Korosec Branka, Glavac Damjan, Volavsek Metka, Ravnik-Glavac Metka
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia.
Cancer Genet Cytogenet. 2009 Jan 15;188(2):88-94. doi: 10.1016/j.cancergencyto.2008.10.007.
The sarco/endoplasmatic reticulum calcium-ATPase (SERCA) translocates Ca(2+) from cytosol to the lumen of the ER and thus regulates Ca(2+) homeostasis, perturbations of which have been suggested to contribute to cancer. We have previously detected an increased number of alterations in the ATP2A2 gene in various cancer types and in the ATP2A3 gene in head and neck squamous cell carcinoma. Here, we further analyzed the ATP2A3 gene in colon, lung, and CNS cancers. We identified a statistically significant increase of alterations in each (colon cancer, p=0.0052, lung cancer, p=0.0026, CNS tumors, p=0.0045) cancer type, and all 3 types together (p=0.0016). Epigenetic study of the ATP2A3 gene indicated an unchanged methylation status, whereas expression of the ATP2A3 gene was normal for exon 14 mutations and reduced in connection with a nucleotide change in intron VI in all studied cancer types. Identification of a significant number of alterations in cancer patients suggests that ATP2A3 is involved in increased cancer susceptibility in humans. The mostly normal expression and methylation status of the ATP2A3 gene, as well as the absence of somatic alterations, further suggest that the ATP2A3 gene may not act as a classical tumor suppressor gene, but rather haplo-insufficiency of this gene may be enough to change the cell and tissue environment in such a way to predispose to cancer development.
肌浆网/内质网钙ATP酶（SERCA）将Ca²⁺从细胞质转运至内质网腔，从而调节Ca²⁺稳态，有人认为其紊乱与癌症有关。我们之前在多种癌症类型中检测到ATP2A2基因的改变数量增加，在头颈部鳞状细胞癌中检测到ATP2A3基因的改变数量增加。在此，我们进一步分析了结肠癌、肺癌和中枢神经系统癌症中的ATP2A3基因。我们发现每种癌症类型（结肠癌，p = 0.0052；肺癌，p = 0.0026；中枢神经系统肿瘤，p = 0.0045）以及所有三种类型一起（p = 0.0016）的改变数量均有统计学意义的增加。对ATP2A3基因的表观遗传学研究表明甲基化状态未改变，而对于外显子14突变，ATP2A3基因的表达正常，在所有研究的癌症类型中，与内含子VI中的核苷酸变化相关的表达降低。在癌症患者中发现大量改变表明ATP2A3参与了人类癌症易感性的增加。ATP2A3基因的表达和甲基化状态大多正常，以及不存在体细胞改变，进一步表明ATP2A3基因可能并非作为经典的肿瘤抑制基因起作用，而是该基因的单倍体不足可能足以改变细胞和组织环境，从而易患癌症。
