Determination of Cathepsin B Expression May Offer Additional Prognostic Information for Ovarian Cancer Patients

Scorilas, Andreas; Fotiou, Stelios; Tsiambas, Evangelos; Yotis, Julia; Kotsiandri, Fani; Sameni, Mansoureh; Sloane, Bonnie F.; Talieri, Maroulio

doi:10.1515/bc.2002.146

Cited by 46 publications

(33 citation statements)

References 16 publications

(10 reference statements)

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“…M17S2 is a surface marker in ovarian cancer (25), and the expression of M17S2 was found to be inversely correlated to the survival in renal cell carcinoma patients (26). Cathepsin B is a lysosomal cysteine protease, and the overexpression of cathepsin B has been associated with ovarian cancer, adenocarcinoma, and other tumors (27). The ability of these proteins to inhibit p53 activity may underlie these correlations to oncogenesis.…”

Section: Resultsmentioning

confidence: 99%

Identification of p53 regulators by genome-wide functional analysis

Huang

Raya

DeJesus

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

142

128

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The p53 tumor-suppressor protein is a critical mediator of cellular growth arrest and the induction of apoptosis. To identify proteins involved in the modulation of p53 transcriptional activity, a gainof-function cellular screen was carried out with an arrayed matrix of Ϸ20,000 cDNAs. Nine genes previously unknown to be involved in regulating p53 activity were identified. Overexpression of seven of these genes (Hey1, Hes1, TFAP4, Osr1, NR2F2, SFRS10, and FLJ11339) resulted in up-regulation of p53 activity; overexpression of two genes (M17S2 and cathepsin B) resulted in down-regulation of p53 activity in mammalian cells. HES1, HEY1, and TFAP4, which are members of the basic helix-loop-helix transcription family, and OSR1 were shown to activate p53 through repression of HDM2 transcription. Ectopic expression of these basic helix-loop-helix transcription factors in both zebrafish and avian developmental systems activated p53 and induced apoptosis in vivo, resulting in a phenotype similar to that of p53 overexpression. Furthermore, ras-and myc-mediated transformation of mouse embryonic fibroblasts was abrogated by expression of HEY1 in a p53-dependent manner. These results suggest that these transcription factors are members of an evolutionarily conserved network that governs p53 function.

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Section: Resultsmentioning

confidence: 99%

Identification of p53 regulators by genome-wide functional analysis

Huang

Raya

DeJesus

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

142

128

View full text Add to dashboard Cite

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“…A role of CTSB and CTSL in tumor cell invasion was suggested by the observation of the increased invasiveness of cells overexpressing CTSB and CTSL (17) and by the decreased invasion in the presence of specific inhibitors of CTSB and CTSL (18). Moreover, immunohistochemical analysis demonstrated that CTSB and CTSL exist in the cytoplasm of tumor cells in human ovarian cancer (9,19). Similarly, in the present study increased expression of CTSB and CTSL was noted in cancer, but not normal ovarian tissue, suggesting that CTSB and CTSL are survival prognostic factors in ovarian cancer, and may contribute to the invasiveness of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of cysteine cathepsin L is a marker of invasion and metastasis in ovarian cancer

Zhang

Wang

et al. 2014

Oncology Reports

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Abstract. Cysteine cathepsins (CTSs) are involved in the degradation and remodeling of the extracellular matrix and are associated with cellular transformation, differentiation, motility and adhesion in cancer development. Previous studies indicate that CTSs may be involved in ovarian cancer invasion and metastasis. However, due to the lack of large sample clinical studies and direct experimental evidence for the relationship between the expression of CTSs and invasion and metastasis, the diagnostic and prognostic value of CTSs in ovarian cancer progression has not been elucidated. In the present study, we observed that expression levels of CTSB, CTSL and CC in malignant ovarian tumors were significantly higher than the expression levels in benign tumors and normal ovarian tissues, yet their associations with clinicopathological features varied. In particular, CTSL was related to lymph node metastasis, CC was related to liver metastasis and omental metastasis, and CTSB and CTSL expression levels were found to be independent prognostic factors in ovarian cancer. Further study indicated that the serum level of CTSL was significantly higher in patients with ovarian malignant tumors than the levels in benign tumors and healthy controls, and the levels were elevated in low grade and advanced stage compared to the levels in high grade and early stage disease, suggesting that the serum level of CTSL may be a useful serum marker for the diagnosis of ovarian cancer. Furthermore, the expression of CTSL in ovarian cancer cells can greatly enhance the ability of cell invasion and metastasis, although no change was observed for cell adhesion. Taken together, we demonstrated that the overexpression of CTSL is involved in tumor invasion and metastasis, and the CTSL level in serum may be a marker for invasion and metastasis in ovarian cancer.

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“…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 actions of a multitude of kinases (21).High expression levels of CTSB have been linked to aggressiveness and poor prognosis in several cancers, such as colorectal and ovarian carcinomas (15,29,34,37,38). Compared to the amount…”

mentioning

confidence: 99%

“…High expression levels of CTSB have been linked to aggressiveness and poor prognosis in several cancers, such as colorectal and ovarian carcinomas (15,29,34,37,38). Compared to the amount…”

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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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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Determination of Cathepsin B Expression May Offer Additional Prognostic Information for Ovarian Cancer Patients

Cited by 46 publications

References 16 publications

Identification of p53 regulators by genome-wide functional analysis

Identification of p53 regulators by genome-wide functional analysis

Overexpression of cysteine cathepsin L is a marker of invasion and metastasis in ovarian cancer

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

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