Expression of a splicing variant of the CADM1 specific to small cell lung cancer
Expression of a splicing variant of the CADM1 specific to small cell lung cancer
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DOI：
10.1111/j.1349-7006.2012.02277.x
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发表时间：
2012-06-01
期刊：
影响因子：
5.7
通讯作者：
Murakami, Yoshinori
中科院分区：
文献类型：
--
作者：
Kikuchi, Shinji;Iwai, Miwako;Murakami, Yoshinori
CADM1是免疫球蛋白超家族细胞粘附分子的一员，在多种人类癌症中起肿瘤抑制作用。CADM1也在成人t细胞白血病（ATL）中异位表达，赋予ATL侵袭性表型特征。因此，CADM1在人类肿瘤发生中起双重作用。在这里，我们研究CADM1在小细胞肺癌（SCLC）中的作用。免疫组化显示35例原发性SCLC肿瘤中有10例（29%）表达CADM1蛋白。Western blotting和RT-PCR分析显示，悬浮培养的14个SCLC细胞中有11个细胞显著表达CADM1，而附着在塑料培养皿上生长的2个SCLC细胞均未表达CADM1，这表明CADM1参与了SCLC的非锚定生长。在本研究中，我们证明SCLC表达一种独特的CADM1剪接变体（变体8/9），除了变体8（上皮中常见的同种异构体）外，还含有额外的细胞外片段，对应于外显子9。CADM1的变体8/9几乎只在SCLC和睾丸中观察到，尽管这种变体蛋白沿着膜定位，并表现出与变体8相似的细胞聚集活性。有趣的是，当转染到缺乏CADM1的SCLC细胞SBC5中时，CADM1的变体8/9和变体8在裸鼠中的致瘤性都增强了。相反，shRNA抑制CADM1表达减少了NCI-H69的球状细胞聚集，NCI-H69是一种表达大量CADM1的SCLC细胞。这些发现表明，CADM1增强了SCLC的恶性特征，正如在ATL中观察到的那样，可能是SCLC特异性的分子标志物。（癌症科学2012；103:10511057）
CADM1, a member of the immunoglobulin superfamily cell adhesion molecule, acts as a tumor suppressor in a variety of human cancers. CADM1 is also ectopically expressed in adult T-cell leukemia (ATL), conferring an invasive phenotype characteristic to ATL. Therefore, CADM1 plays dual roles in human oncogenesis. Here, we investigate the roles of CADM1 in small cell lung cancer (SCLC). Immunohistochemistry demonstrates that 10 of 35 (29%) primary SCLC tumors express CADM1 protein. Western blotting and RT-PCR analyses reveal that CADM1 is significantly expressed in 11 of 14 SCLC cells growing in suspension cultures but in neither of 2 SCLC cells showing attached growth to plastic dishes, suggesting that CADM1 is involved in anchorage-independent growth in SCLC. In the present study, we demonstrate that SCLC expresses a unique splicing variant of CADM1 (variant 8/9) containing additional extracellular fragments corresponding to exon 9 in addition to variant 8, a common isoform in epithelia. Variant 8/9 of CADM1 is almost exclusively observed in SCLC and testis, although this variant protein localizes along the membrane and shows similar cell aggregation activity to variant 8. Interestingly, both variant 8/9 and variant 8 of CADM1 show enhanced tumorigenicity in nude mice when transfected into SBC5, a SCLC cell lacking CADM1. Inversely, suppression of CADM1 expression by shRNA reduced spheroid-like cell aggregation of NCI-H69, an SCLC cell expressing a high amount of CADM1. These findings suggest that CADM1 enhances the malignant features of SCLC, as is observed in ATL, and could provide a molecular marker specific to SCLC. (Cancer Sci 2012; 103: 10511057)