KAI1 , CAR , and Smad4 expression in the progression of colorectal tumor

Mikami, Taisei; Ookawa, Keizou; Shimoyama, Tadashi; Fukuda, Shinsaku; Saitō, Hiroshi; Munakata, Akihiro

doi:10.1007/s005350170069

Cited by 20 publications

(14 citation statements)

References 22 publications

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“…Kaplan-Meier analysis of the survival curves showed a significantly worse overall and disease-free survival for patients whose tumors had low SMAD4 levels (log-rank test, P = 0.025 and P = 0.013, respectively), indicating that low SMAD4 tumor protein level is a marker of poor prognosis for patients with Dukes C colorectal cancer. This is in agreement with previous studies linking increased SMAD4 mutation frequency and reduced SMAD4 mRNA levels with tumor progression (12,14).…”

Section: Smad4 and Prognosis In Colorectal Cancersupporting

confidence: 94%

“…In addition, frequent somatic mutations have been found in human colorectal tumors in several studies, further suggesting an important role for this gene in colorectal carcinogenesis (11,12). Moreover, animal studies have shown that SMAD4 inactivation is involved in the malignant transformation of gastrointestinal adenomas (13) and a reduction in SMAD4 mRNA levels has been observed during tumor progression (14).…”

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confidence: 99%

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SMAD4 as a Prognostic Marker in Colorectal Cancer

Alazzouzi¹,

Alhopuro²,

Salovaara

et al. 2005

Clinical Cancer Research

170

148

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More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-h superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients.One of the most common cytogenetic abnormalities in colorectal tumors is the loss of genetic material in chromosome 18q. This is believed to be indicative of an important tumor suppressor gene in this genomic location (1, 2). The identity of the gene targeted by these deletions in 18q has remained elusive and several genes, including SMAD2 and DCC (deleted in colorectal carcinoma), have been proposed (3 -5). Recently, SMAD4, a key transducer of transforming growth factor-h (TGF-h) superfamily signaling that is located in chromosome 18q21 and regulates cell proliferation, differentiation, and apoptosis (6 -8), has attracted considerable attention due to several findings. SMAD4 mutations have recently been shown to be associated with the occurrence of juvenile polyposis, an autosomal dominant syndrome predisposing to hamartomatous polyps and colorectal cancer (9, 10). In addition, frequent somatic mutations have been found in human colorectal tumors in several studies, further suggesting an important role for this gene in colorectal carcinogenesis (11,12). Moreover, animal studies have shown that SMAD4 inactivation is involved in the malignant transformation of gastrointestinal adenomas (13) and a reduction in SMAD4 mRNA levels has been observed during tumor progression (14).A significan...

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Section: Smad4 and Prognosis In Colorectal Cancersupporting

confidence: 94%

mentioning

confidence: 99%

SMAD4 as a Prognostic Marker in Colorectal Cancer

Alazzouzi¹,

Alhopuro²,

Salovaara

et al. 2005

Clinical Cancer Research

170

148

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“…KAI-1 expression is high in human normal prostate and benign prostatic hyperplasia, but decreases in a significant way in cancer cell lines derived from metastatic prostate tumors (1), and prostate carcinomas with a low expression level of KAI-1 have shown more aggressive features than those with high expression levels (4). These same characteristics were also reported for pancreatic carcinoma, bladder carcinoma, breast carcinoma, non-small-cell lung carcinoma, gastric carcinoma, esophageal carcinoma, and oral squamous cell carcinoma (2,4,(21)(22)(23)(24). The physiologic and pathologic functions of KAI-1 are largely unknown (4), and it has been proposed that association with other cell-surface proteins may be of utmost importance in directing its biological activities (2).…”

supporting

confidence: 55%

KAI-1 Protein Expression in Odontogenic Cysts

Iezzi

PIATTELLI²,

Artese

et al. 2007

Journal of Endodontics

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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.

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“…Binding to CAR represents the initial event in cell attachment in vitro, and therefore CAR expression levels long have been thought to be critical in determining the transduction efficiency of Ad5 in vivo. Several studies have reported low expression of CAR in primary carcinoma lines and tumor explants (3,21,30,32,37), highlighting the necessity for CAR-independent targeting strategies. However, the nonspecific sequestration of Ad5 in the liver remains the major obstacle to achieving high-efficiency tumor targeting following systemic delivery.…”

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confidence: 99%

In Vivo Retargeting of Adenovirus Type 5 to αvβ6 Integrin Results in Reduced Hepatotoxicity and Improved Tumor Uptake following Systemic Delivery

Coughlan¹,

Vallath²,

Saha³

et al. 2009

J Virol

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A key impediment to successful cancer therapy with adenoviral vectors is the inefficient transduction of malignant tissue in vivo. Compounding this problem is the lack of cancer-specific targets, coupled with a shortage of corresponding high-efficiency ligands, permitting selective retargeting. The epithelial cell-specific integrin ␣v␤6 represents an attractive target for directed therapy since it is generally not expressed on normal epithelium but is upregulated in numerous carcinomas, where it plays a role in tumor progression. We previously have characterized a high-affinity, ␣v␤6-selective peptide (A20FMDV2) derived from VP1 of footand-mouth disease virus. We generated recombinant adenovirus type 5 (Ad5) fiber knob, incorporating A20FMDV2 in the HI loop, for which we validated the selectivity of binding and functional inhibition of ␣v␤6. The corresponding ␣v␤6-retargeted virus Ad5-EGFP A20 exhibited up to 50-fold increases in coxsackievirusand-adenovirus-receptor-independent transduction and up to 480-fold-increased cytotoxicity on a panel of ␣v␤6-positive human carcinoma lines compared with Ad5-EGFP WT . Using an ␣v␤6-positive (DX3-␤6) xenograft model, we observed a ϳ2-fold enhancement in tumor uptake over Ad5-EGFP WT following systemic delivery. Furthermore, ϳ5-fold-fewer Ad5-EGFP A20 genomes were detected in the liver (P ‫؍‬ 0.0002), correlating with reduced serum transaminase levels and E1A expression. Warfarin pretreatment, to deplete coagulation factors, did not improve tumor uptake significantly with either virus but did significantly reduce liver sequestration and hepatic toxicity. The ability of Ad5-EGFP A20 to improve delivery to ␣v␤6, combined with its reduced hepatic tropism and toxicity, highlights its potential as a prototype virus for future clinical investigation.

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KAI1 , CAR , and Smad4 expression in the progression of colorectal tumor

Abstract: These results suggest that the upregulation of CAR and down-regulation of Smad4 are associated with the progression of colorectal tumors, while the upregulation of these genes and of KAI1 seems to be involved in the early stage.

Cited by 20 publications

References 22 publications

SMAD4 as a Prognostic Marker in Colorectal Cancer

SMAD4 as a Prognostic Marker in Colorectal Cancer

KAI-1 Protein Expression in Odontogenic Cysts

In Vivo Retargeting of Adenovirus Type 5 to αvβ6 Integrin Results in Reduced Hepatotoxicity and Improved Tumor Uptake following Systemic Delivery

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