Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility.
Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility.
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重新审视 MCL1 在实体癌肿瘤发生中的作用：基因表达与乳腺癌细胞的抗增殖表型相关，其功能调节变异与癌症易感性降低相关。
DOI：
10.1007/s13277-014-2108-5
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
WANG HAIJIAN
中科院分区：
文献类型：
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作者：
WANG SHENG;JIANG YAN;LIU JIN;ZHAO YUANYUAN;XIANG CHAN;MA RONG;GAO HAIDONG;JIN LI;HE FUCHU;WANG HAIJIAN
与髓细胞白血病序列1（MCL 1）明确的抗凋亡作用相比，其在肿瘤发生中的抗增殖功能研究较少。我们最近报道了MCL 1的调节变体有助于增强启动子活性，但降低肺癌的风险。我们假设MCL 1表达可能表现出抗增殖表型，其功能变异可能与乳腺癌的病因相关。我们通过过表达和敲低来操纵MCF-7细胞和MDA 231中的MCL 1表达，分析对细胞活力和细胞周期时相的影响，并表征与细胞周期关键调控因子表达谱的相关性。我们进一步对745名乳腺癌患者和537名对照者的-190插入多态性和邻近的单核苷酸多态性（SNP）进行基因分型，并分析了它们与癌症风险的相关性。我们证实，MCL 1的表达增加导致乳腺癌细胞增殖能力下降。我们进一步观察到乳腺癌细胞中MCL 1过表达导致细胞周期进程停滞在S期，并伴随p27表达增强，这可以通过p27敲低与小干扰RNA（siRNA）共转染来挽救。此外，我们发现乳腺癌风险显著降低[比值比（OR）= 0.74; 95%置信区间（CI）= 0.59-0.93]与-190插入基因型相关;表达增强调节单体型（OR 0.79; 95% CI 0.66-0.95）和双倍型（OR 0.71; 95% CI 0.57-0.89）与癌症易感性降低一致相关。该研究表明，MCL 1的表达增强调节变体是乳腺癌风险的保护性调节剂，部分由p27介导的细胞增殖减少和细胞周期进展停滞可能是潜在的机制。
Compared to the well-defined anti-apoptotic role of myeloid cell leukemia sequence 1 (MCL1), its antiproliferative function in tumorigenesis is less studied. We had recently reported that regulatory variants ofMCL1contribute to enhanced promoter activity but reduced risk of lung cancer. We hypothesized that MCL1 expression may manifest antiproliferative phenotype and its functional variations may have etiological relevance for breast cancer. We manipulated MCL1 expression in MCF-7 cells and MDA231 with overexpression and knockdown, analyzed the effects on cell viability and cell cycling phase, and characterized the correlation with expression profiles of key regulators of cell cycle. We further genotyped the −190 insertion polymorphism and the neighboring single nucleotide polymorphisms (SNPs) in 745 breast cancer patients and 537 controls and analyzed their association with cancer risk. We confirmed that heightened expression of MCL1 resulted in decreased proliferation ability of breast cancer cells. We further observed that MCL1 overexpression in breast cancer cells resulted in cell cycle progression arresting in S phase and concomitant enhanced expression of p27, which could be rescued by p27 knockdown with co-transfection of small interfering RNA (siRNA). Furthermore, we found a significant reduction in breast cancer risk [odds ratio (OR) = 0.74; 95 % confidence interval (CI) = 0.59–0.93] associated with −190 insertion genotype; the expression-enhancing regulatory haplotype (OR 0.79; 95 % CI 0.66–0.95) and diplotype (OR 0.71; 95 % CI 0.57–0.89) were consistently associated with decreased cancer susceptibility. The study demonstrates that the expression-enhancing regulatory variants ofMCL1are protective modifiers of breast cancer risk, and reduced cell proliferation and arrested cell cycle progression partly mediated by p27 might be the underlying mechanism.