Proteomic Expression Signature Distinguishes Cancerous and Nonmalignant Tissues in Hepatocellular Carcinoma

Lee, Nikki P.; Chen, Lei; Lin, Marie C.M.; Tsang, Felice Ho‐Ching; Yeung, Chun; Poon, Ronnie T. P.; Peng, Jie; Leng, Xi-sheng; Beretta, Laura; Sun, Stella; Day, Philip J.; Luk, John M.

doi:10.1021/pr800637z

Cited by 57 publications

(50 citation statements)

References 57 publications

(92 reference statements)

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“…Recently, the cysteine protease cathepsin B has been associated with metastasis and poor prognosis in multiple cancer types, including cervical, colorectal, and ovarian carcinomas and highgrade glioma (15,23,26,29,34,37,38,45). Using a proteomic signature model, Lee et al have identified cathepsin B as one of six biomarkers allowing discrimination of HCC from nonmalignant and normal liver tissues with high accuracy (19). However, what role this protein serves in HCC development and progression has not been explored by this group or other investigators.…”

Section: Discussionmentioning

confidence: 99%

“…This led us to investigate whether the HBSP could interact with CTSB in the context of hepatoma cells to affect cell migration, invasion, and metastasis, all of which can be modulated by CTSB acting directly and indirectly on extracellular matrix (ECM) component remodeling and degradation (26,47). CTSB is a lysosomal cysteine protease that plays an important role in physiological protein turnover and processing (19,41). In nonmalignant cells, CTSB is mainly stored in the lysosome, whereas in malignant cells, CTSB redistributes into exocytic vesicles at the cell periphery, leading to its secretion and association with binding partners on the tumor cell surface (22,33).…”

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confidence: 99%

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Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Chen

Jiao

et al. 2012

J Virol

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C hronic hepatitis B virus (HBV) infection has been proven to be one of the most important risk factors for the development of hepatocellular carcinoma (HCC) (3, 9). However, the pathogenesis of cancer in HBV infection is still not fully understood, and it appears that multiple factors and cellular signaling pathways are involved in hepatocarcinogenesis (28). Integration of HBV genome into host DNA can lead to alterations in cellular gene function or generate chromosomal instability (1, 10, 43). Expression of some oncogenic HBV proteins such as HBx and truncated Pre-S2/S has been shown to have a direct effect on malignant transformation of the liver (42) and to promote metastasis of the malignant cells, and there is thus a very high mortality rate for HCC patients (18). Another HBV protein, encoded by a singly spliced 2.2-kb HBV DNA and referred to as the hepatitis B spliced protein (HBSP), is found to be expressed in liver biopsy tissues from four out of five chronic patients but not from two hepatitis C virus-infected patient samples and one normal liver sample (39). Our prior study also showed that a 2.2-kb splice variant was present in all tumor and peritumor samples from 12 HCC patients studied (20). Exogenous expression of HBSP in transfected Huh-7 cells can induce cell apoptosis (40). However, the cytopathic effect of the HBSP was unclear, and its role in progression, invasion, and metastasis of HBV-related HCC has not yet been elucidated.We previously showed that cathepsin B (CTSB) was one of the major intracellular interacting partners of HBSP, and it was identified using a yeast two-hybrid screening assay (8). This led us to investigate whether the HBSP could interact with CTSB in the context of hepatoma cells to affect cell migration, invasion, and metastasis, all of which can be modulated by CTSB acting directly and indirectly on extracellular matrix (ECM) component remodeling and degradation (26,47). CTSB is a lysosomal cysteine protease that plays an important role in physiological protein turnover and processing (19,41). In nonmalignant cells, CTSB is mainly stored in the lysosome, whereas in malignant cells, CTSB redistributes into exocytic vesicles at the cell periphery, leading to its secretion and association with binding partners on the tumor cell surface (22,33). CTSB can cleave and activate a wide variety of substrates in proteolytic pathways that increase neoplastic progression. It has been shown that activation of urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) by CTSB not only enhances ECM degradation and cancer cell motility and invasion (14) but also induces in vitro angiogenesis (2). In addition to interacting with other proteases, CTSB may regulate the activity of kinase signaling networks, cell surface receptors, and signaling molecules such as chemokines, cytokines and growth factors (25). However, such interactions are usually bidirectional because kinases can also regulate many proteases through phosphorylation while proteases can control the actio...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Chen

Jiao

et al. 2012

J Virol

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“…In our earlier proteomic studies, 11,28,29 we identified members of the heat shock family proteins that are often upregulated in HCC and associated prognostic outcomes, and mortalin as a marker for predicting HCC metastasis and recurrence. In our study, we demonstrated the interaction of mortalin and p53 in liver tumors and HCC-derived cell lines that harbored mutant p53.…”

Section: Discussionmentioning

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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“…Immunohistochemistry was performed as previously described with modifications (Lee et al, 2006(Lee et al, , 2009b. Tissue sections were deparaffinized by submerging the slides in xylene and rehydrated in decreasing concentrations of ethanol (100% followed by 90 and 75%, each twice).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Western blot (Lu et al, 2011) and immunohistochemical analysis (Lee et al, 2006(Lee et al, , 2009b were performed as described previously.…”

Section: Dkk4 Antibody Specificitymentioning

confidence: 99%

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

et al. 2012

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Deregulation of Wnt/b-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of b-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/b-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in b-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated b-catenin responsive luciferase activity, and decreased both b-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n ¼ 8), reduction in tumour sizes was observed (P ¼ 0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with b-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of b-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

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Proteomic Expression Signature Distinguishes Cancerous and Nonmalignant Tissues in Hepatocellular Carcinoma

Cited by 57 publications

References 57 publications

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

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

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

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