Identification of liver–intestine cadherin in hepatocellular carcinoma—a potential disease marker

Wong, Bonnie; Luk, John M.; Ng, Irene Oi–Lin; Hu, Mengbo; Liu, Kang D; Fan, Sheung‐Tat

doi:10.1016/j.bbrc.2003.10.032

Cited by 73 publications

(57 citation statements)

References 23 publications

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“…Human HCC cell lines, MHCC97H (97H), MHCC97L (97L), H2M, H2P, PLC/PRF/5 (PLC), Hep3B and a immortalized human hepatocyte liver cell line (MIHA), were cultured as described 19 in Dulbecco's modified Eagle's minimal essential medium (DMEM) (Gibco BRL, Grand Island, NY) containing 10% heat-inactivated fetal bovine serum (Gibco BRL, Grand Island, NY) in a 5% CO 2 humidified atmosphere at 37 C.…”

Section: Cell Lines and Culturementioning

confidence: 99%

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Lü

Lee

Kaul

et al. 2011

Intl Journal of Cancer

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Stress protein mortalin (mtHSP70) is highly expressed in cancer cells. It was shown to contribute to carcinogenesis by sequestrating the wild type p53, a key tumor suppressor protein, in the cytoplasm resulting in an abrogation of its transcriptional activation function. We have found that the level of mortalin expression has significant correlation with human hepatocellular carcinoma (HCC) malignancy and therefore investigated whether it interacts with and influences the activities of mutant p53, frequently associated with HCC development. We have detected mortalin-p53 interactions in liver tumor and five HCC cell lines that harbored mutant p53. The data was in contrast to the normal liver and immortalized normal hepatocytes that lacked mortalin-p53 interaction. Furthermore, we have found that the shRNA-mediated mortalin silencing could induce mutant p53-mediated tumor-specific apoptosis in HCC. Such allotment of apoptotic function to mutant p53 by targeting mortalin-p53 interaction in cancer cells is a promising strategy for HCC therapy.Hepatocellular carcinoma (HCC) is a lethal malignancy associated with poor prognosis and the fifth most common cancer worldwide. Effective HCC therapeutics still await molecular understanding of the mechanisms and development of effective reagents that could selectively kill cancer cells. Like any other tumors, HCC has high rate of mutations in tumor suppressor protein p53, and is afflicted in p53-mediated functions including cell cycle arrest and apoptosis.1 Recently, several studies have identified that the mutant p53 executes transcription and nontranscription activities.2,3 Several p53 mutants with a low level of transcriptional activation function were also shown to induce apoptosis in cancer cells demonstrating nontranscriptional apoptotic ability of mutant p53. 4,5 However, in cancer cells such apoptotic function of p53 is often deregulated by multiple pathways including its binding with other proteins.6,7 Restoration of p53-mediated apoptosis is an attractive strategy for cancer therapy.Mortalin/mthsp70/GRP75/PBP74 is a member of the heat shock protein 70 family and has been shown to have multiple functions including chaperoning, mitochondrial import, energy generation and intracellular trafficking. 8,9 It exists in multiple subcellular sites and possesses multiple binding partners. 8,9 Several studies have shown that mortalin is frequently upregulated in cancers and contributes to carcinogenesis. [10][11][12][13][14] It was shown to cause cytoplasmic sequestration of wild type p53 resulting in inhibition of its transcriptional activation and control of centrosome duplication functions, both commonly associated with cancers.15-17 Furthermore, mortalin binding p53 peptides and cationic inhibitor of mortalin (MKT-077) were shown to (i) release p53 from mortalin-p53 complexes, (ii) cause nuclear translocation of p53 and (iii) cause growth arrest of cancer cells that contained wild type p53. 16,18 Mortalin was identified as a marker for HCC metastasis and recurrence by prot...

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Section: Cell Lines and Culturementioning

confidence: 99%

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Lü

Lee

Kaul

et al. 2011

Intl Journal of Cancer

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“…The TCF/LEF family has several spliced forms with unknown functional significance and it is suggested that they may activate preferential genes [86] . In HCC, mutations of TCF-4 are rare with 315 August 10, 2011|Volume 2|Issue 8| WJCO|www.wjgnet.com [70][71][72] phospho-GSK3β High 52 IHC [73] Axin1 Low 67 IHC [76] Dvl High 71 Western blotting [82] Prickle-1 Low 55 PCR [82] HDPR1 Low 58 PCR [83] PIN1 High 53 Western blotting [65] TCF-4 High 91 PCR [87] LEF-1 High 52 IHC [88] CDH17 High 72 IHC [90] CDH17: Cadherin-17; Dvl: Dishevelled; FZD: Frizzled; phospho-GSK3β: Phosphorylated glycogen synthase kinase 3β; HDPR1: Human homologue of Dapper; IHC: Immunohistochemistry; LEF: Lymphoid enhancer factor; PCR: Polymerase chain reaction; PIN1: Peptidyl-prolyl cis/trans isomerase; TCF: T-cell factor.…”

Section: Tcf/lefmentioning

confidence: 99%

“…Since β-catenin plays an essential role in cadherin-mediated cell-cell adhesion as well as in Wnt/β-catenin signalling, our laboratory identified CDH17 to affect Wnt/β-catenin signalling in HCC. CDH17 is overexpressed in HCC cells and in more than 70% of HCC cases [90] . In addition, overexpression of an alternative splice variant of CDH17 (lacking exon 7) in more than 50% of HCC is correlated to tumour recurrence, venous infiltration and reduced overall survival [91] .…”

Section: Cadherin-17mentioning

confidence: 99%

Dickkopfs and Wnt/β-catenin signalling in liver cancer

Fatima¹

2011

WJCO

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Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/ β-catenin pathway for potential therapy of HCC. hepatocellular carcinoma anD the unmet meDical neeDSLiver cancer ranks the fifth most common cancer in men and the second leading cause of cancer-related death. In women, it is the seventh most frequent cancer and sixth leading cause of cancer death [1] . Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Men are three times more likely to develop HCC than women and the incidence increases with age [2] . HCC is prevalent in Asia and Africa, but recently it is on the rise in the Western world due to an increase in hepatitis C virus (HCV) infection [3] . Risk factors for HCC include chronic hepatitis B virus (HBV) and HCV infections, cirrhosis, chronic alcohol abuse, aflatoxin ingestion, non-alcoholic steatohepatitis and other metabolic liver diseases [4,5] . Much of HCC occurs in the background of cirrhosis. About 80%-90% of patients with cirrhosis go on to develop HCC eventually and the remaining 10%-20% of cases develop HCC without cirrhosis. Furthermore, HBV and HCV infections increase the risk of developing cirrhosis and later HCC. Among the HCC

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“…Ribosomal 18s was used as an internal control. Realtime Q-PCR was performed according to the previously described procedures (14). To determine COX-2 expression levels in different patients, 2 ml of each cDNA were subjected to AmpliTaq Gold DNA polymerase in 1 £ PCR buffer (25 ml) containing 200 mmol/l dNTPs, 1.5 mmol/l MgCl 2 , 0.5 mmol/l of each of the paired primers, and 200 nmol/l TaqMan probe.…”

Section: Rna Isolation and Reverse Transcriptasepolymerase Chain Reacmentioning

confidence: 99%

High prevalence of cyclooxygenase 2 expression in papillary thyroid carcinoma

Lo¹,

Lam²,

Leung³

et al. 2005

eur j endocrinol

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Background: Cyclooxygenase-2 (COX-2) seems to play a role in the development and carcinogenesis of papillary thyroid carcinoma. Its incidence of expression and potential application as a tumor marker remain to be elucidated. Materials and methods: Immunohistochemical staining for COX-2 expression was performed for 30 papillary thyroid carcinoma (PTC) and 40 benign thyroid specimens. COX-2 mRNA expression was analyzed using a reverse transcriptase-polymerase chain reaction (RT-PCR) for paired fresh frozen tissues removed from surgically resected PTC specimens. Results: COX-2 expression was detected by immunohistochemistry in 27 of 30 (90%) PTC but was absent in 40 benign thyroid specimens, including 27 nodular hyperplasia, 7 follicular adenoma and 6 lymphocytic thyroiditis. Two of the three COX-2 negative carcinomas were follicular variant of PTC. RT-PCR analysis confirmed COX-2 mRNA over-expression in 14 of 20 (70%) paired specimens of PTC. Real-time quantitative RT-PCR showed that the level of COX-2 mRNA expression was significantly higher in PTC than in both the adjacent non-cancerous tissues and the benign thyroid specimens. Conclusion: COX-2 is frequently expressed in PTC but not in benign thyroid specimens. COX-2 expression may serve as a useful molecular marker for PTC in cases of diagnostic difficulty.

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Identification of liver–intestine cadherin in hepatocellular carcinoma—a potential disease marker

Cited by 73 publications

References 23 publications

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Dickkopfs and Wnt/β-catenin signalling in liver cancer

High prevalence of cyclooxygenase 2 expression in papillary thyroid carcinoma

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