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Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

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Influence of CAR on colon cancer cell proliferation. Proliferation was determined in DLD1, HCT116, SW480, and SW620 cells stably transfected with either a CAR-specific siRNA (upper panels) or a human full-length CAR expression vector ‘hCARpcDNA3.1' (lower panels) and ‘vector only' controls. Data represent typical results from a series of three independent experiments.
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fig3: Influence of CAR on colon cancer cell proliferation. Proliferation was determined in DLD1, HCT116, SW480, and SW620 cells stably transfected with either a CAR-specific siRNA (upper panels) or a human full-length CAR expression vector ‘hCARpcDNA3.1' (lower panels) and ‘vector only' controls. Data represent typical results from a series of three independent experiments.

Mentions: To clarify the influence of CAR on the growth of colon cancer cells, we performed in vitro proliferation assays following ectopic regulation of CAR expression. The RNAi-mediated functional CAR knockdown resulted in significantly higher cell numbers in DLD1 and HCT116 compared with vector controls, whereas for SW480 and SW620, a minor insignificant increase was found. Ectopic CAR upregulation resulted in a significant decline of cell numbers in SW480, SW620, and DLD1 compared with matching controls, whereas for the HCT116 cell line, no significant differences were noted (Figure 3). Subcutaneous xenograft tumours of colon cancer cell lines displayed a markedly reduced tumour size upon ectopic CAR upregulation compared with ‘vector only' controls (SW480 (P=0.02) (Figure 4) and DLD1 (P=0.11) (data not shown)).


Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Influence of CAR on colon cancer cell proliferation. Proliferation was determined in DLD1, HCT116, SW480, and SW620 cells stably transfected with either a CAR-specific siRNA (upper panels) or a human full-length CAR expression vector ‘hCARpcDNA3.1' (lower panels) and ‘vector only' controls. Data represent typical results from a series of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101933&req=5

fig3: Influence of CAR on colon cancer cell proliferation. Proliferation was determined in DLD1, HCT116, SW480, and SW620 cells stably transfected with either a CAR-specific siRNA (upper panels) or a human full-length CAR expression vector ‘hCARpcDNA3.1' (lower panels) and ‘vector only' controls. Data represent typical results from a series of three independent experiments.
Mentions: To clarify the influence of CAR on the growth of colon cancer cells, we performed in vitro proliferation assays following ectopic regulation of CAR expression. The RNAi-mediated functional CAR knockdown resulted in significantly higher cell numbers in DLD1 and HCT116 compared with vector controls, whereas for SW480 and SW620, a minor insignificant increase was found. Ectopic CAR upregulation resulted in a significant decline of cell numbers in SW480, SW620, and DLD1 compared with matching controls, whereas for the HCT116 cell line, no significant differences were noted (Figure 3). Subcutaneous xenograft tumours of colon cancer cell lines displayed a markedly reduced tumour size upon ectopic CAR upregulation compared with ‘vector only' controls (SW480 (P=0.02) (Figure 4) and DLD1 (P=0.11) (data not shown)).

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

Show MeSH
Related in: MedlinePlus