Molecular Mechanisms Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Cancer Lett. 2019 Feb 1;442:362-372. doi: 10.1016/j.canlet.2018.11.010. Epub 2018 Nov 14.
Even if thyroid tumors are generally curable, a fraction will develop resistance to therapy and progress towards undifferentiated forms, whose treatment remains a demanding challenge. To identify potential novel targets for treatment of thyroid cancer, in a previous study using siRNA-mediated functional screening, we identified several genes that are essential for the growth of thyroid tumor, but not normal cells. Among the top-ranking hits, we found microtubule associated serine/threonine kinase-like (MASTL), which is known to play an essential role in mitosis regulation, and is also involved in the DNA damage response. Herein, we examine the effects of MASTL depletion on growth and viability of thyroid tumor cells. MASTL depletion impaired cell proliferation and increased the percentage of cells presenting nuclear anomalies, which are indicative of mitotic catastrophe. Furthermore, MASTL depletion was associated with enhanced DNA damage. All these effects eventually led to cell death, characterized by the presence of apoptotic markers. Moreover, MASTL depletion sensitized thyroid tumor cells to cisplatin. Our results demonstrate that MASTL represents vulnerability for thyroid tumor cells, which could be explored as a therapeutic target for thyroid cancer.
即使甲状腺肿瘤通常可以治愈，但仍有一部分会对治疗产生耐药性，并向未分化形式发展，其治疗仍然是一个具有挑战性的难题。为了确定治疗甲状腺癌的潜在新靶点，在之前使用 siRNA 介导的功能筛选的研究中，我们发现了几个对甲状腺肿瘤生长至关重要但对正常细胞不重要的基因。在排名靠前的命中基因中，我们发现了微管相关丝氨酸/苏氨酸激酶样（MASTL），它在有丝分裂调控中起着至关重要的作用，也参与了 DNA 损伤反应。在此，我们研究了 MASTL 耗竭对甲状腺肿瘤细胞生长和活力的影响。MASTL 耗竭会损害细胞增殖并增加出现核异常的细胞比例，这表明有丝分裂灾难。此外，MASTL 耗竭与增强的 DNA 损伤有关。所有这些影响最终导致细胞死亡，表现为凋亡标志物的存在。此外，MASTL 耗竭使甲状腺肿瘤细胞对顺铂敏感。我们的结果表明，MASTL 代表了甲状腺肿瘤细胞的脆弱性，这可以作为甲状腺癌的治疗靶点进行探索。
