Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The KAI1 gene was identified as a metastasis suppressor gene for human prostate cancer. Recently, we showed that KAI1 mRNA levels were higher in an immortal, normal-like breast epithelial cell line and nonmetastatic breast cancer cell lines but lower substantially in highly metastatic breast cancer cell lines. In this study, we examined KAI1 protein expression in breast cancer cell lines by Western blot and immunohistochemical study. KAI1 protein levels paralleled KAI1 mRNA levels and were inversely correlated with the metastatic potential of breast cancer cells. Furthermore, we examined KAI1 protein expression immunohistochemically in specimens from 81 patients with breast cancer and then correlated the findings with the clinical and histopathological parameters of the patients. High levels of KAI1 protein expression were found in normal breast tissues and noninvasive breast cancer (ductal carcinoma in situ). In contrast, KAI1 expression was reduced in most of the infiltrating breast tumors. We found that, in general, more malignant tumors demonstrated significantly lower KAI1 expression (P = 0.004). Additionally, among 29 specimens demonstrating multiple stages of malignancy within a single specimen, 23 demonstrated significant differences in KAI1 expression between benign breast tissue, ductal carcinoma in situ, and invasive carcinoma. The higher the incidence for malignancy within a given specimen, the lower the KAI1 expression (P < 0.001). These data suggest that in advanced breast cancer, KAI1 expression is down-regulated. Therefore, KAI1 may be a potentially useful indicator of human breast cancer progression.
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PMID:KAI1 protein is down-regulated during the progression of human breast cancer. 1099 24

KAI1 is a metastasis suppressor gene for human prostate cancer and is also involved in the progression of a variety of other human cancers. Previously, we have demonstrated that KAI1 expression was down-regulated in metastatic breast cancer cell lines as well as in highly aggressive breast cancer specimens. To determine whether KAI1 expression is responsible for the metastasis suppression in breast cancer, we transfected the human KAI1 cDNA into two highly malignant breast cancer cell lines, LCC6 and MDA-MB-231, which both have low levels of endogenous KAI1 expression. Parental, vector-only transfectants and KAI1 transfectant clones were injected into the mammary fat pads and tail veins, respectively, of athymic nude mice and assessed for both spontaneous and experimental lung metastasis. High KAI1 expression significantly suppressed the metastatic potential of KAI1-transfected LCC6 cells. Metastasis suppression correlated with the reduced rate of tumor growth and a decreased clonogenicity in soft agar. Furthermore, KAI1 expression significantly suppressed the in vitro cell invasion in KAI1-transfected MDA-MB-231 cells. Our results suggested that KAI1 may function as a negative regulator of breast cancer metastasis.
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PMID:Overexpression of KAI1 suppresses in vitro invasiveness and in vivo metastasis in breast cancer cells. 1143 71

The KAI1 gene has been identified as a metastasis suppressor gene in human prostate cancer. Decrease or loss of KAI1/CD82 expression has been shown to be associated with poorer prognosis and metastasis in carcinomas of various organs. The purpose of this study was to examine whether KAI1/CD82 is expressed in bone and soft tissue tumors, and whether it is associated with metastasis to the lungs. Immunohistochemically, KAI1/CD82 expression in benign and malignant soft tissue tumors was noted in 83% and 37% of cases, respectively. KAI1/CD82 was- also expressed in benign bone tumors and osteosarcomas in 67% and 36% of the cases, respectively. Four (40%) of 10 osteosarcoma cases with no lung metastasis and one (25%) of four osteosarcoma cases with lung metastasis were positive for KAI1/CD82, respectively. Metastasis of osteosarcoma cells to the lungs was not correlated with the loss of KAI1/CD82 in osteosarcoma cells.
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PMID:Loss of KAI1/CD82 expression in bone and soft tissue tumors is not associated with lung metastasis. 1156 27

Expression of the KAI1 gene, a metastasis-suppressor for prostate cancer, is reduced in all foci of prostatic metastasis. The altered regulatory mechanism is not strongly related to mutations or allelic losses of the KAI1 gene in prostate tumors. Since transcriptional silencing of genes has been found to be caused by epigenetic mechanisms, we have investigated the involvement of this epigenetic regulation of KAI1 expression in prostate cancers. The methylation status of the KAI1 promoter region was examined by restriction-enzyme digestion and sequencing, after amplifying a 331-bp fragment in the GC-rich promoter region from 4 human prostate cancer cell lines treated with bisulfite. The same 4 cell lines were also exposed to various concentrations of the demethylating agent, 5-aza-2'-deoxycytidine (5-AzaC) and / or the histone deacetylase inhibitor, trichostatin A (TSA). To clarify the influence of epigenetic modification on reduced KAI1 mRNA expression in the tumor cells, RT-PCR and northern-blot analyses were performed. Bisulfite-sequencing data showed a few methylated CpG islands in the promoter. RT-PCR analysis of 5-AzaC and / or TSA-treated cells indicated reversal of suppression of KAI1 transcription in two cell lines (PC-3 and DU-145), although the expression could not be detected by northern blots. From these results, it is suggested that epigenetic change is not the main mechanism of KAI1 down-regulation, though there remains a possibility that methylation in a more upstream region might be associated with this regulation.
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PMID:Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines. 1157 62

KAI1, which is identical to CD82, was initially identified as a metastasis-suppressor gene for human prostate cancer, and its expression is reported to be a favorable prognostic factor for operable human lung cancer. In this study, we examined the functional role of KAI1/CD82 in the late phase of metastatic spread of human lung-cancer cells. For this, KAI1/CD82 cDNA was introduced into KAI1/CD82 low-expressing human lung-cancer cell lines, SBC-3 and PC-14, and then the metastatic potential of the transformants was analyzed by i.v. inoculation of KAI1/CD82-transduced cells, SBC-3/KAI1 and PC-14/KAI1, into NK cell-depleted SCID mice. Contrary to our expectations, KAI1/CD82 gene transfer promoted multiorgan metastasis of i.v.-inoculated human lung-cancer cells, while s.c. tumor growth was unaffected. Cancer cells from metastatic tumors of NK cell-depleted SCID mice injected i.v. with SBC-3/KAI1 expressed appreciable cell-surface KAI1/CD82, and cells not expressing KAI1/CD82 (revertants) were not detected in the tumors. Our findings indicate that under conditions where the host's natural cytotoxicity is suppressed, KAI1/CD82 may enhance the formation of tumors by circulating lung-cancer cells at metastatic sites.
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PMID:Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice. 1166 73

The solution structure of the transmembrane-4 superfamily protein KAI1, a recently identified prostate cancer metastasis suppressor gene that encodes a 267-amino acid protein, was modeled. The structure of this four-helical transmembrane protein was developed by defining and modeling sections individually. A complete three-dimensional structure for the solvated protein was developed by combining the individually modeled sections. The four-helix transmembrane bundle structure was predicted combining information from several methods including Fourier transform analysis of residue variability for helix orientation. The structure of the KAI1 large extracellular domain was modeled based on the solved crystal structure of the extracellular domain of another tetraspanin superfamily protein member, CD81 (hepatitis C virus envelope E2 glycoprotein receptor). This is a novel protein fold consisting of five alpha helices held together by two disulfide bonds for which the CD81 protein is the first solved representative. Molecular dynamics studies were performed to test stability and to relax the total model KAI1 structure's solution. The resulting KAI1 structural model should be a useful tool for predicting modes of self-association and associations with other TM4SF proteins, integrins, cadherins, and other KAI1 binding partners. Mutations for probing the interactions of KAI1 with antibodies and with other binding partners are suggested. Published 2001 Wiley-Liss, Inc.
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PMID:KAI1, a prostate metastasis suppressor: prediction of solvated structure and interactions with binding partners; integrins, cadherins, and cell-surface receptor proteins. 1174 26

Current prognostic methods in primary prostate cancer cannot accurately identify patients with clinically significant disease at highest risk of developing metastases. This study examined KAI1/CD82 metastasis suppressor expression by quantitative immunohistochemical analysis of benign prostatic hyperplasia (BPH) and prostate cancer specimens. Altogether, prostate cancers exhibited significant KAI1 overexpression compared to BPH not associated with cancer (P = 0.022). Increased KAI1 expression in well and moderately differentiated cancers, above levels seen in BPH, with decreased expression in poorly differentiated cancers was observed. Interestingly, KAI1 expression in BPH associated with cancers was significantly higher than in BPH not associated with cancer (P = 0.009). Thus, KAI1 overexpression may restrain onset and early stage prostate cancer development, whilst its loss may predispose the patient to more aggressive cancer behaviour. Altered KAI1 expression in prostate cancers and BPH associated with cancer may have important diagnostic roles.
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PMID:KAI1/CD82 protein expression in primary prostate cancer and in BPH associated with cancer. 1208 6

The molecular basis for the loss of KAI1 expression in invasive and metastatic tumors and tumor cell lines is not understood. Recently, identification of a sequence with homology to the consensus p53-binding motif in the promoter of the KAI1 metastasis suppressor gene, has led to a proposal that transcriptional regulation by p53 controls expression of KAI1, and that a dramatic down-regulation of KAI1 mRNA levels in invasive tumors and many tumor cell lines, is directly due to loss of p53 function. We have tested this hypothesis by assessing KAI1 mRNA levels in a series of 22 cell lines derived from bladder and prostate cancers, in which we confirmed the p53 gene sequence and characterized the functional status of the endogenous p53 protein. We anticipated that cell lines expressing p53 capable of transactivation should express high levels of KAI1 mRNA compared with cell lines expressing defective p53, or which were p53-null. KAI1 mRNA levels were determined by northern analysis using a full-length KAI1 cDNA probe, and varied widely between cell lines examined. However, there was no association between these levels and p53 status. Furthermore, transfection of representative cell lines with wild-type p53, or exposure to DNA damaging agents, had no effect on KAI1 mRNA levels. Our data suggest that p53 is not a major factor regulating levels of KAI1 mRNA in bladder and prostate cancer cell lines.
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PMID:Relationship between expression of KAI1 metastasis suppressor gene, mRNA levels and p53 in human bladder and prostate cancer cell lines. 1247 42

The disease progression and rate of cancer death were analyzed in 52 patients with stage A prostate cancer who underwent transurethral resection of the prostate (TURP) or retropubic subcapsular prostatectomy (SCP) between 1987 and 1998. We performed immunohistochemistry on 16 patients to determine the correlation between the expression of the tumor metastasis suppressor gene KAI1 and the subsequent progression of stage A prostate cancer. Nineteen and 33 of the patients had cancer at stage A1 and stage A2, respectively, and their subsequent courses were followed for an average of 53.7 months (24-134 months). Progression to clinical cancer was found in six patients (one with stage A1, and five with stage A2). This progression was evident 40.8 months (5-80 months) after TURP or SCP. Four (66.7%) of the patients died of cancer progression (average 31 months) after prostatectomy. All four patients had stage A2, poorly differentiated adenocarcinoma, and had been followed with administration of diethylstilbestrol diphosphate (DES-P). The disease-free patients (n=10) showed overexpression of KAI1 protein, compared to those with disease progression (n=6). These results indicate that progression arose mainly in the patients with stage A2 cancer, and that poorly differentiated, focal and weak expression of KAI1 protein is highly associated with disease progression. It is suggested that patients in this group should be treated with immediate total androgen blockade, radiation, or radical prostatectomy after diagnosis.Prostate Cancer and Prostatic Diseases (2001) 4, 150-153.
Prostate Cancer Prostatic Dis 2001
PMID:KAI1 expression can be a predictor of stage A prostate cancer progression. 1249 33

To investigate the functional role of KAI1/CD82, a metastasis suppressor for human prostate cancer, in the regulation of homotypic cell adhesion, we transfected KAI1 cDNA into DU 145 human prostate cancer cells and established stable transfectant clones with high KAI1/CD82 expression. The KAI1 transfectant cells exhibited significantly increased homotypic cell aggregation in comparison with the control transfectant cells. This aggregation of the KAI1 transfectants was further enhanced upon exposure to anti-CD82 antibody, suggesting that KAI1/CD82 may be involved in the intracellular signaling for the cell adhesion. Among several signal pathway inhibitors tested, PP1, an inhibitor of Src family kinases, significantly suppressed homotypic aggregation of the KAI1 transfectant cells. Ligation of KAI1/CD82 with anti-CD82 antibody increased endogenous Src kinase activity of the KAI1 transfectant cells. When different types of src expression constructs were retransfected into the KAI1-transfected DU 145 cells, kinase-negative mutant src transfectant cells exhibited much lower homotypic aggregation than the mock cells transfected with an empty vector. Moreover, homotypic aggregation of the mutant src transfectant cells was not enhanced by KAI1/CD82 ligation with anti- CD82 antibody. These results suggest that Src mediates the intracellular signaling pathway of KAI1/CD82 for the induction of homotypic adhesion of human prostate cancer cells.
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PMID:Metastasis-suppressor KAI1/CD82 induces homotypic aggregation of human prostate cancer cells through Src-dependent pathway. 1264 1


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