前列腺癌中HOXB13错义突变的致癌机制

Marta Cardoso, S. Maia, P. Paulo, M. Teixeira
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引用次数: 13

摘要

复发性生殖系突变hoxb13p .(Gly84Glu) (G84E)最近被确定为前列腺癌的一个危险因素。在最近的一项研究中,我们对462例葡萄牙早发性和/或家族性/遗传性前列腺癌患者的HOXB13基因进行了全测序,发现了两个新的错义突变,p.(Ala128Asp) (A128D)和p.(Phe240Leu) (F240L),预计会损害蛋白质功能。在目前的工作中,我们旨在研究这些突变的潜在致癌作用,并将其与复发性G84E突变和野生型HOXB13进行比较。我们在HOXB13表达载体上诱导定点突变,并建立了稳定过表达野生型或突变型HOXB13变体的前列腺癌体外细胞模型。通过体外实验,我们观察到野生型促进细胞增殖,F240L突变也可以减少细胞凋亡,而A128D突变可以减少细胞凋亡,促进锚定独立生长。在使用的细胞系模型中,未观察到G84E突变对表型的影响。我们的数据显示,特定的HOXB13突变参与了不同癌症相关能力的获得,并进一步支持HOXB13在前列腺癌发生中的致癌作用。
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Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis
The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.
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