KIF11 silencing and inhibition induces chromosome instability that may contribute to cancer
KIF11 silencing and inhibition induces chromosome instability that may contribute to cancer
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DOI：
10.1002/gcc.22471
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发表时间：
2017-09-01
影响因子：
3.7
通讯作者：
McManus, Kirk J.
中科院分区：
文献类型：
--
作者：
Asbaghi, Yasamin;Thompson, Laura L.;McManus, Kirk J.
了解有助于肿瘤发生的异常途径并确定这些途径中涉及的改变基因是制定有效策略以更好地对抗癌症的关键第一步。染色体不稳定性（CIN）是一种异常表型，发生在所有癌症类型的约80%，并与侵袭性肿瘤，获得多药耐药性和患者预后差。尽管存在这些关联，但对CIN的异常基因和分子缺陷仍知之甚少。KIF11是一种进化上保守的微管马达蛋白，在有丝分裂的中心体和染色体动力学中发挥作用。有趣的是，KIF11的酵母直系同源物，即CIN8是CIN基因，因此KIF11的异常表达和功能被怀疑是CIN的基础。为了支持这种可能性，KIF11在大量癌症类型中发生了体细胞改变。使用互补的生物化学和遗传方法，我们检查了用siRNA沉默KIF11或用monastrol抑制KIF11是否能够将两种不同的核型稳定的细胞系转化为核型不稳定的细胞系。事实上，定量成像显微镜和流式细胞术显示，KIF11沉默诱导核面积增加，微核形成，DNA含量和染色体数目相对于对照组，也观察到KIF11抑制后。总的来说，这项研究确定并验证了KIF11作为一个进化上保守的CIN基因，并进一步表明，异常表达和功能可能有助于一个子集的癌症的发病机制。
Understanding the aberrant pathways that contribute to oncogenesis and identifying the altered genes involved in these pathways is a critical first step to develop effective strategies to better combat cancer. Chromosome instability (CIN) is an aberrant phenotype that occurs in approximate to 80% of all cancer types and is associated with aggressive tumors, the acquisition of multidrug resistance and poor patient prognosis. Despite these associations however, the aberrant genes and molecular defects underlying CIN remain poorly understood. KIF11 is an evolutionarily conserved microtubule motor protein that functions in centrosome and chromosome dynamics in mitosis. Interestingly, the yeast ortholog of KIF11, namely CIN8 is a CIN gene and thus aberrant KIF11 expression and function is suspected to underlie CIN. In support of this possibility, KIF11 is somatically altered in a large number of cancer types. Using a complementary biochemical and genetic approach we examined whether KIF11 silencing with siRNAs or inhibition with monastrol was able to convert two distinct and karyotypically stable cell lines into karyotypically unstable cell lines. Indeed, quantitative imaging microscopy and flow cytometry revealed that KIF11 silencing induced increases in nuclear areas, micronucleus formation, DNA content and chromosome numbers relative to controls that was also observed following KIF11 inhibition. Collectively, this study identifies and validates KIF11 as an evolutionarily conserved CIN gene, and further suggests that aberrant expression and function may contribute to the pathogenesis of a subset of cancers.