Differential response to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in non-small cell lung cancer cells with distinct oncogene mutations.
Differential response to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in non-small cell lung cancer cells with distinct oncogene mutations.
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具有不同癌基因突变的非小细胞肺癌细胞对 1α,25-二羟基维生素 D3 (1α,25(OH)2D3) 的差异反应。
DOI：
10.1016/j.jsbmb.2012.09.022
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Hershberger,Pamela
中科院分区：
文献类型：
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作者：
Zhang,Qiuhong;Kanterewicz,Beatriz;Shoemaker,Suzanne;Hu,Qiang;Liu,Song;Atwood,Kristopher;Hershberger,Pamela
我们先前的研究表明，非小细胞肺癌细胞和人原发肺癌细胞都异常表达维生素D3分解代谢酶--细胞色素P24，该酶通过1-羟基-25-二羟基维生素D3(1，25(α)2D3)在非小细胞肺癌细胞中限制转录调控和生长控制。为了确定细胞色素P24基因失调的基础，我们组装了一组代表不同分子类别肺癌的细胞系：所选的细胞系包含K-ras或表皮生长因子受体(EGFR)基因的互斥突变。我们观察到，K-ras突变株表现为基础维生素D受体(VDR)低CYP24高表型，而EGFR突变系表现为VDR高CYP24低表型。临床标本中也观察到与突变相关的细胞色素P24表达的差异。具体地说，在一系列的147例原发肺腺癌病例中，K-ras突变与细胞色素P24基因表达的中位数增加有关(p=4.8x10−7)。由于VDR和CYP24的基础表达不同，我们假设带有EGFR突变的NSCLC细胞对1，25(OH)2D3的处理比具有K-ras突变的NSCLC细胞对1，25(OH)2D3的反应更敏感。为了验证这一点，我们测量了1，25(OH)2D3增加报告基因活性、诱导内源性靶基因转录和抑制克隆形成的能力。在每种检测中，EGFR突变阳性的HCC827和H1975细胞的1，25(OH)2D3反应的幅度大于K-ras突变阳性的A549和128.88T细胞。我们随后检查了1，25(OH)2D3与临床上用于治疗EGFR突变阳性非小细胞肺癌的厄洛替尼联合治疗的效果。1，25(OH)2D3/erlotinib联合用药对对erlotinib敏感的HCC827细胞和耐药的H1975细胞的生长抑制作用均明显强于任何一种药物。这些数据首次表明，EGFR突变可能识别对1，25(OH)2D3治疗保持反应并可能受益于1，25(OH)2D3的肺癌亚群。本文是题为《维生素D工作坊》的特刊的一部分。
We previously demonstrated that non-small cell lung cancer (NSCLC) cells and primary human lung tumors aberrantly express the vitamin D3-catabolizing enzyme, CYP24, and that CYP24 restricts transcriptional regulation and growth control by 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) in NSCLC cells. To ascertain the basis for CYP24 dysregulation, we assembled a panel of cell lines that represent distinct molecular classes of lung cancer: cell lines were selected which harbored mutually exclusive mutations in either the K-ras or the Epidermal Growth Factor Receptor (EGFR) genes. We observed that K-ras mutant lines displayed a basal vitamin D receptor (VDR)lowCYP24highphenotype, whereas EGFR mutant lines had a VDRhighCYP24lowphenotype. A mutation-associated difference in CYP24 expression was also observed in clinical specimens. Specifically, K-ras mutation was associated with a median 4.2-fold increase in CYP24 mRNA expression (p=4.8×10−7) compared to EGFR mutation in a series of 147 primary lung adenocarcinoma cases. Because of their differential basal expression of VDR and CYP24, we hypothesized that NSCLC cells with an EGFR mutation would be more responsive to 1,25(OH)2D3treatment than those with a K-ras mutation. To test this, we measured the ability of 1,25(OH)2D3to increase reporter gene activity, induce transcription of endogenous target genes, and suppress colony formation. In each assay, the extent of 1,25(OH)2D3response was greater in EGFR mutation-positive HCC827 and H1975 cells than in K-ras mutation-positive A549 and 128.88T cells. We subsequently examined the effect of combining 1,25(OH)2D3with erlotinib, which is used clinically in the treatment of EGFR mutation-positive NSCLC. 1,25(OH)2D3/erlotinib combination resulted in significantly greater growth inhibition than either single agent in both the erlotinib-sensitive HCC827 cell line and the erlotinib-resistant H1975 cell line. These data are the first to suggest that EGFR mutations may identify a lung cancer subset which remains responsive to and is likely to benefit from 1,25(OH)2D3administration. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.