KAI1 Protein Research Articles

The expression of tumor metastasis suppressor gene KAI1 and matrix metalloproteinase 2 in breast cancer tissues

The objective of this study is to investigate the expression of tumor metastasis suppressor gene KAI1 protein and matrix metalloproteinase 2 (MMP-2) in breast carcinoma. We retrospectively analyzed 60 cases of patients from June 2005 to June 2011 treated with radical mastectomy for invasive ductal breast cancer in our department. The carcinoma tissue was stained for KAI1 and MMP2 with immunohistochemistry. In breast cancer group, the positive expression rate of KAI1 was 41.7%, which was significantly lower than control (83.3%) (c2 = 17.328, P < 0.05); the positive expression rate of MMP-2 was 80.0%, which was significantly higher than control group (16.7%) (c2 = 41.637, P < 0.05). Within the breast cancer patients, the group with lymph node metastasis showed higher positive rate of KAI1 and MMP2 expression than those without lymph node metastasis (P < 0.05). The patients with tumor diameter more than 5 cm showed lower positive rate of KAI1 but higher positive rate of MMP-2 expression than patient group with tumor diameter less than 5 cm. Additionally, tumor-nodes-metastasis III (TNM III) grade patients showed lower positive rate of KAI1 but higher positive rate of MMP-2 expression than patient group in I and II grades. KAI1 and MMP-2 were highly expressed in breast cancer tissues. The positive expression of KAI1 and MMP-2 were associated with tumor metastasis, tumor size, TNM grades etc. Key words: Breast cancer, KAI1, matrix metalloproteinase 2 (MMP-2), immunohistochemistry.

AICD Overexpression in Neuro 2A Cells Regulates Expression of PTCH1 and TRPC5

Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a transmembrane protein of undetermined function. APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro and in vivo studies have implicated the role of AICD in cell signaling and transcriptional regulation of Gsk3β, KAI1, BACE1, EGFR, and other proteins. In this study, by overexpressing AICD in mouse neuroblastoma cell lines, we have demonstrated the alteration in the expressions of two proteins, patched homolog 1 (PTCH1), a receptor for sonic hedgehog signaling, and transient receptor potential cation channel subfamily C member 5 (TRPC5), a component of receptor-activated nonselective calcium permeant cation channel. Our results indicate the possibility of regulation by AICD in developmental processes as well as in the maintenance of calcium homeostasis at the transcription level.

Expression of KAI1 protein in primary hepatocellular carcinoma and its clinical significance

Expression of KAI1 protein in primary hepatocellular carcinoma and its clinical significance

Identification of the KAI1 metastasis suppressor gene as a hypoxia target gene

KAI1 is a metastasis suppressor gene known to inhibit cancer metastasis without affecting primary tumorigenicity. Although KAI1 expression has been reported to undergo transcriptional regulation, how its expression is up- or down-regulated by specific upstream signaling pathways has not been studied in detail. In this study, we characterized the regulatory elements within the 500bp upstream region of mouse KAI1 gene and identified a functional hypoxia-response element (HRE) within the promoter region. Hypoxia-dependent induction of KAI1 was directly mediated by hypoxia-inducible factor (HIF)-1α binding on the promoter, which subsequently caused increased recruitment of RNA polymerase II for transcriptional activation. The failure of HIF-1α recruitment to the KAI1 promoter was observed in Hif-1α knockout mouse embryonic fibroblasts. Furthermore, KAI1 protein synthesis was markedly increased in ischemic tissues, suggesting that KAI1 is a hypoxia target gene in vivo.

Determination of expressions of KiSS-1 and KAI-1 proteins in gallbladder carcinoma by tissue microarrays

We investigated the expression levels of KiSS-1 and KAI-1 in gallbladder carcinoma and their relationship with clinicopathologic parameters and metastasis potential. Pathological specimens from 59 gallbladder carcinoma tissues (including 23 invasion tissues), matched 7 para-tumor and 6 normal gallbladder tissues were examined for the expression of KiSS-1 and KAI-1 protein by tissue microarray technique and immunohistochemistry (EnVision). The positive rate of KiSS-1 and KAI-1 was down-regulated (P < 0.05) in tumor tissues, compared with non-tumor tissues. The positive rate of KiSS-1 and KAI-1 were down-regulated (P < 0.01) in invasion tissues, compared with para-tumor tissues. Down-regulating expression levels of KiSS-1 and KAI-1 were significantly correlated with some malignant behavior of gallbladder carcinoma. The positive rate of KiSS-1 and KAI-1 were all negatively correlated with the Nevin staging of gallbladder carcinoma (P < 0.01). Moreover, a strong positive correlation was found between the positive expression of KiSS-1 and KAI-1 in gallbladder carcinoma (P < 0.001). It was indicated that KiSS-1 and KAI-1 were all associated with high metastasis potential of gallbladder carcinoma. KiSS-1 and/or KAI-1 may be important markers of reflecting invasive and metastatic potential and prognosis in gallbladder carcinoma, and may be the target genes to inhibit metastasis of gallbladder carcinoma. Detection of the expression of KiSS-1 and/or KAI-1 may have important clinical value for finding early-stage and evaluating the prognosis of gallbladder carcinoma.

The expression and clinical significance of KAI1 and CD44v6 protein in human osteosarcoma

Objective To investigate the expressions of KAI1 and CD44v6 in human osteosarcoma and the relationship between expressions of them and their clinic pathological features and prognosis.

Differential Expression of KAI1 Metastasis Suppressor Protein in Renal Cell Tumor Histological Subtypes

The similar appearance of renal tumor histological subtypes can complicate differential diagnoses. This problem is most notable for the chromophobe subtype of renal cell carcinoma, which can be histologically indistinguishable from oncocytoma with investigational molecular markers failing to provide reliable differentiation. KAI1 is a metastasis suppressor gene whose expression correlates inversely with the metastatic potential of most solid tumor cancer types. We tested the hypothesis that KAI1 is differentially expressed among renal tumor histological subtypes. Immunohistochemical staining for KAI1 protein was performed in 152 nephrectomy specimens, including 48 clear cell, 35 papillary and 31 chromophobe renal cell carcinoma samples, 28 oncocytomas and 10 tumor-free kidneys. Staining was scored as none/minimal, low, moderate or high. KAI1 mRNA levels were compared by quantitative reverse transcriptase-polymerase chain reaction in an additional 22 chromophobe renal cell carcinoma and oncocytoma samples. In all 10 tumor-free kidneys KAI1 protein was detected exclusively in distal tubule cell membranes. Of the tumor specimens KAI1 protein was absent in all papillary renal cell carcinoma specimens. It was present in only 1 of 48 clear cell renal cell carcinomas (2%) and 2 of 28 oncocytomas (7%) but only at low levels. In contrast, 27 of 31 chromophobe renal cell carcinoma specimens (87%) expressed KAI1 protein, most at moderate or high levels. The diagnostic accuracy of KAI1 immunostaining for discerning chromophobe renal cell carcinoma from oncocytoma was 90% with similar results observed at the RNA level. KAI1 is an accurate biomarker for chromophobe renal cell carcinoma that may aid in the diagnostic differentiation of chromophobe renal cell carcinoma from oncocytoma. It remains to be determined whether KAI1 expression contributes to the low metastatic potential of chromophobe renal cell carcinoma.

KAI1/CD82 is a novel target of estrogen receptor-mediated gene repression and downregulated in primary human breast cancer (Int J Cancer 123: 2239-2246, 2008)

With interest I read the article by Christgen et al. that was recently published under the Fast Track heading in the International Journal of Cancer.1 The major reported findings, nicely summarized in the article's title, are that (a) KAI1/CD82 is downregulated in 77% of human breast carcinomas and (b) KAI1 downregulation is strongly correlated with ER positivity. I do not question the accuracy of the reported data. However, I take exception to the authors' claim, repeated several times throughout their article, that their major findings are novel. The fact is that my colleagues and I published practically identical observations 3 years ago.2 Specifically, we reported downregulation of KAI1 expression in 74 of 98 (76%) archival breast carcinomas, and we mentioned that KAI1 downregulation was significantly more common in ER-positive (48 of 55, 87%) versus ER-negative (22 of 36, 61%) tumors (p = 0.0052). Although the focus of our manuscript was on new cell membrane biomarkers involved in breast oncogenesis, we very clearly detailed our observations on KAI1 expression in human breast cancer tissues and 9 cell lines including MCF-7, which Christgen used as a negative control. We published our data in Clinical Cancer Research, which can hardly be considered an obscure journal. It is hard to imagine that even a cursory review of the literature involving KAI1/CD82 and breast cancer would not have brought our article to Christgen et al.'s attention. A scientific finding does not become novel by ignoring its previous description by other investigators. It would have been appropriate for Christgen etal. to acknowledge our published data. Of course, in so doing they would have had to admit that most of their data are confirmatory rather than novel, notwithstanding the fact that they documented the inverse relationship between ER and KAI1 expression in greater detail. Christgen et al. also give the impression that their immunohistochemical staining method for KAI1 is a major technological advance. In fact, they used the same anti-KAI1 antibody and the same heat induced epitope retrieval method that we published in 2005.2 Already in 1999, we had demonstrated that KAI1 protein expression can reliably be evaluated in fixed tissues by immunohistochemistry using a different antibody.3 Christgen also confirms our original observation that KAI1 expression is not correlated with axillary lymph node involvement, tumor grade, or c-erbB-2 status.2 Christgen et al. describe several in vitro experiments as well. They show that the growth and migration of ER-positive, but not ER-negative, breast cancer cells is inhibited by fulvestrant, an antiestrogenic agent, and that this is correlated with up- or downregulation of 4 indicator genes. The authors acknowledge that those experiments confirm previously published observations by other research groups.4-7 It seems that Christgen et al.'s only original and novel contribution is the finding that KAI1 is upregulated by fulvestrant in 2 ER-positive breast cancer cell lines. The International Journal of Cancer may consider following the example of other scientific journals that discourage authors from inserting superlatives (“first”, “largest”, etc.) into their manuscripts. Some of those claims do not stand up to scrutiny. Evidently the reviewers assigned to Christgen's article were not sufficiently familiar with the literature to rebut the authors' exaggerated claims of novelty. In conclusion, I believe the data presented by Christgen et al. are interesting and a useful addition to the scientific literature. However, their major findings are confirmatory (rather than novel) in nature. It is inappropriate for the authors to suggest that their methodology and experimental results are groundbreaking, when they essentially replicate portions of an article that they unfortunately chose not to cite. Yours sincerely, Joseph Geradts MD

KAI-1 Protein Expression in Odontogenic Cysts

The KAI-1 tumor suppressor gene is widely distributed in normal tissues and its down-regulation may be correlated with the invasive phenotype and metastases in several different epithelial tumors. The aim of the present study was an evaluation of KAI-1 expression in radicular cysts (RC), follicular cysts (FC), orthokeratinized keratocysts (OOKC), and parakeratinized keratocysts (POKC). Eighty-five odontogenic cysts, 28 RC, 22 FC, and 35 OKC (16 OOKC, 19 POKC) were selected. All the POKC were negative and only four of 16 of the OOKC were positive for KAI-1. On the contrary, all RC and FC cases were positive and immunoreactivity for KAI-1 was detected throughout all the layers of the cyst epithelium. The lack of KAI-1 expression in POKC could help to explain the differences in the clinical and pathologic behavior of OKC and, according to what has been reported for epithelial tumors, could be related to the increased aggressive behavior and invasiveness of OKC.

Expression of the Metastasis Suppressor KAI1 in Decidual Cells at the Human Maternal-Fetal Interface: Regulation and Functional Implications

At the human maternal-fetal interface, the decidua forms a dense matrix that is believed to limit trophoblast invasion. We investigated whether the metastasis suppressor KAI1 (CD82) is expressed at the maternal-fetal interface. Immunohistochemistry showed strong expression of KAI1 in decidual cells, whereas trophoblast cells were negative for KAI1. In luteal phase endometrium, KAI1 was present in decidualizing endometrial stromal cells. We investigated whether KAI1 expression in endometrial stromal cells is regulated by the decidualizing stimuli cAMP and progesterone or by the cytokine interleukin (IL)-1beta. Western blot analysis revealed induction of KAI1 protein by cAMP analog, but not by progesterone, in a delayed fashion. In contrast, IL-1beta rapidly stimulated KAI1 expression at the transcript level and at the protein level. Cultured decidual cells from term placenta expressed a basal level of KAI1 protein that was elevated on cAMP stimulation. Silencing of KAI1 by RNA interference attenuated expression of decorin, a decidual product implicated in limiting trophoblast invasion. This study shows for the first time the expression of KAI1 in decidual cells at the human maternal-fetal interface, where the metastasis suppressor might participate in intercellular communication with trophoblast cells and the control of trophoblast invasion.

Masthead

The multistep process of carcinogenesis implies the accumulation of multiple molecular defects. Alteration of tumor suppressor and metastasis suppressor genes are the important steps. Increasing experimental evidence indicates that decreased expression of tumor-metastasis/suppressor genes and gene products are involved in the progression of a variety of human malignancies. In the present study, we have extended this analysis to non-small cell lung carcinomas (NSCLC). The expression and prognostic significance of the tumor suppressor gene PTEN and metastasis suppressor genes nm23-H1 and KAI-1 was evaluated in NSCLCs. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissues from 53 bronchogenic adenocarcinomas and 51 squamous cell carcinomas using monoclonal antibodies against PTEN, nm23H-1, and KAI-1 proteins. Immunohistochemical results were correlated with tumor stage, grade, lymph nodes positivity, metastasis, and patient survival. Significant co-expression of PTEN, nm23-H1 and KAI-1 was observed in NSCLC (P <.001 to .002). The immunohistochemical expression of these proteins was significantly higher in stages 1 and 2 compared with stages 3 and 4 (P =.04 for PTEN and KAI-1, P =.039 for nm23-H1). When all stages were considered together, loss of immunoreactivity for PTEN, nm23-H1 and KAI-1 was found in advanced NCSCLs (P =.015 for PTEN, P =.001 for KAI-1, P =.004 for nm23-H1), which is suggestive of co-downregulation of these proteins in the process of tumor progression. On multivariate analysis, negative staining for PTEN (P =.014), KAI-1 (P =.034), and nm23-H1 (a trend toward association for nm23-H1 reached near significance P =.08) correlated with disease-related death. Positive lymph node status was associated with negative immunostaining for PTEN (P=.007) but no correlation was observed for nm23-H1 and KAI-1. Loss of expression was linked to distant metastasis (P =.006 for PTEN, P =.002 for nm23H1, P =.001 for KAI-1). On multivariate analysis, co-downregulation of PTEN (P =.009), KAI-1 (P =.02), and nm23-H1 (P =.011) independently predicted shortened survival in NSCLC. Although NSCLC exhibits strong co-expression of PTEN, nm23-H1 and KAI-1, there is a loss of these proteins in high-stage tumors. Co-downregulation of PTEN, KAI-1, and nm23-H1 significantly correlates with distant metastasis and predicts shortened survival. Our study supports a role of these tumor suppressor and metastasis suppressor genes in the evolution and progression of NSCLC.

Characterization of an antibody that can detect the Kai1/CD82 murine metastasis suppressor

Kai1, also known as CD82, is a member of the tetraspanin family (TM4SF). The human homolog, KAI1, is an activation antigen of T-cells and is a metastasis suppressor for prostate and other cancers. Little is known about the mouse protein because of the lack of antibody reagents. Peptide immunized rabbits were used to generate polyclonal antibody to Kai1. The antibody was analyzed using immunoblotting, flow cytometry, and immunohistochemistry. This antibody specifically recognizes murine Kai1 protein, crossreacts with rat Kai1 but not with human KAI1. The normal tissue distribution of this protein in mice is shown to be similar to that of the human homolog. Interestingly, mouse prostatic epithelium showed differential expression within the lobes. This antibody, the first described that can specifically detect murine Kai1/CD82, should be very useful in addressing the mechanism of action of Kai1 in metastatic suppression.

Expression of KAI1 protein in tissue microarray and its biological significances in patients with lung cancer

KAI1 is a new identified metastasis-suppressor gene whose expression in many types of tumors has been reported. The aim of study is to investigate the role of KAI1 protein in development of lung cancer and its values in predicting the prognosis of lung cancer. The expressions of KAI1 protein were detected in benign pulmonary disease tissue, precancerous disease tissue, lung cancer tissue and metastatic lung cancer tissue in local lymph node using tissue microarray and immunohistochemical method. The relationship between expression of KAI1 protein and clinicopathological parameters of patients with lung cancer was analyzed by Chi-Square test and Fisher exact test. The positive rate of KAI1 expression was 100.0% in 10 cases of benign pulmonary diseases, 66.7% in 12 cases of precancerous diseases, 24.7% in 89 cases of primary lung cancer and 0 in metastatic lung cancer tissue in local lymph node respectively. The KAI1 protein expression in primary lung cancer tissues had no remarkable relationship with age and gender of the patients and the location of cancer, but had significant relationship with the histological type and differentiated degree of tumor, P-TNM stages and lymph node metastatic status. The abnormal expression of KAI1 protein may participate in malignant progression of lung cancer. Its downregulation may promote the invasion and metastasis of tumor cell. Detection of the expression of KAI1 protein may be helpful to predict the prognosis of lung cancer.

下顎歯肉へん平上皮癌の発生とリンパ節転移におけるＫＡＩ１遺伝子発現減弱の関与

KAI1is a tumor suppressor gene originally identified in prostate cancer. Recent studies of oral cancer, including our investigations, have shown frequent down-regulation ofKAI1expression in many tumor types, whereas mutation of the gene is infrequent. However, the role of the down-expression ofKAI1in oncogenesis and the progression of oral carcinoma remains unclear. In this study, we analyzed the mutational status of KAI1and both the mRNA and protein levels of the gene in a series of gingival carcinomas and precancerous lesions (20 leukoplakias, 50 squamous cell carcinomas, and 20 lymph node metastatic tumors). Although no mutation was found in any sample tested, immunohistochemical studies revealed high frequencies of KAI1 down-regulation not only in the metastatic tumors (20 of 20, 100 %), but also in the primary carcinomas (39 of 50, 78 %) and leukoplakias (9 of 20, 45 %). Down-regulation of KAI1 protein expression was significantly related to carcinogenesis and metastasis (precancerous lesions, primary carcinomas, and metastatic tumors)(p<0.001) as well as to lymph node metastasis (p=0.0022). RT PCR analysis confirmed these results. Therefore, suppressed expression ofKAI1was suggested to play clinically significant roles in carcinogenesis and lymph node metastasis.

Decreased expression of KAI1 metastasis suppressor gene is a recurrence predictor in primary pTa and pT1 urothelial bladder carcinoma.

To examine the expression of the KAI1 metastasis suppressor gene and to evaluate its relationship with tumor recurrence in primary pTa and pT1 urothelial bladder carcinoma. Samples were obtained from 87 patients after transurethral resection (TUR). Tumor stage and grade were reviewed in 33 patients with pTa and in 54 patients with pT1, with a mean follow-up time of 47.4 +/- 30.1 months. The KAI1 protein immunohistochemical assay was performed. Prognosis was analyzed using the Kaplan-Meier method and Cox's proportional hazards model. Correlation between KAI1 expression and recurrence according to each clinicopathological factor was comparatively evaluated using the chi-squared test. Decreased expression of KAI1 protein failed to reach statistical significance for stage (P = 0.25) or morphology of tumor stem (P = 0.19), but it was significantly related to tumor size (P = 0.016). The recurrence-free 5-year survival rates of the group with decreased KAI1 expression was 69.7%, which was significantly higher than the 22.2% for the KAI1-positive group (P < 0.0001). In univariate and multivariate analyses, decreased expression of KAI1 protein, stage pT1, tumor size >3 cm and sessile tumors were independent prognosis factors of recurrence. Despite the lower recurrence rate expected by considering only the clinicopathological factors, decreased KAI1 expression was able to identify the group with a high risk of recurrence. Downregulated KAI1 expression in bladder tumors tends to relate to stage and morphology of the tumor stem and was significantly correlated to tumor size. Decreased expression of KAI1 was associated with the degree of invasiveness and progression of the cancer and was an independent prognostic factor of recurrence in primary pTa and pT1 urothelial bladder carcinoma.

Role of tumor metastasis suppressor gene KAI1 in digestive tract carcinomas and cancer cells.

The KAI1 gene is identified as a tumor metastasis suppressor gene in many types of cancer. We examined KAI1 gene and its protein KAI1/CD82 expression by in situ hybridization and immunohistochemical analysis, and found that KAI1 mRNA and protein expression were inversely correlated with lymph node and distant metastasis in digestive tract carcinomas, but not with age and gender of the patient, or with tumor differentiation. Moreover, KAI1/CD82 protein expression positively reflected the survival outcome of patients. Western blot analysis showed that VP-16 increased KAI1/CD82 protein expression obviously in various cancer cell lines, especially in those that were highly metastatic. This increased KAI1/CD82 expression was associated with its translocation from the cytomembrane to the nucleus, in which it interacted with nuclear p53 protein, forming a strong complex, observed by confocal microscopy and co-immunoprecipitation, respectively. In nude mice, after feeding with VP-16, the number of tumors metastasized from spleen to liver was obviously reduced, and KAI1/CD82 protein expression became stronger in those metastatic tumors. Accordingly, this demonstrated that KAI1 might be used as an indicator for predicting the clinical outcome, and VP-16 may be clinically considered as a promising candidate for anti-metastasis with regard to its potential to upregulate KAI1 expression.

An Alzheimer's Tail

Scientists are buzzing about the β-amyloid precursor protein (APP) because its midsection appears in the brain plaques of Alzheimer's disease. Although scientists have swarmed over this sticky protein fragment, a different one might also deserve attention. A new study reveals that the tail chopped from APP helps turn on a gene. The results uncover a function for the ephemeral tail in normal cells and suggest that some potential anti-Alzheimer's drugs might rob the brain of a necessary control molecule. The β-amyloid protein that gunks up the brains of Alzheimer's disease patients derives from APP. To release β amyloid, enzymes snip off APP's head and a short tail known as AICD. A molecular ghost, AICD breaks down so quickly that scientists have never isolated it from brain cells--and only with great difficulty from other cell types, says molecular neurobiologist Sam Sisodia of the University of Chicago. Last year, researchers caught the first glimpse of AICD at work; it linked with two proteins to flick on a gene the researchers had inserted into mammalian cells. But no one had shown that the tail activates anything but an artificial gene. Baek and colleagues were studying how cells control a protein corepressor that straddles a gene called KAI1 and helps shut it down. In cell culture experiments, they noticed that the AICD-carrying trio could muscle the corepressor away, presumably activating the gene. Mutating the tail of APP so that it can't link to its partners prevented the AICD team from alighting on KAI1 , as did blocking the enzyme that releases AICD from APP. Together, these findings indicate that AICD enables the group to fasten to the gene. Mice that pump out abnormally large amounts of APP produce extra KAI1 protein and messenger RNA, which suggests that the AICD-containing crew turns on KAI1 in whole organisms. Sisodia describes the work as a good start toward pinning a function on AICD. However, he wants stronger evidence linking the tail to KAI1 activation; no one has yet measured whether the extra APP in the mice that also manufacture extra KAI1 translates into additional AICD, for example. He also warns that researchers who try to implicate AICD in Alzheimer's disease will be chasing their tails. If the AICD-containing conglomerate activates genes, rising concentrations of the tail could cause potentially hazardous overproduction of some proteins, although no current evidence supports that idea, according to Sisodia and the paper's authors. But to get more AICD, APP production would also have to mount, and that doesn't happen in Alzheimer's patients, Sisodia says; although they accumulate β amyloid, amounts of the precursor protein don't change. Edward Koo, a neuroscientist on the research team, says the results raise questions about new drugs that diminish the amount of β amyloid in the brain by blocking one of the enzymes that cleaves APP. If AICD turns out to be part of an essential gene switch, this strategy could backfire. "It's a potential warning that if you inhibit AICD signaling, you may get unwanted side effects," he says. Only further work will reveal whether this tail packs a sting. --Mitch Leslie C. S. H. Baek, K. A. Oghi, D. W. Rose, E. H. Koo, C. K. Glass, M. G. Rosenfeld, Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein. Cell 110 , 56-67 (2002). [Abstract] [Full text]

Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression.

Impairment of cell adhesion plays a vital role in tumor progression. E- and N-cadherin, CD9, and KAI1 are all adhesion molecules that have been implicated in the progression of several different tumor types. To help explain the potential role these adhesion molecules have in ovarian cancer, comparisons were made between expression patterns in normal ovary and various grades of primary and metastatic epithelial ovarian cancers. Thirty-two primary and 8 metastatic human ovarian epithelial carcinomas and 18 samples of normal ovarian tissue were examined for adhesion molecule expression using immunohistochemistry. KAI1 and CD9 revealed an inverse relationship between tumor grade and expression levels, characterized by high expression in low-grade tumors and low expression in high-grade tumors and metastases. KAI1 and CD9 also demonstrated a shift in cellular localization from the membrane in grade 1 tumors to the cytoplasm in grade 3 tumors. N-cadherin expression showed a positive trend between expression levels and tumor grade. E-cadherin expression varied little between different tumor grades and metastases. Inclusion cysts (n = 6) and surface invaginations often strongly expressed KAI1, CD9, and E-cadherin. KAI1 expression was variable in ovarian follicles and corpora lutea depending on their stage of development. Although sample size is limited, these findings suggest that progression of ovarian epithelial carcinomas is associated with down-regulation and altered cellular localization of KAI1 and CD9. In addition, variable KAI1 expression during follicular and luteal development suggests that it has a physiological function in the ovary. Further investigation will be needed to see if it is also regulated this way during progression of ovarian cancers.

KAI1 expression can be a predictor of stage A prostate cancer progression.

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.

Mutation and expression of the metastasis suppressor gene KAI1 in esophageal squamous cell carcinoma.

KAI1/CD82, a tumor metastasis suppressor gene, is correlated inversely with the progression and invasion of several tumors. It also has been reported that the KAI1 gene is related to the tumor suppressor gene p53. This study was performed to clarify the correlation between KAI1/CD82 expression and clinicopathologic characteristics and p53 expression in patients with esophageal squamous cell carcinoma (ESCC). The authors also investigated mutation of the KAI1 gene coding region to determine whether this may reduce KAI1 expression in ESCC. Using immunohistochemistry with anti-KAI1 polyclonal antibody and monoclonal antibody against p53, KAI1/CD82 and p53 expression were detected in 55 patients with ESCC who had undergone surgery. The authors examined the KAI1 gene mutation in 22 patients with ESCC by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and DNA sequencing. KAI1/CD82 expression was positive in 36 of 55 patients (65.5%). There was a significant inverse correlation between KAI1/CD82 expression and regional lymph node metastasis (P = 0.0045), distant metastasis (P = 0.0092), the number of lymph node metastases (P = 0.0019), and pathologic stage (P = 0.0046). The survival rates of KAI1/CD82 negative patients were poorer than those of positive patients (P = 0. 024). The correlation between KAI1 positive and p53 positive tumors was not statistically significant. None of the 22 patients with ESCC showed mutation of the KAI1 gene by PCR-SSCP. In one patient, there was polymorphism in the SSCP assay and DNA sequencing. The authors demonstrated immunohistochemically that the expression of KAI1 protein appeared to be correlated with lymph node metastasis. Mutation does not seem to be a mechanism for dysregulation of the KAI1 protein in ESCC.