Osteopontin regulates multiple functions contributing to human colon cancer development and progression

Irby, Rosalyn; McCarthy, Susan; Yeatman, Timothy J.

doi:10.1007/s10585-004-2873-4

Cited by 64 publications

(51 citation statements)

References 21 publications

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“…Using RNA interference, stable downregulation of OPN protein levels by ϳ3.0-fold compared with CT26 wild type resulted in a Ͼ3.0-fold decrease in MMP-2 expression, a 3.6-fold decrease in tumor cell motility in vitro, a 4.1-fold reduction in tumor invasiveness in vitro, and a 2.0-fold attenuation of in vivo hepatic metastasis (17). This demonstration of OPN function in colorectal metastasis supports similar data from various cancer models (32)(33)(34). Although the target genes activated by OPN in metastasis are being actively investigated, the molecular mechanisms that regulate this increased OPN expression in colorectal cancer remain unknown.…”

Section: Discussionsupporting

confidence: 80%

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

Wai

Gao

et al. 2006

Journal of Biological Chemistry

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Osteopontin (OPN) is a sialic acid-rich phosphoprotein secreted by a wide variety of cancers. We have shown previously that OPN is necessary for mediating hepatic metastasis in CT26 colorectal cancer cells. Although a variety of stimuli can induce OPN, the molecular mechanisms that regulate OPN gene transcription in colorectal cancer are unknown. We hypothesized that cis-and trans-regulatory elements determine OPN transcription in CT26 cells. OPN transcription was analyzed in CT26 cancer cells and compared with YAMC (young adult mouse colon) epithelial cells. Clonal deletion analysis of OPN promoter-luciferase constructs identified cis-regulatory regions. A specific promoter region, nucleotide (nt) ؊107 to ؊174, demonstrated a >8.0-fold increase in luciferase activity in CT26 compared with YAMC. Gel-shift assays sublocalized two cis-regulatory regions, nt ؊101 to ؊123 and nt ؊121 to ؊145, which specifically bind CT26 nuclear proteins. Competition with unlabeled mutant oligonucleotides revealed that the regions nt ؊115 to ؊118 and nt ؊129 to ؊134 were essential for protein binding. Subsequent supershift and chromatin immunoprecipitation assays confirmed the corresponding nuclear proteins to be Ets-1 and Runx2. Functional relevance was demonstrated through mutations in the Ets-1 and Runx2 consensus binding sites resulting in >60% decrease in OPN transcription. Ets-1 and Runx2 protein expression in CT26 was ablated using antisense oligonucleotides and resulted in a >7-fold decrease in OPN protein expression. Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.Colorectal cancer continues to be the second leading cause of cancer-related deaths in the United States (1, 2). Many patients with advanced or recurrent disease develop distant metastases and fail locoregional therapy. The molecular mechanisms underlying tumor metastasis are not completely understood, but recent evidence implicates osteopontin (OPN) 2 as a key regulator of cancer cell metastasis.OPN, an extracellular matrix protein secreted by a wide variety of cancers, functionally enables tumor progression (3-8).The secreted phosphoprotein binds the ␣ v ␤ integrin and CD44 families of receptors to propagate cellular signals (8 -14). In colorectal cancer, gene profiling studies have identified a positive correlation between advanced or metastatic colon tumors and abundant OPN expression (15, 16). We have previously shown that stable, RNAi-mediated down-regulation of OPN expression in CT26 colon adenocarcinoma cells results in suppression of matrix metalloproteinase-2 (MMP-2) expression, decreased in vitro tumor cell motility and invasiveness, and attenuation of functional in vivo hepatic metastasis (17). Together, these data suggest that OPN is necessary for CT26 colorectal metastasis. Subsequent studies in our laboratory have confirmed that OPN protein expression is highly up-regulated in meta...

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Section: Discussionsupporting

confidence: 80%

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

Wai

Gao

et al. 2006

Journal of Biological Chemistry

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“…OPN has been linked to various cancer types, for example, breast, colon, prostate, or lung cancer (28)(29)(30)(31). A special focus has been its contribution to tumor cell invasion and metastasis making it a promising tumor marker, although serum concentrations reported by Fedarko et al were not elevated in colon cancer (31).…”

Section: Discussionmentioning

confidence: 99%

A Combination of Serum Markers for the Early Detection of Colorectal Cancer

Wild

Andres

Rollinger

et al. 2010

Clinical Cancer Research

121

110

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Purpose: Fecal occult blood testing is recommended as first-line screening to detect colorectal cancer (CRC). We evaluated markers and marker combinations in serum as an alternative to improve the detection of CRC.Experimental Design: Using penalized logistic regression, 6 markers were selected for evaluation in 1,027 samples (301 CRC patients, 143 patients with adenoma, 266 controls, 141 disease controls, and 176 patients with other cancer). The diagnostic performance of each marker and of marker combinations was assessed.Results: To detect CRC from serum samples, we tested 22 biomarkers. Six markers were selected for a marker combination, including the known tumor markers CEA (carcinoembryonic antigen) and CYFRA 21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin (OPN), anti-p53, and seprase. CEA showed the best sensitivity at 95% specificity with 43.9%, followed by seprase (42.4%), CYFRA 21-1 (35.5%), OPN (30.2%), ferritin (23.9%), and anti-p53 (20.0%). A combination of these markers gave 69.6% sensitivity at 95% specificity and 58.7% at 98% specificity. Focusing on International Union against Cancer (UICC) stages 0-III reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a subcollective, with matched stool samples (75 CRC cases and 234 controls), the sensitivity of the marker combination was comparable with fecal immunochemical testing (FIT) with 82.4% and 68.9% versus 81.8% and 72.7% at 95% and 98% specificity, respectively.Conclusions: The performance of the serum marker combination is comparable with FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis. Clin Cancer Res; 16(24); 6111-21. Ó2010 AACR.The early detection of colorectal cancer (CRC) significantly improves the prognosis of patients and is a key factor to reduce the mortality from CRC (1). Recently, the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology have issued joint guidelines for CRC screening to include well-known procedures as guaiac-based fecal occult blood testing (FOBT) and fecal immunochemical testing (FIT), colonoscopy, sigmoidoscopy, and double-contrast barium enema, but also 2 more recent methods, computer tomography colonography and fecal DNA testing (2). The guidelines of the U.S. Preventive Services Task Force have also been updated but do not include the latter 2 methods (3).Serum-based, minimally invasive markers would be highly attractive for CRC screening as they could easily be integrated in any health checkup without the need of additional stool sampling. Although numerous biomarkers are under evaluation for the detection of CRC from serum, none of them has sufficient sensitivity and specificity to be considered in the current guidelines (4). Carcinoembryonic antigen (CEA) and carbohydrate antigens, for example, CA19-9 have been assessed more intensely but with varying results depending on the study design and the s...

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“…To date, an association between the up-regulation of OPN and tumor progression has been demonstrated, and it was determined as an independent prognostic factor in multivariate regression analysis. Notably, the role of OPN in metastasis has been intensively researched since its expression was not only reserved, but was also increased in metastases (9,12,13).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin is overexpressed in colorectal carcinoma and is correlated with P53 by immunohistochemistry

Li¹,

Yang²,

Zhu

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Osteopontin (OPN), a secreted phosphorylated glycoprotein, has been found to be involved in carcinogenesis, progression and metastasis of several types of cancers. The aim of the present study was to investigate the immunohistochemical expression of OPN in colorectal carcinoma (CRC) and its relationship with clinicopathological parameters and P53. Expression of OPN, Ki-67 and TP53 was detected in 77 cases of CRC by immunohistochemistry and the correlation of the expression of OPN with clinicopathological features, Ki-67 and P53 staining was investigated. Thirty-eight cases (49.4%) of CRC demonstrated OPN overexpression. Overexpression of OPN was associated with lymph node metastasis (P=0.025) and Dukes' stages (P=0.031), but not with gender, histological differentiation, depth of tumor invasion, TNM stages or Ki-67 index. The correlation between expression of OPN and TP53 was statistically significant (P=0.030). In conclusion, OPN is overexpressed in CRC, and plays a role in tumor progression and metastasis, which is possibly regulated by P53.

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Osteopontin regulates multiple functions contributing to human colon cancer development and progression

Cited by 64 publications

References 21 publications

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

A Combination of Serum Markers for the Early Detection of Colorectal Cancer

Osteopontin is overexpressed in colorectal carcinoma and is correlated with P53 by immunohistochemistry

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