Frequent Down-Regulation and Lack of Mutation of the KAI1 Metastasis Suppressor Gene in Epithelial Ovarian Carcinoma

Liu, Fu-Shing; Dong, Jin‐Tang; Chen, Jung‐Ta; Hsieh, Yeun-Ting; Ho, Esther Shih-Chu; Hung, Man‐Jung

doi:10.1006/gyno.2000.5801

Cited by 54 publications

(34 citation statements)

References 16 publications

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“…However, the underlying cause for loss of KAI1 expression in advanced tumours and tumour cell lines remains unknown. Available evidence suggests that mechanisms including loss of heterozygosity at the KAI1 locus on human chromosome 11p11.2, gene or promoter mutation and promoter hypermethylation are not responsible (Dong et al, 1996;Tagawa et al, 1999;Liu et al, 2000;Miyazaki et al, 2000;Sekita et al, 2001). Another possible explanation is that loss of KAI1 expression might reflect altered transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

et al. 2004

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A molecular mechanism to explain reduced KAI1 expression in invasive and metastatic tumour cells remains elusive. In this report, we extend an earlier study in bladder cells to confirm that a 76 bp region of the KAI1 promoter (residues À922 to À847), with binding motifs for p53, AP1 and AP2, is required for high level activity of a KAI1 reporter in prostate cancer cell lines. Gel shift and supershift experiments supported binding of p53, junB and heterodimers of AP2a/AP2c or AP2b/AP2c to this sequence. Introduction of mutations into specific motifs demonstrated an essential requirement for p53 and junB to reporter activity, and that functional synergy between these two factors enhanced activity. A further elevation of reporter activity required AP2. Roles of individual p53, junB and AP2 proteins, as well as functional synergy between p53 and junB, were confirmed in transfection experiments. Western blotting analysis showed that an absence of wild-type p53, and/or a loss of junB and AP2 protein expression, correlated with downregulation of KAI1 mRNA levels in a series of prostate cancer cell lines. A loss of p53 function and/or expression of junB, combined with reduced expression of specific AP2 proteins may underly downregulated KAI1 expression in tumour cells.

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Section: Introductionmentioning

confidence: 99%

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

et al. 2004

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“…There is little evidence for gene mutation, loss of heterozygosity, promoter mutation, or hypermethylation to explain the loss of CD82 expression in clinical isolates of metastatic cancers [22][23][24][25][26][27][28]. Altered transcription or splice variants remain as possible mechanisms for loss of CD82 mRNA.…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Mechanisms of KAI1/CD82-Induced Prostate Cancer Metastasis

Miranti¹

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER Mechanisms of KAI1/CD82-Induced Prostate Cancer Metastasis Cynthia Miranti Metastatic prostate cancer kills over 28,000 American men every year. The mechanisms that drive metastasis are poorly understood. We investigated the hypothesis that loss of the metastasis suppressor gene, CD82/KAI1 in primary prostate tumors of genetically engineered mice would be sufficient to induce metastasis. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTWhile CD82 was sufficient to suppress metastasis of metastatic tumor cells lines and did so by repressing c-Met, the reverse was not true, i.e. loss of CD82 was not sufficient to induce metastasis. This was the case in at least two genetically engineered prostate cancer models. Ongoing studies in different models may yet prove otherwise.Our other hypothesis, that CD82 was suppressing c-Met and invasion through integrins, was proven invalid in these studies. Other tetraspanins that CD82 associates with, i.e. CD9 and CD151 were required to suppress cMet, but not invasion. Thus, these two events must be occurring via different mechanisms. Nonetheless, we are finding several interesting phenotypes in the CD82 null mice which will shed additional light on CD82 function overall and be useful in developing new hypotheses about how CD82 functions as a metastasis suppressor. cell biology, integrins, KAI1/CD82, tetraspanins, metastasis, c-Met, HGF, mouse models cindy.miranti@vai.org 3 INTRODUCTIONProstate cancer is the most frequently diagnosed cancer and the third leading cause of cancer deaths in men in the United States. 1 Death is due to invasion and metastasis beyond the prostate gla...

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“…Reduced expression of KAI1 is associated with progression of PCa (Lijovic et al, 2002) and epithelial ovarian carcinoma (Liu et al, 2000), as well as with bladder (Su et al, 2004), breast (Yang et al, 2000), gastric , and colorectal (Lombardi et al, 1999) cancer. Reduced expression of KAI1 was also detected in metastatic forms of esophageal squamous cells (Uchida et al, 1999) and hepatocellular carcinoma (Guo et al, 1998).…”

Section: Introductionmentioning

confidence: 97%

Chromosome 18 suppresses tumorigenic properties of human prostate cancer cells

Gagnon¹,

Ripeau²,

Zvieriev³

et al. 2005

Genes Chromosomes & Cancer

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Although prostate cancer is still the most diagnosed cancer in men, most genes implicated in its progression are yet to be identified. Chromosome abnormalities have been detected in human prostate tumors, many of them associated with prostate cancer progression. Indeed, alterations (including deletions or amplifications) of more than 15 human chromosomes have been reported in prostate cancer. We hypothesized that transferring normal human chromosomes into human prostate cancer cells would interfere with their tumorigenic and/or metastatic properties. We used microcell-mediated chromosome transfer to introduce human chromosomes 10, 12, 17, and 18 into highly tumorigenic (PC-3M-Pro4) and highly metastatic (PC-3M-LN4) PC-3-derived cell lines. We tested the in vitro and in vivo properties of these hybrids. Introducing chromosome 18 into the PC-3M-LN4 prostate cancer cell line greatly reduced its tumorigenic phenotype. We observed retarded growth in soft agar, decreased invasiveness through Matrigel, and delayed tumor growth into nude mice, both subcutaneously and orthotopically. This phenotype is associated with a marker in the 18q21 region. Combined with the loss of human chromosome 18 regions often seen in patients with advanced prostate cancer, our results show that chromosome 18 encodes one or more tumor-suppressor genes whose inactivation contributes to prostate cancer progression.

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Frequent Down-Regulation and Lack of Mutation of the KAI1 Metastasis Suppressor Gene in Epithelial Ovarian Carcinoma

Cited by 54 publications

References 16 publications

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

Mechanisms of KAI1/CD82-Induced Prostate Cancer Metastasis

Chromosome 18 suppresses tumorigenic properties of human prostate cancer cells

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