Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.
Br J Cancer. 2011 Apr 26;104(9):1426-33. doi: 10.1038/bjc.2011.116. Epub 2011 Apr 5.
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.
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.
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.
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.
柯萨奇病毒和腺病毒受体（CAR）被认为具有肿瘤抑制作用。然而，其对结肠腺瘤-癌序列的影响尚不清楚。
采用免疫组织化学和定量 RT-PCR 分析非癌性和肿瘤性结肠样本中的 CAR。应用 CAR siRNA 或外源性表达人全长 CAR cDNA 来确定 CAR 在结肠癌细胞系中的功能。
与健康黏膜相比，腺瘤中 CAR-mRNA 表达增加，而原发性癌和转移瘤则明显下降。在质膜上，CAR 存在于正常黏膜样本（93%）、腺瘤和转移瘤（100%，各）中，而在结肠癌细胞中则较少见（49%，P<0.0001）。细胞质 CAR 免疫阳性从正常黏膜（22%）增加到腺瘤（73%，P=0.0006）、原发性癌（83%，P<0.0001）和转移瘤（67%，P=0.0019）。在癌细胞系中，CAR 抑制导致增殖增加，而强制异位表达 CAR 则导致相反的结果。阻断 CAR 的细胞外部分增加了细胞在体外的侵袭。在小鼠中，强制表达 CAR 的结肠癌细胞异种移植形成的肿瘤明显较小，而 CAR 抑制则增加了肝转移的形成。
我们得出结论，CAR 在结肠癌变过程中具有复杂的作用，其潜在机制可能与其亚细胞分布的阶段性有关；CAR 高表达可能防止腺瘤细胞凋亡，质膜上 CAR 的缺失促进肿瘤的生长和扩散，而高膜结合 CAR 的存在可能支持远处转移的建立。
