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Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.

Mori J, Tanikawa C, Funauchi Y, Lo PH, Nakamura Y, Matsuda K - Cancer Sci. (2016)

Bottom Line: We showed that cathepsin L activity was decreased in HCT116 p53(+/+) cells after adriamycin treatment, but not in HCT116 p53(-/-) cells.We also found that knockdown of cystatin C reduced adriamycin-induced caspase-3 activation.Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.

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Expression and prognostic impact of cystatin C in cancer tissues. (a, b) Box‐plot of cystatin C expression in colorectal adenocarcinoma (a) or breast adenocarcinoma (b) tissues. The vertical axis indicates the normalized expression level of cystatin C, top bar represents maximum observation, lower bar represents minimum observation, top of the box is upper or third quartile, bottom of the box is lower or first quartile, middle bar is median value. P‐value was calculated by Mann–Whitney U‐test. (c, d) Kaplan–Meier curves among breast adenocarcinoma patients. The patients were stratified into two groups according to p53 mutation (mut) (c), or cystatin C expression (above or below median) (d) in tumors tissues. P‐value was assessed by log–rank test. wt, wild‐type.
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cas12881-fig-0006: Expression and prognostic impact of cystatin C in cancer tissues. (a, b) Box‐plot of cystatin C expression in colorectal adenocarcinoma (a) or breast adenocarcinoma (b) tissues. The vertical axis indicates the normalized expression level of cystatin C, top bar represents maximum observation, lower bar represents minimum observation, top of the box is upper or third quartile, bottom of the box is lower or first quartile, middle bar is median value. P‐value was calculated by Mann–Whitney U‐test. (c, d) Kaplan–Meier curves among breast adenocarcinoma patients. The patients were stratified into two groups according to p53 mutation (mut) (c), or cystatin C expression (above or below median) (d) in tumors tissues. P‐value was assessed by log–rank test. wt, wild‐type.

Mentions: To explore the role of cystatin C in human carcinogenesis, we investigated the expression of cystatin C by using RNA sequence data of colorectal adenocarcinoma and breast adenocarcinoma tissues released from the TCGA database. Notably, expression of cystatin C was significantly decreased in both colorectal and breast adenocarcinoma tissues compared with the corresponding normal tissues (Fig. 6a,b). Moreover, cystatin C expression in breast cancer tissues with p53 mutation was significantly lower than those without p53 mutation (Fig. 6b). As cystatin C expression was not reduced in breast cancer tissues with wild‐type p53 compared to the corresponding normal tissues, p53 inactivation is likely to be the major cause of cystatin C suppression in breast cancer tissues. We further assessed the impact of cystatin C expression and p53 mutation on clinical outcome by using the TCGA dataset. Concordant with the previous reports,42, 43 breast cancer patients without p53 mutation indicated better prognosis (Fig. 6c). We also found that breast cancer patients with high cystatin C expression showed significantly longer survival than those with low cystatin C expression (Fig. 6d). To investigate whether cystatin C is an independent prognostic factor, we used multivariate analyses including several clinical factors as covariates and found that the cystatin C level was still associated with overall survival of breast cancer patients (Table 1), while p53 mutation was not significantly associated with prognosis. These results suggest that the p53–cystatin C pathway plays an important role in the development and progression of human cancers.


Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.

Mori J, Tanikawa C, Funauchi Y, Lo PH, Nakamura Y, Matsuda K - Cancer Sci. (2016)

Expression and prognostic impact of cystatin C in cancer tissues. (a, b) Box‐plot of cystatin C expression in colorectal adenocarcinoma (a) or breast adenocarcinoma (b) tissues. The vertical axis indicates the normalized expression level of cystatin C, top bar represents maximum observation, lower bar represents minimum observation, top of the box is upper or third quartile, bottom of the box is lower or first quartile, middle bar is median value. P‐value was calculated by Mann–Whitney U‐test. (c, d) Kaplan–Meier curves among breast adenocarcinoma patients. The patients were stratified into two groups according to p53 mutation (mut) (c), or cystatin C expression (above or below median) (d) in tumors tissues. P‐value was assessed by log–rank test. wt, wild‐type.
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cas12881-fig-0006: Expression and prognostic impact of cystatin C in cancer tissues. (a, b) Box‐plot of cystatin C expression in colorectal adenocarcinoma (a) or breast adenocarcinoma (b) tissues. The vertical axis indicates the normalized expression level of cystatin C, top bar represents maximum observation, lower bar represents minimum observation, top of the box is upper or third quartile, bottom of the box is lower or first quartile, middle bar is median value. P‐value was calculated by Mann–Whitney U‐test. (c, d) Kaplan–Meier curves among breast adenocarcinoma patients. The patients were stratified into two groups according to p53 mutation (mut) (c), or cystatin C expression (above or below median) (d) in tumors tissues. P‐value was assessed by log–rank test. wt, wild‐type.
Mentions: To explore the role of cystatin C in human carcinogenesis, we investigated the expression of cystatin C by using RNA sequence data of colorectal adenocarcinoma and breast adenocarcinoma tissues released from the TCGA database. Notably, expression of cystatin C was significantly decreased in both colorectal and breast adenocarcinoma tissues compared with the corresponding normal tissues (Fig. 6a,b). Moreover, cystatin C expression in breast cancer tissues with p53 mutation was significantly lower than those without p53 mutation (Fig. 6b). As cystatin C expression was not reduced in breast cancer tissues with wild‐type p53 compared to the corresponding normal tissues, p53 inactivation is likely to be the major cause of cystatin C suppression in breast cancer tissues. We further assessed the impact of cystatin C expression and p53 mutation on clinical outcome by using the TCGA dataset. Concordant with the previous reports,42, 43 breast cancer patients without p53 mutation indicated better prognosis (Fig. 6c). We also found that breast cancer patients with high cystatin C expression showed significantly longer survival than those with low cystatin C expression (Fig. 6d). To investigate whether cystatin C is an independent prognostic factor, we used multivariate analyses including several clinical factors as covariates and found that the cystatin C level was still associated with overall survival of breast cancer patients (Table 1), while p53 mutation was not significantly associated with prognosis. These results suggest that the p53–cystatin C pathway plays an important role in the development and progression of human cancers.

Bottom Line: We showed that cathepsin L activity was decreased in HCT116 p53(+/+) cells after adriamycin treatment, but not in HCT116 p53(-/-) cells.We also found that knockdown of cystatin C reduced adriamycin-induced caspase-3 activation.Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus