TIMELESS contributes to the progression of breast cancer through activation of MYC.
TIMELESS contributes to the progression of breast cancer through activation of MYC.
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TIMELESS 通过激活 MYC 促进乳腺癌的进展
DOI：
10.1186/s13058-017-0838-1
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发表时间：
2017-05-02
期刊：
影响因子：
--
通讯作者：
Wu Z
中科院分区：
文献类型：
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作者：
Chi L;Zou Y;Qin L;Ma W;Hao Y;Tang Y;Luo R;Wu Z
背景乳腺癌是女性最常见的恶性肿瘤，也是女性癌症死亡的主要原因。TIMELESS（TIM）是一种昼夜节律调节剂，最近被认为与人类癌症的进展有关。然而，TIM在乳腺癌的进展中的作用还没有得到很好的characterized.MethodsImmunohistochemistry（IHC）染色被用来检查乳腺癌标本中的TIM水平。乳腺球形成分析和侧群分析用于检查TIM对乳腺癌干细胞自我更新的影响。伤口愈合试验和Transwell试验用于确定TIM在乳腺癌细胞迁移和侵袭中的作用。软琼脂生长试验在体外和体内致瘤性被用来确定TIM在tumorigenicity.ResultsTIM水平在乳腺癌细胞系和组织中的作用显着上调。高TIM患者的预后比低TIM患者差。TIM的过表达显著增强了乳腺癌干细胞的自我更新能力，而TIM的敲低则抑制了乳腺癌细胞的体外侵袭和迁移能力。此外，TIM的过表达显着增加，而TIM的敲低则降低了乳腺癌细胞在体内的致瘤性。机制研究表明，TIM上调了众所周知的癌基因MYC的表达和反式活性。MYC的抑制显着阻断TIM对CSC的人口，细胞侵袭和锚非依赖性细胞growth.ConclusionTIM在促进乳腺癌的进展中起着重要作用，可能是一个新的治疗乳腺癌的靶点。
BackgroundBreast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized.MethodsImmunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity.ResultsTIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth.ConclusionTIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.