Hertervig E, Nilsson A, Björk J, Hultkrantz R, Duan R D
Department of Medicine, Lund University Hospital, Sweden.
Br J Cancer. 1999 Sep;81(2):232-6. doi: 10.1038/sj.bjc.6690682.
The hydrolysis of sphingomyelin generates key molecules regulating cell growth and inducing apoptosis. Data from animal cancer models support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. In the intestinal tract, a sphingomyelinase with an optimum alkaline pH has been identified. We recently found that the activity of alkaline sphingomyelinase is significantly decreased in colorectal adenocarcinomas, indicating a potential anticarcinogenic role of this enzyme. To further examine whether the reduction of sphingomyelinase is present already in the premalignant state of neoplastic transformation, we measured sphingomyelinase activities in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal tubulovillous adenomas. Tissue samples were taken from adenomas and surrounding macroscopically normal mucosa from 11 FAP patients operated with ileorectal anastomosis, from three FAP patients with intact colon, from 13 patients with sporadic colorectal adenomas and from 12 controls. Activities of acid, neutral and alkaline sphingomyelinase were measured together with alkaline phosphatase. In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05). Similar reductions were found in the surrounding mucosa. In sporadic adenoma tissue, only alkaline sphingomyelinase was reduced significantly, by 57% (P < 0.05). Alkaline phosphatase was not changed in FAP adenomas, but decreased in the sporadic adenomas. We conclude that the markedly reduced levels of alkaline sphingomyelinase activities in FAP adenomas and in the surrounding mucosa may be a pathogenic factor that can lead to unrestrained cell proliferation and neoplastic transformation.
鞘磷脂的水解产生调节细胞生长和诱导细胞凋亡的关键分子。来自动物癌症模型的数据支持该途径在结肠黏膜恶性转化中起抑制作用。在肠道中，已鉴定出一种最适pH为碱性的鞘磷脂酶。我们最近发现，结直肠癌中碱性鞘磷脂酶的活性显著降低，表明该酶具有潜在的抗癌作用。为了进一步研究在肿瘤转化的癌前状态下是否已经存在鞘磷脂酶的减少，我们测量了家族性腺瘤性息肉病（FAP）患者和散发性结直肠管状绒毛状腺瘤患者的鞘磷脂酶活性。从11例行回直肠吻合术的FAP患者、3例结肠完整的FAP患者、13例散发性结直肠腺瘤患者和12例对照者的腺瘤及周围肉眼正常的黏膜中采集组织样本。同时测量酸性、中性和碱性鞘磷脂酶以及碱性磷酸酶的活性。在FAP腺瘤组织中，碱性鞘磷脂酶活性与对照相比降低了90%（P<0.0001），酸性鞘磷脂酶降低了66%（P<0.01），中性鞘磷脂酶降低了54%（P<0.05）。在周围黏膜中也发现了类似的降低。在散发性腺瘤组织中，只有碱性鞘磷脂酶显著降低，降低了57%（P<0.05）。碱性磷酸酶在FAP腺瘤中没有变化，但在散发性腺瘤中降低。我们得出结论，FAP腺瘤及其周围黏膜中碱性鞘磷脂酶活性的显著降低可能是导致细胞不受控制地增殖和肿瘤转化的致病因素。
