[Health-related quality of life assessed by EuroQol in home care patients with stroke].
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Activities of Daily Living↗
Biomedical subjects
M Kuwano
Publications and source records attributed to M Kuwano.
Direct interaction of p53 with the Y-box binding protein, YB-1: a mechanism for regulation of human gene expression.
The Y-box binding protein, YB-1, belongs to a family of multifunctional proteins which regulate gene expression on both transcriptional and translational levels. The tumor suppressor gene p53 displays growth suppressive properties by regulating gene expression through transcriptional regulation. We now demonstrate that YB-1 directly interacts with p53 using an in vitro pull-down assay. Using immunochemical co-precipitation methods, we also found that the two proteins are bound in vivo. Deletion analysis showed that three independent domains of YB-1, one at the N-terminal and two at the C-terminal, interact with p53. Conversely, a 14 amino acid sequence at the C-terminal of p53 was required for its interaction with YB-1. Gel mobility shift assays showed that the interaction of YB-1 with p53 stimulated the sequence-specific DNA binding of p53 to its consensus sequence. By contrast, this interaction inhibited the binding of YB-1. Using a p53-responsive p21 promoter linked to a reporter gene, it can be shown that antisense expression of YB-1 inhibits the induction of this promoter by p53 in transient transfection assays. These findings delineate a straightforward mechanism for gene expression through p53-YB-1 interaction.
CCAAT-Enhancer-Binding Proteins↗
Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells.
Angiostatin, a potent endogenous inhibitor of angiogenesis, is generated by cancer-mediated proteolysis of plasminogen. The culture medium of human prostate carcinoma cells, when incubated with plasminogen at a variety of pH values, generated angiostatic peptides and miniplasminogen. The enzyme(s) responsible for this reaction was purified and identified as procathepsin D. The purified procathepsin D, as well as cathepsin D, generated two angiostatic peptides having the same NH(2)-terminal amino acid sequences and comprising kringles 1-4 of plasminogen in the pH range of 3.0-6.8, most strongly at pH 4.0 in vitro. This reaction required the concomitant conversion of procathepsin D to catalytically active pseudocathepsin D. The conversion of pseudocathepsin D to the mature cathepsin D was not observed by the prolonged incubation. The affinity-purified angiostatic peptides inhibited angiogenesis both in vitro and in vivo. Importantly, procathepsin D secreted by human breast carcinoma cells showed a significantly lower angiostatin-generating activity than that by human prostate carcinoma cells. Since deglycosylated procathepsin D from both prostate and breast carcinoma cells exhibited a similar low angiostatin-generating activity, this discrepancy appeared to be attributed to the difference in carbohydrate structures of procathepsin D molecules between the two cell types. The seminal vesicle fluid from patients with prostate carcinoma contained the mature cathepsin D and procathepsin D, but not pseudocathepsin D, suggesting that pseudocathepsin D is not a normal intermediate of procathepsin D processing in vivo. The present study provides evidence for the first time that cathepsin D secreted by human prostate carcinoma cells is responsible for angiostatin generation, thereby causing the prevention of tumor growth and angiogenesis-dependent growth of metastases.
Angiostatins↗
Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein.
To elucidate the role of P-glycoprotein in human placenta, we examined its expression in placenta, and the transcellular transport and uptake of P-glycoprotein substrates in cultured human placental choriocarcinoma epithelial cells (BeWo cells). The uptake of [(3)H]vinblastine and [(3)H]vincristine into BeWo cells was increased in the presence of a metabolic inhibitor, sodium azide. The basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was greater than the apical-to-basolateral transcellular transport. In the presence of cyclosporin A, the basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was significantly increased, and the apical-to-basolateral transcellular transport was decreased. The uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells was significantly enhanced in the presence of several inhibitors, such as verapamil or mouse monoclonal antibody anti-P-glycoprotein MX-MDR (MRK16) as well as cyclosporin A. Although progesterone significantly enhanced the uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells, the uptake of [(3)H]progesterone was not affected by these inhibitors. Immunoblot analysis revealed that P-glycoprotein with a molecular weight of 172 kDa was expressed in BeWo cells and isolated trophoblast cells. Furthermore, P-glycoprotein was detected in human placental brush-border membrane vesicles, but not in human placental basolateral membrane vesicles. In conclusion, these data suggest that P-glycoprotein is expressed on the brush-border membrane (maternal side) of human placental trophoblast cells. P-Glycoprotein is considered to regulate the transfer of several substances including vinblastine, vincristine and digoxin from mother to fetus, and to protect the fetus from toxic substances.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13.
IL-13 is a multifunctional lymphokine sharing a number of biological properties with IL-4. We previously observed that IL-4 shows angiogenic activities in vitro as well as in vivo. In this study we examined the effect of IL-13 on angiogenesis in vitro and in vivo and also the underlying mechanisms. Human IL-13 significantly stimulated the formation of tube-like structures in collagen gels by human microvascular endothelial cells and bovine aortic endothelial cells by about 3-fold over the controls in the absence of the cytokines. Administration of murine IL-13 led to neovascularization when implanted in the rat cornea. Coadministration of neutralizing mAb to the IL-4R inhibited both tubular morphogenesis in vitro and activation of STAT6 induced by IL-4 or IL-13. Both IL-4 and IL-13 markedly increased mRNA levels of VCAM-1 in vascular endothelial cells, and the production of the soluble form of VCAM-1 was also stimulated in response to IL-4 or IL-13. Administration of anti-VCAM-1 Ab in vitro blocked tubular morphogenesis induced by IL-4 and IL-13. Angiogenesis induced in vivo in rat cornea by IL-4 and IL-13 was also inhibited by Ab against the rat alpha4 integrin subunit. These findings suggest that angiogenesis dependent on IL-4 and IL-13 is mainly mediated through a soluble VCAM-1/alpha4 integrin pathway.
Animals↗
Alu-associated interstitial deletions and chromosomal re-arrangement in 2 human multidrug-resistant cell lines.
Previous studies have shown that gene re-arrangements play a significant role in tumorigenesis. Gene re-arrangements involving the human multidrug resistance-1 (MDR1) gene have been identified as a mechanism for MDR1 over-expression in human malignant cells. In 2 multidrug-resistant human cancer sublines with high levels of MDR1 and P-glycoprotein (MCF7/TX400 and S48-3s/Adr10), hybrid mRNAs containing sequences from MDR1 and an unrelated gene have previously been identified. To characterize and determine the site of the re-arrangements resulting in generation of hybrid mRNAs, we first constructed a lambda phage library extending over a contiguous genomic region of 100 kb and containing the region upstream of MDR1. In MCF7/TX400 cells, homologous recombination was observed involving an Alu repeat 80 kb upstream of the MDR1 gene, with a 79 bp intra-Alu deletion flanked by chi-like sequences at the re-arrangement junction. By contrast, non-homologous recombination was observed in S48-3s/Adr10 cells with Alu repeats near the junction sequence. While the specific features of the breakpoints appear to be different, Alu repeats might be involved in both gene re-arrangements. The gene re-arrangements at or near the Alu sequence should be regarded as potentially involved in the transcriptional activation of human MDR1.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha.
We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.
Adult↗
Molecular analysis of mechanisms regulating drug sensitivity and the development of new chemotherapy strategies for genitourinary carcinomas.
The emergence of drug-resistant tumors during treatment remains one of the major obstacles in cancer chemotherapy. Overexpression of P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene or multidrug resistance-associated protein (MRP) (or both) and decreased expression of DNA topoisomerase II are responsible for expression of the multidrug resistance (MDR) phenotype. The expression of P-glycoprotein is also often observed in untreated cancers showing spontaneous MDR, such as renal cell carcinoma. Regarding cisplatin resistance, decreased cisplatin accumulation, an increase in cisplatin detoxification by glutathione-related enzymes or metallothionein (or both), and increased repair of DNA damage are all considered to play an important role. The combination of reversal agents targeting such drug resistance markers may be a way to improve the outcome of chemotherapy. Regarding the presently available reversal agents, however, clinically relevant chemosensitizing doses cannot be given to humans without inducing significant toxicity. The development of new agents that reverse drug resistance without causing significant toxicity and their clinical application based on the mechanisms regulating drug sensitivity may therefore be a potentially effective new treatment strategy for genitourinary carcinomas.
Drug Resistance, Multiple↗
Up-regulation of urokinase-type plasminogen activator and its receptor correlates with enhanced invasion activity of human glioma cells mediated by transforming growth factor-alpha or basic fibroblast growth factor.
Glioblastoma multiforme is a highly malignant tumor that is extremely refractory to therapy. One reason is its highly invasive nature into brain tissue. Metalloproteinases and their inhibitors, plasminogen activators (PA) and their inhibitors and cathepsins are thought to be involved in invasion by tumor cells. In this study, we determined if the urokinase-type plasminogen activator (uPA) and/or the urokinase-type plasminogen activator receptor (uPAR) were responsible for the invasion activity of a human glioma cell line. We determined the invasion activity of a human glioma U251 cell line using an in vitro invasion assay system. A 2.4- to 5.8-fold increase in invasion activity was observed in the presence of basic fibroblast growth factor (bFGF) or transforming growth factor (TGF)-alpha. Northern blot analysis showed that bFCF and TGF-alpha treatment was associated with increases in cellular mRNA levels of uPA and uPAR. Zymographic activity correlated to mRNA levels of uPA and uPAR. Addition of an anti-uPAR monoclonal antibody significantly inhibited the invasion activity induced by bFGF- and TGF-alpha. Irsogladine, an inhibitor of uPA synthesis, also blocked the invasion activity. These observations suggest that uPA and its receptor have a role in the invasion process of human gliomas.
Fibroblast Growth Factor 2↗
Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells.
Vascular Endothelial Growth Factor (VEGF)/Vascular Permeability Factor plays an important role in angiogenesis and cell proliferation of cancer cells. Glioblastoma cells are most malignant and show resistance to radiation therapy inducing VEGF to cause angiogenesis and brain edema. In the present study, the regulatory mechanism of the expression of VEGF by ionizing radiation was studied in three human glioblastoma cells. Induction of VEGF mRNA by ionizing radiation was dependent on dose and incubation time. Activator protein-1 (AP-1) was activated by 10 Gy of ionizing radiation in 1 h in T98G glioblastoma cells on an electrophoretic mobility shift assay. We constructed chimeric genes containing various regions of the VEGF promoter gene and the coding region for chloramphenicol acetyltransferase (CAT) and transiently transfected them to T98G cells. CAT assay with the VEGF promoter gene containing an AP-1 site demonstrated that the promoter activity of the VEGF gene was enhanced by ionizing radiation. Immunological analysis of the activity of mitogen-activated protein kinase, ERK1/2, showed that this activity is up-regulated by ionizing radiation. These results suggest that ERK1/2 pathway is involved in the up-regulation of VEGF expression ionizing radiation mediated by AP-1, which may lead to further neovascularization and proliferation of glioblastoma cells resistant to radiation therapy.
Blotting, Northern↗
Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation.
IL-4 and IL-13 are pleiotropic cytokines whose biological activities overlap with each other. IL-13 receptor alpha chain 1 (IL-13R alpha 1) is necessary for binding to IL-13, and the heterodimer composed of IL-13R alpha 1 and IL-4R alpha chain transduces IL-13 and IL-4 signals; however, the functional mapping of the intracellular domain of IL-13R alpha 1 is not fully understood. In this study, we constructed wild and mutated types of human IL-13R alpha 1, and analyzed IL-4 and IL-13 signals using an IL-13R alpha 1-transfected human B cell line. Expression of IL-13R alpha 1 evoked STAT3 activation by IL-4 and IL-13, and in stimulated human B cells, on which IL-13R alpha 1 was highly expressed, IL-4 and IL-13 induced STAT3 activation. Replacement of the two tyrosine residues completely abolished STAT3 activation, although replacing either tyrosine residue alone retained it. Furthermore, we found that the Box1 region and the C-terminal tail of IL-13R alpha 1 were critical for binding to Tyk2, and activation of Jak1, Tyk2, the insulin receptor substrate-1 and STAT6 respectively. These results suggest that STAT3 activation is involved with IL-4 and IL-13 signals in human B cells along with the activation of STAT6, and that there is a unique sequence in IL-13R alpha 1 to activate STAT3.
Animals↗
The specific expression of three novel splice variant forms of human metalloprotease-like disintegrin-like cysteine-rich protein 2 gene inBrain tissues and gliomas.
We have previously identified 67 exons on a yeast artificial chromosome contig spanning 1.5 Mb around the multidrug resistance 1 gene region of human chromosome 7q21.1. In this study, we identified three novel cytoplasmic variants (MDC2-gamma, MDC2-delta, and MDC2-epsilon) of the human metalloprotease-like disintegrin-like cysteine-rich protein 2 (MDC2) among these exons by screening a human brain cDNA library and also by using a reverse transcription polymerase chain reaction. Genomic sequence analysis strongly supported the idea that the variations in the cytoplasmic domain were generated by alternative splicing. The expression of MDC2 variant forms in human brain tissue and gliomas was examined by reverse transcription polymerase chain reaction and RNase protection assay. MDC2-epsilon was expressed only in the cortical and hippocampal regions in human brain, but not in gliomas. In contrast, MDC2-gamma was a major form expressed in human gliomas. Specific expression of these cytoplasmic variants of MDC2 in human brain and its malignancies is discussed.
ADAM Proteins↗
Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas.
Expression of thymidine phosphorylase (TP) is often associated with tumor angiogenesis and / or prognosis in patients. Further, infiltration of macrophages is closely correlated with the depth of tumor and angiogenesis in melanomas. In this study, we examined the expression of TP and an activated macrophage-specific enzyme, heme oxygenase-1 (HO-1), involved in malignancy in 22 cases with melanomas. TP was strongly expressed not only in CD68-positive macrophages in and around tumors, but also in S100 protein-positive melanoma cells, fibroblasts and keratinocytes. By contrast, HO-1 was specifically expressed in macrophages, but only slightly in melanoma cells and other cell types in the stroma of melanomas. We thus observed apparent co-expression of TP and HO-1 in macrophages infiltrating in the late stage of malignant melanomas. There appeared increasing numbers of TP-positive cells in Clark level IV and V melanoma compared with Clark level I (in situ) melanoma, and there was also a close correlation between numbers of TP-positive cells and HO-1-positive cells. Both TP- and HO-1-positive macrophages could be observed in the stroma in and around tumors in vertical growth melanomas.
Antigens, CD↗
Overproduction of IL-8 results in suppression of bone metastasis by lung cancer cells in vivo.
HARA-B cells were established from the bone lesion in nude mice formed after an intracardiac inoculation of the human lung cancer-derived cells (HARA), and production of IL-8 in HARA-B cells was decreased as compared to that in the parental HARA cells. This suggests a possible relationship between IL-8 production and bone metastasis. Thus, we examined the effect of IL-8 on bone metastasis using HARA-B cells transfected with experimental (IL-8-cDNA) and/or control plasmid in the experimental bone metastasis model in nude mice. Growth rates of both cells in vitro were similar. Control cells developed radiologically detectable bone metastases in 50% of nude mice tested, whereas experimental cells did not develop bone metastases. Osteoclastic bone resorption is an important step in the process of bone metastasis, and IL-8 possesses an inhibitory effect on osteoclastic bone resorption. These results suggest that IL-8 suppresses bone metastasis, which might be attributed to the inhibitory effect of IL-8 on osteoclastic bone resorption.
Animals↗
Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas.
The expression of ATP-binding cassette superfamily transporter genes, such as P-glycoprotein/multidrug resistance (MDR) 1 and MDR protein (MRP) 1, is often up-regulated in various tumor types and is involved in responses to some anticancer chemotherapeutic agents. Five human MRP subfamily members (MRP2-6) with structural similarities to MRP1 have been identified. The relationships between MRP2-6 mRNA levels and drug resistance are not well understood. Data on 45 patients with colorectal cancer were analyzed. Of the ATP-binding cassette superfamily genes, we asked whether mRNA levels of MDR1, MRP1, MRP2, and MRP3 correlated with drug resistance to anticancer agents. For this analysis, we used quantitative reverse transcription-PCR, and the sensitivity to anticancer agents in surgically resected colon carcinomas was determined using the in vitro succinate dehydrogenase inhibition test. MDR1, MRP1, and MRP3 were highly expressed in normal colorectal mucosa, and the relative mRNA levels of MDR1, MRP1, and MRP3 in cancerous tissues compared with noncancerous tissues were decreased or unchanged. By contrast, MRP2 mRNA expression was low in normal colorectal mucosa and specifically increased in cancer regions compared with noncancerous regions. Of the anticancer agents prescribed for patients with colorectal cancers, including doxorubicin, mitomycin C, cisplatin, 5-fluorouracil, etoposide, and a camptothecin derivative, mRNA expression of MRP2 was significantly associated with resistance to cisplatin. MRP2 may be important for resistance to cisplatin treatment in colorectal cancer.
ATP Binding Cassette Transporter, Subfamily B↗
MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment.
Overexpression of the multidrug resistance 1 (MDR1) gene is closely associated with the clinical outcome of hematopoietic malignancies, but the alteration of its expression during chemotherapeutic treatment and the precise mechanism underlying MDR1 gene overexpression in solid tumors remains unclear. We determined the expression and degree of methylation at the promoter of the MDR1 gene in bladder cancer. The mRNA levels of the MDR1 gene were found to be markedly enhanced, 3.5- to 5.7-fold higher in bladder cancers after chemotherapeutic treatment than those in untreated primary tumors. The MDR1 gene was overexpressed in recurrent tumors in 89% of patients who showed rerecurrence, whereas overexpression was observed in 25% of the patients without re-recurrence. A statistically significant inverse correlation existed between MDR1 expression and the methylation of 5'CpG sites at the promoter in patients with bladder cancer after chemotherapeutic treatment, with the degree of methylation at several CpG sites, rather than other specific sites, involved in this regulation. Consistent with the increase in MDR1 expression, the frequency of patients with a hypermethylated promoter decreased to 50 and 17% after intravesical and systemic chemotherapy, respectively. Thus, overexpression of the MDR1 gene might be a prognostic marker for intravesical recurrence, whereas methylation of the promoter region negatively regulates MDR1 expression and the appearance of multidrug resistance mediated by P-glycoprotein in bladder cancers.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Structural basis for the regulation of UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 gene expression in adenocarcinoma cells.
The UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 (Gal NAc-T3) gene, a member of the Gal NAc transferase gene family, is expressed in a tissue-specific manner. To elucidate the function of this gene, we have focused on the molecular mechanism underlying regulation of gene expression. We have cloned Gal NAc-T3 cDNA and used it to show that Gal NAc-T3 mRNA is expressed in tumor cell lines derived from secretory epithelial tissue adenocarcinomas but not in cell lines derived from bladder and epidermoid carcinomas. Using a polyclonal antibody to Gal NAc-T3, we observed protein expression in adenocarcinoma but not non-adenocarcinoma cell lines, and in breast carcinoma cells but not in normal breast tissue. We used Gal NAc-T3 cDNA to isolate three overlapping genomic clones containing the 5'-portion of the human Gal NAc-T3 gene, and we sequenced 1.6 kb around the first exon. A transient expression assay using the luciferase gene showed that promoter activity was much higher in MCF-7 cells than in KB cells. In vivo footprint experiments showed significant protection of a distal GC box, an NRF-1 site, and an AP-2 site in MCF-7 cells. A novel stem and loop structure extending from nucleotide -103 to nucleotide -165 and contiguous to these transcription factor binding sites seemed to be functional in regulating Gal NAc-T3 gene transcription, and a KMnO4 footprint experiment showed that this stem and loop structure could be formed in vivo. We also observed dimethyl sulfate hypersensitive sites in the untranslated region around nucleotide +50 in MCF-7 but not in KB cells. These findings indicate that Gal NAc-T3 gene expression is regulated by multiple systems, including transcription factor binding sites and a stem-and-loop structure, and that this regulation is restricted to cell lines derived from epithelial gland adenocarcinomas but not cells derived from nonsecretory epithelial tissue carcinomas. In addition, our immunohistochemical results suggest that our anti-Gal NAc-T3 antibody may be useful for diagnostic purposes in the early stages of breast cancer.
Adenocarcinoma↗
Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human colorectal carcinomas.
The transcription factor YB-1 is expressed in a wide range of cell types and has been implicated in the regulation of various genes involved in cell proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene expression in breast cancer and osteosarcoma. In this study, we asked whether YB-1 expression is enhanced in human colorectral carcinoma and if it is associated with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed by Western blotting, Northern blotting and immunohistochemistry in 26 human colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene expression was examined by transient DNA transfection assays. YB-1 was overexpressed in almost all cancerous lesions in comparison with normal mucosa in surgically resected colorectal carcinomas of 26 patients. YB-1 expression correlated well with both DNA topoisomerase II alpha and PCNA expression. In contrast, no correlation was observed between YB-1 and MDR-1 expression. We also found that a transient co-transfection with a DNA topoisomerase II alpha promoter-luciferase plasmid and an antisense YB-1 expression construct resulted in a significant reduction of the promoter activity in KM12C human colon cancer cells. YB-1 may be an excellent proliferation-associated marker and may be a transcription factor regulating DNA topoisomerase II alpha gene expression in human colorectal carcinoma.
Aged↗