K, Jagadeesan A, Revathy R, Balasubramanian M. Chemotherapeutic efficacy of limonin against Aflatoxin B1 induced primary hepatocarcinogenesis in Wistar albino rats. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.biomag.2012.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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High ADAM8 expression is associated with poor prognosis in patients with hepatocellular carcinoma. Pathol Oncol Res 2012; 19:79-88. [PMID: 22965687 DOI: 10.1007/s12253-012-9560-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 07/31/2012] [Indexed: 10/27/2022]
Abstract
In this study,we investigated the ADAM8 expression in hepatocellular carcinoma (HCC) and its correlation with clinicopathologic features,including the survival of patients with HCC. Furthermore,we examined the biological processes regulated by ADAM8 during the development of using HepG2 cell line as a model system. We used immunohistochemistry to compare ADAM8 protein expression in HCC and normal liver tissues and further analyze the ADAM8 protein expression in clinicopathologically characterized 105 HCC cases.We stably knocked down the endogenous expression level of ADAM8 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells,we examined in vitro cell growth by MTT assay,anchorage-independent growth by soft-agar colony formation assay and cell migration/invasion by transwell and boyden chamber assay. And in addition,we also investigated the in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Protein expression level of ADAM8 was markedly higher in HCC tissues than that in the normal liver tissues (P = 0.0058).In addition,high expression of ADAM8 protein was positively correlated with serum AFP elevation,tumor size,histological differentiation,tumor recurrence,tumor metastasis,and tumor stage. Patients with higher ADAM8 expression showed a significantly shorter overall survival time than patients with low ADAM8 expression. Multivariate analysis suggested that ADAM8 expression might be an independent prognostic indicator (p = 0.016) for the survival of patients with HCC. ADAM8-specific shRNA (shADAM8) successfully knocked down its endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells,the shADAM8 cells exhibited significantly reduced in vitro cell growth,anchorage-independent growth,cell migration and invasion (p < 0.05).In vivo,the xenograft transplants from shADAM8 cells gave rise to much smaller tumors as compared to those from shCtrl cells. High ADAM8 expression is associated with poor overall survival in patients with HCC. Down-regulation of ADAM8 inhibits the growth,anchorage-independent growth,migration and invasion of HepG2 cells. ADAM8 may be a potential target of antiangiogenic therapy for HCC.
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10
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Expression of ADAM8 and its clinical values in diagnosis and prognosis of hepatocellular carcinoma. Tumour Biol 2012; 33:2167-72. [PMID: 22941466 DOI: 10.1007/s13277-012-0477-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 07/27/2012] [Indexed: 10/27/2022] Open
Abstract
ADAM8 behaves as an active metalloprotease in vitro, hydrolyzing myelin basic protein and a variety of peptide substrates based on the cleavage sites of membrane-bound cytokines, growth factors, and receptors. Other studies have demonstrated overexpression of some ADAM family proteins in a variety of human tumors, but no report is available on the actual expression of ADAM8 and the correlation between clinicopathologic features and prognosis of hepatocellular carcinoma (HCC) patients. In this study, serum levels of ADAM8 were measured by ELISA in 126 patients with HCC, 50 patients with liver cirrhosis (LC), and 50 healthy individuals. The expression of ADAM8 in liver tissue was further studied using Western blotting in 126 patients with HCC and 50 with LC. The correlations between ADAM8 status and various clinicopathological parameters including survival were analyzed. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. The ELISA assay showed that the serum levels of ADAM8 in the HCC, LC, and healthy groups were 136.4 ± 34.5, 64.2 ± 20.1, and 63.2 ± 22.7 U/ml, respectively. Analysis of variance was used for inter-group comparison, and differences were found between the HCC group and the other two groups (both P < 0.001), while no difference was found between the LC group and the healthy group (P = 0.365). Western blotting assay showed that ADAM8 protein expression was detected in 62.7 % (79/126) HCC and in 32 % (16/50) LC tissues. Further, ADAM8 expression was associated closely with serum AFP elevation, tumor size, histological differentiation, tumor recurrence, tumor metastasis, and tumor stage. Kaplan-Meier survival analysis showed that patients with ADAM8-positive tumors had a shorter postoperative survival time than those with ADAM8-negative tumors (P < 0.001). Multivariate analysis revealed that ADAM8 expression was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that the expression of ADAM8 serves as a poor prognostic biomarker for HCC. ADAM8 may be a potential target of antiangiogenic therapy for HCC.
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Zhang Y, Zha TZ, Hu BS, Jiang C, Ge ZJ, Zhang K, Tan YF. High expression of ADAM8 correlates with poor prognosis in hepatocellular carcinoma. Surgeon 2012; 11:67-71. [PMID: 22878099 DOI: 10.1016/j.surge.2012.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 06/16/2012] [Accepted: 07/13/2012] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To evaluate the association between ADAM8 tissue expression and patient prognosis in hepatocellular carcinoma (HCC). METHODS ADAM8 expression was analyzed using immunohistochemical staining methods on tissue samples from a consecutive series of 105 HCC patients who underwent resections between 2000 and 2006. The correlation of ADAM8 expression and patients' clinicopathological parameters was evaluated. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. RESULTS ADAM8 was highly expressed in 54.3% of the HCC patients. The ADAM8 expression level was closely associated with serum AFP elevation, tumor size, histological differentiation, tumor recurrence, tumor metastasis, and tumor stage. Kaplan-Meier survival analysis showed that a high expression level of ADAM8 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that ADAM8 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. CONCLUSIONS These findings provide evidence that a high expression level of ADAM8 serves as a biomarker for poor prognosis for HCC. Thus, we speculate that ADAM8 may be a potential target of antiangiogenic therapy for HCC.
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Affiliation(s)
- Yun Zhang
- Department of General Surgery, Yixing People's Hospital, No. 75, Tongzhen Guan Rd., Yixing 214200, China
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Ma SH, Chen GG, Yip J, Lai PBS. Therapeutic effect of alpha-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice. Gene Ther 2010; 17:905-12. [PMID: 20336154 DOI: 10.1038/gt.2010.34] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Previous studies have shown that the application of Ad/AFPtBid significantly and specifically killed hepatocellular carcinoma (HCC) cells in culture and subcutaneously implanted in mice. This study was to test the therapeutic efficacy of Ad/AFPtBid in an orthotopic hepatic tumor model. Four weeks after implantation of tumor cells into the liver, nude mice were treated with Ad/AFPtBid alone or in combination with 5-fluorouracil (5-FU). Serum alpha-fetoprotein (AFP) was measured as a marker for tumor progression. The results showed that Ad/AFPtBid significantly inhibited Hep3B tumor growth. Ad/AFPtBid and 5-FU in combination was more effective than either agent alone. Tumor tissues of Ad/AFPtBid alone or combination treatment groups showed a decrease in cells positive for proliferation cell nuclear antigen, but an increase in apoptosis. Ad/AFPtBid did not suppress the hepatic tumor formed by non-AFP-producing hepatoma SK-HEP-1 cells or colorectal adenocarcinoma DLD-1 cells. The survival rate was higher in mice treated with Ad/AFPtBid plus 5-FU than those treated with either agent alone. No acute toxic effect was observed in mice receiving Ad/AFPtBid. Collectively, Ad/AFPtBid can specifically target and effectively suppress the AFP-producing orthotopic liver tumor in mice without obvious toxicity, indicating that it is a promising tool in combination with chemotherapeutic agents for treatment of AFP-producing HCC.
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Affiliation(s)
- S-H Ma
- Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
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Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy composed of cells with histopathological features of both cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC). It reportedly accounts for 0.4-14.2% of all primary liver carcinomas, with incidence varying in different regions. The clinical features are similar to those of either HCC or CC. Preoperative noninvasive diagnosis of cHCC-CC with conventional radiography is difficult. Because the origin of cHCC-CC is from two different tumour entities, despite intensive preoperative imaging studies, most studied patients were misdiagnosed either as HCC or CC. Accurate preoperative diagnosis is important because the most appropriate treatment depends on the major component of the tumour (HCC or CC). A high index of suspicion, imaging studies (ultrasound, computed tomography, positron emission tomography), levels of serum tumour markers (alpha-fetoprotein, carbohydrate antigen 19-9), and histology assist case detection and treatment choice. Patients who qualify for surgery should have a partial hepatectomy with hilar lymph node dissection, which can result in 5-year survival rates exceeding 50%. The role of liver transplantation is not yet known.
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Affiliation(s)
- W T Kassahun
- Department of Surgery II, University of Leipzig, Leipzig, Germany.
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Wangensteen KJ, Wilber A, Keng VW, He Z, Matise I, Wangensteen L, Carson CM, Chen Y, Steer CJ, McIvor RS, Largaespada DA, Wang X, Ekker SC. A facile method for somatic, lifelong manipulation of multiple genes in the mouse liver. Hepatology 2008; 47:1714-24. [PMID: 18435462 PMCID: PMC5808937 DOI: 10.1002/hep.22195] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED Current techniques for the alteration of gene expression in the liver have a number of limitations, including the lack of stable somatic gene transfer and the technical challenges of germline transgenesis. Rapid and stable genetic engineering of the liver would allow systematic, in vivo testing of contributions by many genes to disease. After fumaryl acetoacetate hydrolase (Fah) gene transfer to hepatocytes, selective repopulation of the liver occurs in FAH-deficient mice. This genetic correction is readily mediated with transposons. Using this approach, we show that genes with biological utility can be linked to a selectable Fah transposon cassette. First, net conversion of Fah(-/-) liver tissue to transgenic tissue, and its outgrowth, was monitored by bioluminescence in vivo from a luciferase gene linked to the FAH gene. Second, coexpressed short hairpin RNAs (shRNAs) stably reduced target gene expression, indicating the potential for loss-of-function assays. Third, a mutant allele of human alpha1-antitrypsin (hAAT) was linked to Fah and resulted in protein inclusions within hepatocytes, which are the histopathological hallmark of hAAT deficiency disorder. Finally, oncogenes linked to Fah resulted in transformation of transduced hepatocytes. CONCLUSION Coexpression with FAH is an effective technique for lifelong expression of transgenes in adult hepatocytes with applicability to a wide variety of genetic studies in the liver.
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Affiliation(s)
- Kirk J. Wangensteen
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN
| | - Andrew Wilber
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Gene Therapy Program, Institute of Human Genetics, University of Minnesota, Minneapolis, MN
| | - Vincent W. Keng
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Cancer Center, University of Minnesota, Minneapolis, MN
| | - Zhiying He
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ilze Matise
- College of Veterinary Medicine, University of Minnesota, Minneapolis, MN
| | | | - Corey M. Carson
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Cancer Center, University of Minnesota, Minneapolis, MN
| | - Yixin Chen
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
| | | | - R. Scott McIvor
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Gene Therapy Program, Institute of Human Genetics, University of Minnesota, Minneapolis, MN
- Cancer Center, University of Minnesota, Minneapolis, MN
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
| | - David A. Largaespada
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Cancer Center, University of Minnesota, Minneapolis, MN
| | - Xin Wang
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
- Stem Cell Institute, University of Minnesota, Minneapolis, MN
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Stephen C. Ekker
- The Arnold and Mabel Beckman Center for Transposon Research, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN
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15
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Yuan RH, Jeng YM, Pan HW, Hu FC, Lai PL, Lee PH, Hsu HC. Overexpression of KIAA0101 predicts high stage, early tumor recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res 2007; 13:5368-76. [PMID: 17875765 DOI: 10.1158/1078-0432.ccr-07-1113] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE KIAA0101 is a proliferating cell nuclear antigen-associated factor and involved in cell proliferation. This study is to elucidate its role in the progression, early tumor recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN KIAA0101 mRNA was measured by reverse transcription-PCR in 216 resected, unifocal, primary HCCs and its protein in 164 cases by immunohistochemistry. RESULTS KIAA0101 mRNA was overexpressed in 131 (61%) HCCs, and protein was detected in 105 (64%). KIAA0101 mRNA overexpression correlated with higher tumor grade (P = 0.0001), higher tumor stage with vascular invasion and various extents of intrahepatic spread (P = 1 x 10(-8)), ETR (P = 1.8 x 10(-6)), and lower 5-year survival (P = 0.0026). Multivariate analysis confirmed that KIAA0101 overexpression was an independent risk factor associated with high-grade tumor (P = 0.0001), high-stage tumor (P < 0.0001), and ETR (P = 0.0052) and thus contributed to poor prognosis. KIAA0101 protein-positive tumor cells accumulated at the borders of tumor macro-trabeculae and were more abundant in tumor thrombi than in the main tumors. Hence, KIAA0101 may contribute to growth advantage and resistance to hypoxic insult. In this series, p53 mutation was detected in 93 of 184 (51%) HCCs. In both p53-mutated and non-p53-mutated HCCs, KIAA0101 overexpression correlated with higher vascular invasion (stages IIIA to IV; all Ps < 0.0001) and, accordingly, led to lower 5-year survival rates (P = 0.011 and 0.029, respectively). CONCLUSION KIAA0101 correlates with enhanced metastatic potential and is a significant prognostic factor of HCC.
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Affiliation(s)
- Ray-Hwang Yuan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
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16
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Cho YG, Song JH, Kim CJ, Lee YS, Kim SY, Nam SW, Lee JY, Park WS. Genetic alterations of the ATBF1 gene in gastric cancer. Clin Cancer Res 2007; 13:4355-4359. [PMID: 17671116 DOI: 10.1158/1078-0432.ccr-07-0619] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alpha-fetoprotein (AFP)-producing gastric cancers are aggressive tumors with venous and lymphatic invasion and hepatic metastasis. The goal of the present study was to investigate whether somatic changes of the AFP-negative regulator AT motif binding factor-1 (ATBF1) gene are involved in the development or progression of gastric cancers and the production of AFP in gastric cancer cells. EXPERIMENTAL DESIGN We searched for genetic alterations of the ATBF1 gene by single-strand conformational polymorphism and sequencing methods as well as allelic loss analysis with the microsatellite markers D16S3066 and D16S3139. Immunochemistry for AFP expression in gastric cancer cells was also done. RESULTS In 81 sporadic gastric cancers, four mutations were detected in seven cases: one was a missense mutation and three were deletions; loss of heterozygosity at the ATBF1 locus was detected in 52.9% of informative samples. Five of the eight cancers with AFP expression showed ATBF1 genetic alterations. CONCLUSIONS These results suggest that genetic alteration of the ATBF1 gene may contribute to the aggressive nature of gastric cancers and the production of AFP in gastric cancer cells.
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Affiliation(s)
- Yong Gu Cho
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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17
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Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, Lin CY, Lee PH, Hsu HC. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol 2006; 209:549-58. [PMID: 16739096 DOI: 10.1002/path.2011] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stathmin, a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. This study aimed to elucidate its role in the progression, early tumour recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). Stathmin mRNA was overexpressed in 88/156 (56%) resected, unifocal, primary HCCs, while p53 mutation was present in 72 (46%) and osteopontin mRNA overexpression in 79 (51%). Stathmin mRNA expression exhibited high concordance (93%) with protein expression in 107 cases examined by immunohistochemistry. Stathmin overexpression correlated with high alpha-fetoprotein (>200 ng/ml, p = 0.02), larger tumour size (>5 cm, p = 0.012), high tumour grade (p < 0.0002), high tumour stage (stage IIIA-IV) with vascular invasion and various degrees of intrahepatic metastasis (p < 1 x 10(-8)), ETR (p = 0.003), and lower 5-year survival (p = 0.0007). Stathmin protein expression was often more intense in the peripheral regions of tumour trabeculae, tumour borders, and portal vein tumour thrombi. Stathmin overexpression correlated with p53 mutation (p = 0.017) and osteopontin overexpression (p = 1 x 10(-8)), both of which were associated with vascular invasion (both p < 0.0001) and poorer prognosis (p < 0.0004 and p = 0.0004, respectively). Regardless of the status of p53 mutation or osteopontin expression, stathmin overexpression was associated with higher vascular invasion (all p < 0.0001). Approximately 90% of HCCs harbouring stathmin overexpression with concomitant p53 mutation or osteopontin overexpression exhibited vascular invasion, and hence the lowest 5-year survival, p = 0.00018 and p = 0.0009, respectively. However, we did not find that stathmin overexpression exerted prognostic impact independent of tumour stage. In conclusion, stathmin expression correlates with metastatic potential, is an important prognostic factor for HCC, and may serve as a useful marker to predict ETR.
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Affiliation(s)
- R-H Yuan
- Department of Surgery, National Taiwan University Hospital, Taipei
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18
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Hiraoka A, Kumagi T, Hirooka M, Uehara T, Kurose K, Iuchi H, Hiasa Y, Matsuura B, Michitaka K, Kumano S, Tanaka H, Yamashita Y, Horiike N, Mochizuki T, Onji M. Prognosis following transcatheter arterial embolization for 121 patients with unresectable hepatocellular carcinoma with or without a history of treatment. World J Gastroenterol 2006; 12:2075-9. [PMID: 16610060 PMCID: PMC4087688 DOI: 10.3748/wjg.v12.i13.2075] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To retrospectively evaluate the prognosis of patients with hepatocellular carcinoma (HCC) with or without a history of therapy for HCC following transcatheter arterial embolization (TAE).
METHODS: One hundred and twenty-one patients with HCC treated with TAE from 1992 to 2004 in our hospital were enrolled in this study. Eighty-four patients had a history of treatment for HCC, while 37 did not. At the time of entry, patients with extra-hepatic metastasis, portal vein tumor thrombosis, or Child-Pugh class C were excluded. TAE was repeated when recurrence of HCC was diagnosed by elevated tumor markers, or ultrasonography or dynamic computed tomography findings.
RESULTS: Tumor size was larger and the number of tumors was fewer in patients without past treatment (P < 0.01). However, there were no differences in tumor node metastasis (TNM) stage or survival rate between the 2 groups. A bilobular tumor and high level of α-fetoprotein (AFP) (>100 ng/mL) were factors related to a poor prognosis in patients with a history of HCC.
CONCLUSION: The prognosis following TAE is similar between HCC patients with and without past treatment. Early diagnosis of HCC or recurrent HCC and obtaining good local control against HCC before entry to a repeated TAE course can improve prognosis.
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Affiliation(s)
- Atsushi Hiraoka
- Third Department of Internal Medicine, Ehime University School of Medicine, Ehime 791-0295, Japan
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19
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Görög D, Regöly-Mérei J, Paku S, Kopper L, Nagy P. Alpha-fetoprotein expression is a potential prognostic marker in hepatocellular carcinoma. World J Gastroenterol 2005; 11:5015-8. [PMID: 16124056 PMCID: PMC4321920 DOI: 10.3748/wjg.v11.i32.5015] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [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 characterize the alpha-fetoprotein (AFP) positive and negative hepatocellular carcinoma (HCC) samples.
METHODS: Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for the following antigens: AFP, β-catenin, p53, CD44, MSH-2, MLH-1, and HNF-4. The tumors were divided into two groups based on the AFP expression. The immunophenotypic data and important clinical parameters were studied between the two groups.
RESULTS: Twenty-one of the thirty-seven examined HCCs were AFP positive. Seven with nuclear p53 staining were AFP positive, while seven tumors with nuclear β-catenin staining were AFP negative. CD44 staining and high histological tumor grade were more frequent among the AFP-positive HCCs. The other immunophenotypical and clinical parameters did not show statistically significant difference in their distribution between the AFP positive and negative samples.
CONCLUSION: AFP expression in HCC correlates with unfavorable prognostic factors, while nuclear β-catenin positivity is more common among the AFP-negative liver tumors. This observation supports the microarray data on in vivo human tumors.
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Affiliation(s)
- Dénes Görög
- Department of Transplantation and Surgery, Semmelweis University, Budapest H-1086, Hungary
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20
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Su MC, Lien HC, Jeng YM. Absence of epidermal growth factor receptor exon 18-21 mutation in hepatocellular carcinoma. Cancer Lett 2005; 224:117-21. [PMID: 15911107 DOI: 10.1016/j.canlet.2004.10.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2004] [Revised: 10/05/2004] [Accepted: 10/07/2004] [Indexed: 01/21/2023]
Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial tumors and plays an important role in the tumorigenesis of these tumors. Inhibitors of EGFR reduce the proliferation rate of cancers and are promising therapeutic agents of cancers. Recently, two studies have identified somatic mutations in the exons 18-21 of EGFR that were strongly correlated with robust clinical response to gefitinib treatment in patients with non-small cell lung cancer. To investigate whether EGFR mutation is involved in the tumorigenesis of hepatocellular carcinoma (HCC), we performed direct sequencing of exons 18-21 on 89 HCCs. No mutations causing amino acid changes or deletions were identified. The results indicate mutation of the kinase domain of EGFR does not play a significant role in the tumorigenesis of HCC and gefitinib is unlikely to be used as single-drug therapy for HCC.
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Affiliation(s)
- Min-Cheng Su
- Department of Pathology, Min-Sheng General Hospital, 168, Ching-Kuo Road, Taoyuan City, Taiwan, ROC
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21
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Huang LR, Coughtrie MWH, Hsu HC. Down-regulation of dehydroepiandrosterone sulfotransferase gene in human hepatocellular carcinoma. Mol Cell Endocrinol 2005; 231:87-94. [PMID: 15713538 DOI: 10.1016/j.mce.2004.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2004] [Revised: 10/01/2004] [Accepted: 10/12/2004] [Indexed: 11/27/2022]
Abstract
Differential display (DD) PCR cloning of differentially expressed genes in hepatocellular carcinoma (HCC) and adjacent unaffected tissue demonstrated preferential down-regulation of a vital sex steroid precursor (dehydroepiandrosterone sulfotransferase; DHEA-ST; SULT2A1) in HCC. SULT2A1 mRNA and/or protein expression in HCC were markedly reduced in 61 of 120 (50.8%) primary unicentric HCCs. The down-regulation was more frequent in grade III versus grade I HCC (68.1% versus 32.1%, P = 0.0025), and in stage 3 versus stage 1 HCC (62.7% versus 29.2%, P = 0.007). The lowered expression in tumor cells of SULT2A1 in HCC tissues involved in metabolism and/or inactivation of sex steroids is consistent with a regulatory role of the SULT2A1 gene product in the development and/or tumor cell differentiation and progression of human HCC. This suggestion is partly supported by our observations that the down-regulated SULT2A1 gene expression correlated with a higher grade and stage of HCC.
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Affiliation(s)
- Lan-Ru Huang
- Chungtai Institute of Health Sciences and Technology, Department of Medical Technology, No. 11, Pu-tzu Lane, Pei-tun Distr., Taichung 406, Taiwan.
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22
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Jeng YM, Peng SY, Lin CY, Hsu HC. Overexpression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 2004; 10:2065-71. [PMID: 15041727 DOI: 10.1158/1078-0432.ccr-1057-03] [Citation(s) in RCA: 248] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Aurora-A/STK15/BTAK, a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation. The purpose of this study was to investigate the expression and amplification of Aurora-A in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN Aurora-A mRNA levels were measured in 224 HCCs and 199 paired nontumorous liver tissues by reverse transcription-PCR. Aurora-A mRNA and protein levels of 8 were also measured by reverse transcription-PCR and Western blot hybridization in 8 liver cancer cell lines. Amplification of Aurora-A was determined by Southern blot hybridization in 99 cases. RESULTS Aurora-A was overexpressed in 137 of 224 (61%) HCCs and all 8 of the cell lines. Overexpression of Aurora-A was associated with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53 mutation, infrequent beta-catenin mutation, and poor outcome. Aurora-A overexpression and p53 mutation acted synergistically toward poor prognosis. Amplification of Aurora-A was detected only in 3 HCCs. CONCLUSION The results show that Aurora-A is overexpressed frequently in HCC, and correlated with high grade and high stage, indicating that overexpression of Aurora-A plays a role in the development and progression of HCC.
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Affiliation(s)
- Yung-Ming Jeng
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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23
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Kim JH, You KR, Kim IH, Cho BH, Kim CY, Kim DG. Over-expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma. Hepatology 2004; 39:129-138. [PMID: 14752831 DOI: 10.1002/hep.20017] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Using messenger RNA (mRNA) differential display, we identified a single complementary DNA (cDNA) fragment (HG23T1) that was over-expressed in a hepatocellular carcinoma (HCC) specimen. We cloned the full-length HG23T1 gene by the rapid amplification of cDNA end (RACE) polymerase chain reaction (PCR) method. It perfectly matched the gene encoding human ribosomal protein L36a (RPL36A also referred to as RPL44). RPL36A mRNA was preferentially over-expressed in 34 of 40 HCC cases (85%, P <.001) and in all of 8 HCC cell lines. Ectopically over-expressed L36a ribosomal protein localized in the nucleoli of cells, and this localization seemed to be controlled by the N-terminal or the internal tetrapeptide consensus with its adjacent N-terminal domain. Over-expression of L36a led to enhanced colony formation and cell proliferation, which may have resulted from rapid cell cycling, and an antisense cDNA effectively reversed these alterations. In conclusion, RPL36A plays a role in tumor cell proliferation and may be a potential target for anticancer therapy of HCC.
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Affiliation(s)
- Jong-Hyun Kim
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Institute for Medical Science, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk, South Korea
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24
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Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer 2003; 98:119-27. [PMID: 12833464 DOI: 10.1002/cncr.11487] [Citation(s) in RCA: 192] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression. METHODS OPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription-polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis. RESULTS Osteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with alpha-fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high-grade HCC (P < 0.001), late-stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10-year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early-stage HCC, which has no vascular invasion and a lower early tumor recurrence than late-stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003). CONCLUSIONS OPN mRNA overexpression was correlated closely with high-grade, late-stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early-stage HCC.
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Affiliation(s)
- Hung-Wei Pan
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
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25
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Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:2295-307. [PMID: 12057932 PMCID: PMC1850847 DOI: 10.1016/s0002-9440(10)61177-7] [Citation(s) in RCA: 290] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic alpha-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for beta-catenin. Sequencing of the tumor DNA encoding beta-catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.
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Affiliation(s)
- Katrina Nicholes
- Department of Pathology, Genentech Incorporated, South San Francisco, California 94080, USA
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26
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Liu SH, Lin CY, Peng SY, Jeng YM, Pan HW, Lai PL, Liu CL, Hsu HC. Down-regulation of annexin A10 in hepatocellular carcinoma is associated with vascular invasion, early recurrence, and poor prognosis in synergy with p53 mutation. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:1831-7. [PMID: 12000734 PMCID: PMC1850863 DOI: 10.1016/s0002-9440(10)61129-7] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Annexins (ANXs) are a large group of calcium-binding proteins participating in diverse important biological processes. ANXA10 is the least expressed new member of unknown function. We showed that ANXA10 mRNA was expressed in adult liver and hepatocellular carcinoma (HCC), but not in multiple adult and fetal tissues, cholangiocarcinoma, and several other common carcinomas. Of 182 unifocal primary HCCs, ANXA10 mRNA was dramatically reduced in 121 (66%), and the down-regulation correlated with p53 mutation (P = 0.024), early intrahepatic tumor recurrence (P = 0.0007), and lower 4-year survival (P = 0.0014). Down-regulation of ANXA10 was twofold more frequent in large than small HCCs (P = 0.0012), in grade II to III than grade I HCC (P < 0.00001), and in stage IIIA to IV than stage I to II HCC (P < 0.00001). Moreover, ANXA10 down-regulation and p53 mutation acted synergistically toward high-grade (P < 0.00001), high-stage HCC (P < 0.00001), and poorer prognosis (P = 0.0025). Our results indicate that the expression of the tissue- and tumor-restricted ANXA10 is a marker of liver cell differentiation and growth arrest, and its down-regulation associated with malignant phenotype of hepatocytes, vascular invasion, and progression of HCC, leading to poor prognosis. Thus, ANXA10 might serve as a new potential target of gene therapy for HCC.
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Affiliation(s)
- Shu-Hsiang Liu
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei
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27
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Abstract
DNA methylation is the main epigenetic modification in humans. The methylation of promoter inhibits the transcription in most genes. In normal tissues, isolated CpG dinucleotides in bulk chromatin are often methylated, whereas cytosines in CpG islands are unmethylated. In neoplasms including gastrointestinal cancer, this pattern of methylation is commonly reversed. The alteration of DNA methylation plays a key role in the process of carcinogenesis. The gastrointestinal carcinogenesis is suggested to be associated with the decrease of total genomic DNA methylation; hypomethylation of certain specific oncogenes such as c-myc, c-Ha-ras, c-fos and alpha-fetoprotein; and hypermethylation of the promoter of some tumor suppressor genes containing p16(INK4A), E-cadherin and hMLH1 genes. This review focuses on the analysis methods for methylation, studies for aberrant DNA methylation in gastrointestinal carcinogenesis, and the intervention changing methylation, including the treatment of 5-azacytidine, supplement of folate and gene therapy.
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Affiliation(s)
- J Y Fang
- Shanghai Institute of Digestive Disease, Shanghai Second Medical University, Shanghai, People's Republic of China.
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28
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Kim MY, Park E, Park JH, Park DH, Moon WS, Cho BH, Shin HS, Kim DG. Expression profile of nine novel genes differentially expressed in hepatitis B virus-associated hepatocellular carcinomas. Oncogene 2001; 20:4568-75. [PMID: 11494152 DOI: 10.1038/sj.onc.1204626] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2001] [Revised: 04/26/2001] [Accepted: 05/08/2001] [Indexed: 11/08/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is known to be one of the major causes in the development of hepatocellular carcinoma (HCC), although the biomolecular mechanism(s) involved remain unclear. To identify the cellular gene(s) involved in HBV-associated hepatocarcinogenesis, we used the mRNA differential display method and examined three paired tumor and nontumor tissues, all of which had chromosomally integrated HBV-DNA through chronic infection. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13-mers, genes decreased or increased in expression more than twofold between each tumor tissue and its paired nontumor tissue were identified. Twenty-nine known genes and four novel genes were differentially over-expressed in the HCC tumor tissues. In contrast, 27 known genes and five novel genes were under-expressed in those tumor tissues. The nucleotide sequences of the nine novel gene fragments were determined and their expression patterns were examined in 40 HCC samples. HA61T2, PT18, HG63T1, and HG57T1 were preferentially over-expressed in 32 cases (80%, P<0.001), 24 cases (60%), 23 cases (57.5%) and 22 cases (55%) of the 40 tumor tissues, respectively. There was an increased frequency of HG57T1 over-expression in HCC patients with HBV-positive serology and low serum alpha-feto protein (AFP) levels (P<0.05). DNT10, PT8, PT19, ENT25 and HA6T4 were under-expressed in 26 cases (65%), 23 cases (57.5%), 21 cases (53%), 20 cases (50%) and 18 cases (45%) of the 40 tumor samples, respectively. There was a strong correlation of DNT10 under-expression with high serum AFP level in HCC patients, irrespective of HBV serology (P<0.01). HA6T4 was preferentially under-expressed in HCC tumors in patients with HBV-positive serology and high serum AFP levels (P<0.05). Thus, the functional analyses of the known and novel genes identified in this study should prove valuable to further understand the mechanism(s) of hepatocarcinogenesis.
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MESH Headings
- Base Sequence
- Blotting, Northern
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/virology
- Cell Transformation, Neoplastic
- Cell Transformation, Viral
- DNA, Neoplasm/genetics
- DNA, Viral/genetics
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Viral
- Genes
- Hepatitis B virus/genetics
- Hepatitis B virus/physiology
- Hepatitis B, Chronic/complications
- Humans
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/virology
- Molecular Sequence Data
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- RNA, Messenger/biosynthesis
- RNA, Neoplasm/biosynthesis
- Sequence Analysis, DNA
- Subtraction Technique
- Viral Proteins/biosynthesis
- Viral Proteins/genetics
- Virus Integration
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Affiliation(s)
- M Y Kim
- Department of Internal Medicine, Division of GI and Hepatology, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk 561-712, Republic of Korea
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Kataoka H, Miura Y, Joh T, Seno K, Tada T, Tamaoki T, Nakabayashi H, Kawaguchi M, Asai K, Kato T, Itoh M. Alpha-fetoprotein producing gastric cancer lacks transcription factor ATBF1. Oncogene 2001; 20:869-73. [PMID: 11314020 DOI: 10.1038/sj.onc.1204160] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2000] [Revised: 11/30/2000] [Accepted: 12/06/2000] [Indexed: 11/09/2022]
Abstract
Alpha-fetoprotein (AFP) producing gastric cancer (AFP-GC) is very malignant and highly metastatic compared with common gastric cancer. However, the causal relationship between AFP production and the high malignancy of AFP-GC is unclear. We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). RNase protection assays revealed that the production of AFP in gastric cancer cells did not directly associate with HNF1 expression. An inverse relation between the expressions of ATBF1 and AFP was clearly observed in gastric cancer cells. CAT assays showed the direct inhibition of AFP gene expression by ATBF1. Methylation analysis of the AFP promoter region in gastric cancer cells suggested that methylation itself could not explain the silencing of the AFP gene. Immunohistochemistry of resected clinical samples revealed that AFP producing cells lacked ATBF1 immunoreactivity. Our data suggests that the absence of ATBF1 is responsible for AFP gene expression in gastric cancer, and the absence of ATBF1 is a distinct characteristic of AFP-GC and might be important for its highly malignant nature.
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Affiliation(s)
- H Kataoka
- First Department of Internal Medicine, Nagoya City University Medical School Nagoya, 467-8601, Japan
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Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol 2001; 193:95-101. [PMID: 11169521 DOI: 10.1002/1096-9896(2000)9999:9999<::aid-path720>3.0.co;2-3] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
beta-catenin has functions both in the cadherin-mediated cell adhesion system and in the signalling pathway that mediates dorsal axis patterning in the embryo; it has been shown to be aberrantly expressed or mutated in diverse types of human tumour, but the biological significance of this remains to be clarified. To elucidate the clinical implications of aberrant beta-catenin expression and the potential differences between mutant and wild-type beta-catenin protein expression in hepatocellular carcinoma (HCC), the protein expression was analysed by immunohistochemical staining, supplemented by the analysis of gene mutation. Among 372 unifocal primary HCCs, beta-catenin was detected in the tumour cell membrane alone in 272 tumours (group A) and also in the nuclei in 100 (group B). In group A, 148 tumours had decreased beta-catenin expression, but the reduction did not correlate with invasion or prognosis. When compared with group A, however, group B had significantly lower frequencies of hepatitis B surface antigen carrier (p=0.015), and alpha-fetoprotein elevation (p=0.0003), but more often had non-invasive HCC (p<0.001) and better survival (p=0.01). Nuclear beta-catenin expression strongly correlated with mutation of the gene (p<0.00001). In group B, HCC with mutant nuclear beta-catenin correlated positively with non-invasive (stage 1) tumour and inversely with portal vein tumour thrombi (stage 3 HCC), and had significantly better 5-year survival, p<0.001 and p<0.0003, respectively. These results suggest that beta-catenin mutation plays an important role in the tumourigenesis of a subset of HCC of good prognosis, and that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent.
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Affiliation(s)
- T L Mao
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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31
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Tangkijvanich P, Anukulkarnkusol N, Suwangool P, Lertmaharit S, Hanvivatvong O, Kullavanijaya P, Poovorawan Y. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol 2000; 31:302-308. [PMID: 11129271 DOI: 10.1097/00004836-200012000-00007] [Citation(s) in RCA: 229] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The purpose of this study was to determine whether a relation does exist between clinicopathologic features and the prognosis of hepatocellular carcinoma (HCC) with respect to serum alpha-fetoprotein (AFP) levels at diagnosis. We reviewed the clinical data of 309 pathologically proven HCC cases divided into three groups: group 1 with normal AFP (<20 IU/mL), group 2 with moderately elevated AFP (20-399 IU/mL) and group 3 with markedly elevated AFP (> or =400 IU/mL). Of these, there were 76 (24.6%), 78 (25.2%), and 155 patients (50.2%) in groups 1, 2, and 3, respectively. We found that HCC patients with high AFP tended to have greater tumor size, bilobar involvement, massive or diffuse types, and portal vein thrombosis. Nonetheless, we could not establish a correlation between increased AFP and Okuda's stages, degree of tumor differentiation, or extrahepatic metastasis. The median survival rates in groups 1 (6 months) and 2 (7 months) were significantly longer than that of group 3 (3 months). On multivariate logistic regression analysis, positive hepatitis B surface antigen (HBsAg) status and bilobar tumor involvement represented the independent factors for predicting high AFP values. We concluded that AFP is useful not only for diagnosis, but also as a prognostic indicator in patients with HCC . However, it cannot be considered a sensitive tumor marker, particularly during the early stages in HBsAg-negative patients.
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Affiliation(s)
- P Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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32
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Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. THE AMERICAN JOURNAL OF PATHOLOGY 2000; 157:763-70. [PMID: 10980116 PMCID: PMC1885685 DOI: 10.1016/s0002-9440(10)64590-7] [Citation(s) in RCA: 224] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
To better understand the role of beta-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. beta-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had beta-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3beta region of beta-catenin. Outside the GSK-3beta phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P: < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P: < 0.00001), and higher male-to-female ratio (P: < 0.003) and positive familial history of HCC (P: < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, beta-catenin mutations were associated with grade I (P: = 0.005) and stage I and II HCC (P: < 0.0001), and a better 5-year survival rate (P: = 0. 00003). These findings suggest mechanisms for beta-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that beta-catenin mutation is a favorable prognostic factor related to low stage. beta-Catenin mutation was associated with nuclear expression of the protein (P: < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear beta-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear beta-catenin had a better 5-year survival rate (P: < 0.007), suggesting that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent and deserve more studies for further clarification.
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Affiliation(s)
- H C Hsu
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
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33
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Trojan J, Schroeder O, Raedle J, Baum RP, Herrmann G, Jacobi V, Zeuzem S. Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am J Gastroenterol 1999; 94:3314-9. [PMID: 10566736 DOI: 10.1111/j.1572-0241.1999.01544.x] [Citation(s) in RCA: 178] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The detection of increased fluorine-18 fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography (PET) is based on the enhanced glucose metabolism of tumor cells. Because the detection and staging of hepatocellular carcinoma (HCC) in patients with liver cirrhosis can be difficult, we prospectively evaluated the sensitivity of 18F-FDG PET in 14 consecutive patients with HCC. METHODS Whole body and regional 18F-FDG PET of the liver were obtained. The results were compared with ultrasonography, contrast-enhanced, helical CT, histological grading, p53 protein expression of HCC, and serum alpha-fetoprotein (AFP) level. RESULTS In 7 patients PET demonstrated increased tumor 18F-FDG uptake, whereas HCC was not distinguishable from nonmalignant liver tissue in 7 other patients. Hepatic lesions were detected by ultrasonography in all patients, whereas only 11 of 14 HCCs could be identified by CT. In 3 patients extrahepatic spread was demonstrated by 18F-FDG PET. Patients with increased tumor 18F-FDG uptake had significantly larger hepatic lesions and higher serum AFP levels than those with normal 18F-FDG uptake. Lesions could be visualized by 18F-FDG PET in 7 of 8 patients with moderately or poorly differentiated HCC, whereas none of the six well-differentiated tumors was detected. Two patients with strong p53 expression demonstrated increased tumor 18F-FDG uptake and extrahepatic metastases. CONCLUSIONS The sensitivity of 18F-FDG PET for the imaging of HCC is low. Nevertheless, in patients with moderately or poorly differentiated HCC, tumors >5 cm, or with markedly elevated AFP levels 18F-FDG PET may contribute to an effective noninvasive staging.
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Affiliation(s)
- J Trojan
- 2nd Department of Medicine, PET Center, Johann Wolfgang Goethe-University, Frankfurt a.M., Germany
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34
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Luo JC, Hwang SJ, Wu JC, Li CP, Hsiao LT, Lai CR, Chiang JH, Lui WY, Chang FY, Lee SD. Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan. Cancer 1999; 86:799-804. [PMID: 10463978 DOI: 10.1002/(sici)1097-0142(19990901)86:5<799::aid-cncr15>3.0.co;2-#] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common malignancy in Taiwan. Some patients may manifest paraneoplastic syndromes during the clinical course of the disease. In this study, the authors evaluated the clinical significance of these paraneoplastic syndromes, compared the prevalence of these syndromes between cases of hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related HCC, and estimated significant predictors associated with the syndromes. METHODS Clinical data on 1197 HCC patients, including age, gender, Child-Pugh score, survival time, laboratory data (including liver biochemistry, hepatitis markers, and serum alpha-fetoprotein [AFP]), and tumor features (including tumor size, portal vein thrombosis, and histologic pictures), were retrospectively reviewed. RESULTS A total of 232 of 1197 patients (19.4%) had paraneoplastic syndromes. HCC patients with paraneoplastic syndromes had significantly higher serum AFP; higher rates of initial main portal vein thrombosis, metastasis, and bilobal tumor involvement; larger tumor volume; and shorter survival than those without these syndromes. Patients with HBV-related HCC had a significantly higher prevalence of paraneoplastic syndromes than patients with HCV-related HCC (20.1% vs. 11.2%, P = 0.005). In a stepwise multivariate logistic regression analysis, AFP >50,000 ng/mL and tumor volume >30% were significant predictive variables associated with the presence of paraneoplastic syndromes in HCC patients. CONCLUSIONS HCC patients with paraneoplastic syndromes usually had higher levels of serum AFP and larger tumor volumes than those without. Patients with HBV-related HCC had a significantly higher prevalence of paraneoplastic syndromes than those with HCV-related HCC.
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Affiliation(s)
- J C Luo
- Division of Gastroenterology, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan
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35
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He P, Tang ZY, Ye SL, Liu BB. Relationship between expression of α-fetoprotein messenger RNA and some clinical parameters of human hepatocellular carcinoma. World J Gastroenterol 1999; 5:111-115. [PMID: 11819405 PMCID: PMC4688518 DOI: 10.3748/wjg.v5.i2.111] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [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 certify the relationship between AFP-mRNA and some pathological parameters of he patocellular carcinoma (HCC).
METHOD We detected the expression of AFP in mRNA level in tissue samples from 52 patients suffering from HCC by RT-PCR method.
RESULTS The positive rate of AFP mRNA was 76.9% in the HCC tumor tissues, and 69.4% in the paratumor tissues from the HCC patients with severe cirrhosis. However, in HCC patients without cirrhosis, the positive rate reached 50% in tumor tissues, but no AFP mRNA expression was found in the related paratumor tissues.
CONCLUSION The AFP protein was specially expressed by HCC cells and mutated hepatocytes. The AFP mRNA was positively related with cirrhosis, but no significant relationship was found between AFP mRNA and tumor size, capsule status and tumor metastasis.
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36
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Carretero MV, Torres L, Latasa U, García-Trevijano ER, Prieto J, Mato JM, Avila MA. Transformed but not normal hepatocytes express UCP2. FEBS Lett 1998; 439:55-8. [PMID: 9849876 DOI: 10.1016/s0014-5793(98)01335-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Uncoupling protein 2 (UCP2) expression in liver is restricted to non-parenchymal cells. By means of differential display screening between normal rat liver and H4IIE hepatoma cells we have isolated a cDNA clone encompassing part of UCP2 cDNA. Northern blot analysis revealed that UCP2 is expressed in some hepatocarcinoma cell lines, while it is absent in adult hepatocytes. UCP2 mRNA in H4IIE cells was downregulated when cells were cultured for 36 h in 0.1% serum and its expression was restored upon addition of 10% serum or phorbol esters. Hypomethylation of UCP2 was observed in transformed UCP2 expressing cells. Our results indicate that UCP2 is expressed in some hepatocarcinoma cell lines and that serum components may participate in maintaining elevated UCP2 levels.
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Affiliation(s)
- M V Carretero
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain
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37
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Peng SY, Chou SP, Hsu HC. Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation, high tumor grade and poor prognosis in hepatocellular carcinoma. J Hepatol 1998; 29:281-9. [PMID: 9722210 DOI: 10.1016/s0168-8278(98)80014-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The major regulatory events leading to cell proliferation occur in the G1 phase of cell cycle, and the deranged expression of G1 cyclins is related to oncogenesis. In this study, we analyzed the aberrant expressions of cyclins D1 and E, and their role in hepatocellular carcinoma. METHODS We examined paired hepatocellular carcinoma and liver RNAs taken from 71 patients who had been followed for more than 4 years after tumor resection, using reverse transcription-polymerase chain reaction supplemented with Northern blotting and immunohistochemistry. The genetic alterations of the p53 gene were also studied. RESULTS Downregulation of cyclin D1 mRNA was detected in 29 hepatocellular carcinomas (40.8%), while overexpression was detected in only 4 hepatocellular carcinomas (5.6%). Downregulation of cyclin D1 was associated significantly with large hepatocellular carcinomas (p=0.0006) and poorly differentiated (grades III-IV) hepatocellular carcinoma (p=0.057), but not seen in any of 15 minute hepatocellular carcinomas (< or =2.5 cm in size). Cyclin E mRNA was overexpressed in 40 hepatocellular carcinomas, regardless of tumor size. Overexpression of cyclin E was significantly associated with poorly differentiated and invasive hepatocellular carcinoma (p=0.001 and p=0.015, respectively). Downregulation of cyclin D1 and overexpression of cyclin E were significantly associated with the p53 mutation (p=0.023 and p=0.005, respectively). Hepatocellular carcinomas expressing both downregulation of cyclin D1 and overexpression of cyclin E had the worst 4-year survival (p<0.03), and higher frequencies of the p53 mutation (p<0.001), large hepatocellular carcinoma (p<0.001), and invasive tumor (p<0.01). CONCLUSIONS The deranged expressions of G1 cyclins correlate with the p53 mutation, tumor progression, and tumor biologic behavior of hepatocellular carcinoma. Overexpression of cyclin E occurs early, and downregulation of cyclin D1 late in hepatocellular carcinoma growth.
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Affiliation(s)
- S Y Peng
- Graduate Institute of Pathology, College of Medicine, National Taiwan University
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38
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Scuric Z, Stain SC, Anderson WF, Hwang JJ. New member of aldose reductase family proteins overexpressed in human hepatocellular carcinoma. Hepatology 1998; 27:943-50. [PMID: 9537432 DOI: 10.1002/hep.510270408] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. To identify genes whose expression is increased during hepatocarcinogenesis, differential-display polymerase chain reaction (DD-PCR) was used to examine differences in the mRNA composition of hepatocellular carcinoma (HCC) versus normal liver (nontumor) tissues. This approach identified 67 cDNAs that were preferentially expressed in HCC tissue. When these cDNAs were analyzed by reverse-Northern analysis, five were reproducibly expressed at high levels in HCC. Interestingly, Northern blot analysis revealed that one of the genes showed significantly increased mRNA levels in all five tested tumor samples, while its mRNA level in the nontumor samples was minimal. BLAST analysis revealed that this gene has high sequence identity with the genes from aldo-keto reductase family of proteins including the mouse fibroblast growth factor-induced gene (FR-1) (80% identity), mouse vas deferens protein (MVDP) (76%), and human aldose reductase (AR) (62%). Expression of this novel AR-related protein in all five tested HCCs suggests that this protein may play an important role in liver carcinogenesis.
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Affiliation(s)
- Z Scuric
- Gene Therapy Laboratories, University of Southern California School of Medicine, Los Angeles 90033, USA
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39
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Piao Z, Park C, Lee JS, Yang CH, Choi KY, Kim H. Homozygous deletions of the CDKN2 gene and loss of heterozygosity of 9p in primary hepatocellular carcinoma. Cancer Lett 1998; 122:201-7. [PMID: 9464511 DOI: 10.1016/s0304-3835(97)00403-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
To elucidate the alterations of CDKN2 in hepatocarcinogenesis, we performed a loss of heterozygosity (LOH) study using eight polymorphic markers surrounding the CDKN2 gene and analyzed the homozygous deletions and mutations of the CDKN2 gene in 41 primary hepatocellular carcinomas (HCCs). Frequent LOH (27.8-44%) was found in the eight loci on chromosome 9p, however, no intragenic mutations of CDKN2 were observed by PCR-SSCP analysis. Homozygous deletions were detected in 25 of 41 HCCs (61%) by a comparative multiplex PCR. No expression of the CDKN2 protein was noted in five out of nine available HCCs by Western blot analysis. These results suggest that inactivation of the CDKN2 gene in HCC is a frequent event in which homozygous deletions are the most common mechanism of CDKN2 inactivation.
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Affiliation(s)
- Z Piao
- Department of Pathology, Yonsei University, College of Medicine, Seoul, South Korea
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40
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Bui LA, Butterfield LH, Kim JY, Ribas A, Seu P, Lau R, Glaspy JA, McBride WH, Economou JS. In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin-2. Hum Gene Ther 1997; 8:2173-82. [PMID: 9449371 DOI: 10.1089/hum.1997.8.18-2173] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
A recombinant adenovirus (AdVAFP1-IL2) containing the murine alpha-fetoprotein (AFP) promoter was constructed to direct hepatocellular carcinoma (HCC)-specific expression of the human interleukin-2 (IL-2) gene. In vitro testing of AdVAFP1-IL2 showed HCC-specific IL-2 gene expression three to four orders of magnitude higher in AFP-producing HCC lines compared to non-AFP producing non-HCC lines. The in vivo efficacy and tumor specificity of AdVAFP1-IL2 was evaluated compared to AdVCMV-IL2 (in which the IL-2 gene is driven by the strong constitutive cytomegalovirus promoter) in the treatment of established human HCC (Hep 3B/Hep G2) xenografts growing in CB-17/SCID mice. Intratumoral injection of AdV resulted in growth retardation and regression in a majority of established hepatomas, but with a much wider therapeutic index and less systemic toxicity using the AFP vector. This study illustrates the superiority of using transcriptionally targeted recombinant AdV vectors in cytokine-based gene therapy.
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Affiliation(s)
- L A Bui
- Division of Surgical Oncology, UCLA School of Medicine, Los Angeles, CA 90095-1782, USA
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Yamamoto H, Itoh F, Sakamoto H, Nakajima Y, Une Y, Hinoda Y, Imai K. Association of reduced cell adhesion regulator messenger RNA expression with tumor progression in human hepatocellular carcinoma. Int J Cancer 1997; 74:251-4. [PMID: 9221800 DOI: 10.1002/(sici)1097-0215(19970620)74:3<251::aid-ijc3>3.0.co;2-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The recently identified cell adhesion regulator (CAR) modulates the process of integrin-mediated cell adhesion. The CAR gene is located on 16q, a locus at which high levels of allelic losses have been demonstrated in advanced human hepatocellular carcinoma (HCC). We studied the possible involvement of the CAR gene in the progression of HCC. With this aim, we determined the expression of CAR mRNA in 30 cases of HCC. Matching pair samples of tumor and adjacent nontumoral liver were analyzed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The results were compared with the clinicopathological features of the patients. Every nontumoral liver tissue sample analyzed, expressed CAR mRNA. All tumor samples showed amounts of expression that were equal or lower, compared with those found in their matching controls. Thus, in 16 out of 30 cases (53.3%), CAR mRNA expression in tumor was diminished to less than one tenth of that observed in nontumoral tissue. This group of patients exhibited higher amounts of alpha-fetoprotein, and comprised tumors with poor histological differentiation (Edmondson-Steinert's grades III-IV), higher rates of intrahepatic metastasis and recurrence within the first postoperative year (p < 0.05, respectively). Tumors exhibiting low levels of CAR mRNA were also found to be diagnosed at more advanced TNM stages (p < 0.01). We conclude that downregulation of CAR mRNA expression may play an essential role in the progression of HCC.
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Affiliation(s)
- H Yamamoto
- First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Japan
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42
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Raedle J, Roth WK, Oremek G, Caspary WF, Zeuzem S. Alpha-fetoprotein and p53 autoantibodies in patients with chronic hepatitis C. Dig Dis Sci 1995; 40:2587-94. [PMID: 8536517 DOI: 10.1007/bf02220446] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis C virus infection is a common cause of chronic liver disease and hepatocellular carcinoma. Recently, mutations in the p53 tumor suppressor gene with generation of circulating autoantibodies to p53 protein have been detected in a significant proportion of patients with different malignancies. Using ELISA methods we assessed alpha-fetoprotein and anti-p53 as serological screening parameters for hepatocellular carcinoma in 147 consecutive patients with chronic hepatitis C. Liver cirrhosis was histologically diagnosed in 58 patients (39.5%) and a hepatocellular carcinoma confirmed in seven patients (4.8%). Serum alpha-fetoprotein was raised above 20 ng/ml in 26/147 patients and above 100 ng/ml in 5/147 patients. In 6/7 patients with hepatocellular carcinoma, alpha-fetoprotein was raised above 20 ng/ml, but only in 3/7 cases above 100 ng/ml, resulting in a sensitivity and specificity of 85.7% and 85.7% (alpha-fetoprotein > 20 ng/ml) and 42.9% and 98.6% (alpha-fetoprotein > 100 ng/ml) for the detection of hepatocellular carcinoma, respectively. Autoantibodies to p53 were detected in 3/7 patients with hepatocellular carcinoma, but in 0/140 patients without malignancy (sensitivity 42.9%, specificity 100%). Screening for hepatocellular carcinoma was improved by combining alpha-fetoprotein measurement (level > 100 ng/ml) with detection for anti-p53 (sensitivity 71.4%, specificity 98.6%). In conclusion, the presence of anti-p53 was highly specific for malignancy and independent of alpha-fetoprotein status. Further studies including a larger number of patients with hepatitis C virus-related hepatocellular carcinoma are required to investigate whether serological testing for anti-p53 in combination with alpha-fetoprotein might improve the detection of hepatocellular carcinoma in high-risk patients with liver cirrhosis.
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Affiliation(s)
- J Raedle
- Second Department of Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
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43
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Matsumura M, Niwa Y, Kato N, Komatsu Y, Shiina S, Kawabe T, Kawase T, Toyoshima H, Ihori M, Shiratori Y. Detection of alpha-fetoprotein mRNA, an indicator of hematogenous spreading hepatocellular carcinoma, in the circulation: a possible predictor of metastatic hepatocellular carcinoma. Hepatology 1994; 20:1418-25. [PMID: 7527002 DOI: 10.1002/hep.1840200607] [Citation(s) in RCA: 95] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We attempted to detect circulating hepatocellular carcinoma by demonstrating hepatocyte-associated mRNA in the nuclear cell component of peripheral blood using nested reverse transcription-polymerase chain reaction because of the extremely small number of tumor cells in the circulation. Albumin mRNA was demonstrated not only in the liver tissue (hepatocytes) and HepG2 cells but also in nuclear cells of the blood from normal healthy volunteers (neutrophils and lymphocytes) by reverse transcription-polymerase chain reaction. In contrast, alpha-fetoprotein mRNA was demonstrated in the liver tissue, as well as in HepG2 cells, but not in peripheral blood of normal healthy volunteers, indicating the possibility of using alpha-fetoprotein mRNA for detection of benign and malignant hepatocytes among the population of neutrophils and lymphocytes. alpha-Fetoprotein mRNA in peripheral blood was detected in 17 of 33 cases of hepatocellular carcinoma (52%), 2 of 13 cases of cirrhosis (15%) and 2 of 17 cases of chronic hepatitis (12%). alpha-Fetoprotein mRNA was not demonstrated in 26 cases of normal healthy volunteers (0%). Among the patients with hepatocellular carcinoma, total volume of tumor tissue, maximum size of tumor and serum alpha-fetoprotein level were markedly increased in the patients with alpha-fetoprotein mRNA in blood. In addition, alpha-fetoprotein mRNA was detected in the blood of all 6 patients showing metastasis at extrahepatic organs (100%), in contrast to 11 of 27 cases without metastasis (41%). From these results, we conclude that the presence of alpha-fetoprotein mRNA in peripheral blood may be an indicator of circulating malignant or benign hepatocytes, which might predict hematogenous spreading metastasis of tumor cells in patients with hepatocellular carcinoma.
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Affiliation(s)
- M Matsumura
- Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan
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44
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Hsu HC, Peng SY, Lai PL, Sheu JC, Chen DS, Lin LI, Slagle BL, Butel JS. Allelotype and loss of heterozygosity of p53 in primary and recurrent hepatocellular carcinomas. A study of 150 patients. Cancer 1994; 73:42-7. [PMID: 7506118 DOI: 10.1002/1097-0142(19940101)73:1<42::aid-cncr2820730109>3.0.co;2-d] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND The allelotype and loss of heterozygosity (LOH) of the p53 gene in human hepatocellular carcinoma (HCC) were studied in 150 patients with resected primary HCC and 18 with recurrent HCC. METHODS DNA samples of paired HCC and livers were cut with BanII enzyme for the study of p53 allelotype and allele loss. The medical records of the patients were carefully reviewed. RESULTS Sixty-four (42.7%) patients were heterozygous for the p53 gene, 69 (46%) were homozygous for the 1.5/1.4 kb small (S) allele, and 17 (11.3%) were homozygous for the 2.9 kb large (L) allele. The frequencies of the minor L allele (0.323) and of the major S allele (0.677) in this population of Chinese patients differed from the frequencies previously reported for North American Caucasians (0.13 and 0.87, respectively). The heterozygous patients tended to have lower serum hepatitis B surface- and e antigens (HBsAg and HBeAg) and higher diabetes mellitus (DM) than did homozygous patients (SS and LL). Thirty-seven (57.8%) of the 64 heterozygous patients had a tumor-specific p53 allele LOH, being two times more common in HCC tumors larger than 8 cm than in HCC tumors 2 cm or smaller. The frequency of DM was four times higher in the heterozygous patients who had p53 LOH than in those who retained both alleles. LOH of p53 did not correlate with tumor invasiveness or differentiation, hepatitis B or C virus infection, or prognosis. CONCLUSION The allelotype of p53 gene in HCC correlates with HBsAg and HBeAg seropositivities and DM. LOH of the p53 gene is a common event in HCC, correlates with DM, and occurs less often in familial HCC. LOH can identify the clonal origin of recurrent HCC but is not a critical prognostic factor.
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Affiliation(s)
- H C Hsu
- Department of Pathology, National Taiwan University, Taipei, Republic of China
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