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HDAC10 Regulates Cancer Stem-like Cell Properties in KRAS-driven Lung Adenocarcinoma.

HDAC10 调节 KRAS 驱动的肺腺癌中的癌干细胞样细胞特性。

  • 影响因子:6.94
  • DOI:10.1158/0008-5472.CAN-19-3613
  • 作者列表:"Li Y","Zhang X","Zhu S","Dejene EA","Peng W","Sepulveda A","Seto E
  • 发表时间:2020-06-15
Abstract

:Activation of oncogenic KRAS is the most common driving event in lung adenocarcinoma development. Despite the existing rationale for targeting activated KRAS and its downstream effectors, the failure of clinical trials to date indicates that the mechanism of KRAS-driven malignancy remains poorly understood. Here we report that histone deacetylase 10 (HDAC10) might function as a putative tumor suppressor in mice carrying a spontaneously activated oncogenic Kras allele. Hdac10 deletion accelerated KRAS-driven early-onset lung adenocarcinomas, increased macrophage infiltration in the tumor microenvironment, and shortened survival time in mice. Highly tumorigenic and stem-like lung adenocarcinoma (LUAD) cells were increased in Hdac10-deleted tumors compared to Hdac10 wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in Hdac10-deleted tumor cells and depletion of SOX9 in Hdac10 knockout (KO) LUAD cells inhibited growth of tumor spheres. The genes associated with TGF-β pathway were enriched in Hdac10 KO tumor cells, and activation of TGF-β signaling contributed to SOX9 induction in Hdac10 KO LUAD cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis which will inform the rationale for targeting its related regulatory signaling as an anticancer strategy.

摘要

: 致癌 KRAS 的激活是肺腺癌发展中最常见的驱动事件。尽管现有的靶向活化 KRAS 及其下游效应因子的原理,但迄今为止的临床试验失败表明 KRAS 驱动的恶性肿瘤的机制仍然知之甚少。这里我们报道了组蛋白去乙酰化酶 10 (HDAC10) 可能在携带自发激活的致癌 Kras 等位基因的小鼠中作为假定的肿瘤抑制因子发挥作用。Hdac10 缺失加速 KRAS 驱动的早发性肺腺癌,增加肿瘤微环境中巨噬细胞浸润,缩短小鼠生存时间。与 Hdac10 野生型肿瘤相比,高致瘤和干细胞样肺腺癌 (LUAD) 细胞在 Hdac10-deleted 肿瘤中增加。HDAC10 通过靶向 sox9 调控 KRAS 表达肿瘤细胞的干细胞样特性。Hdac10-deleted 瘤细胞中 SOX9 的表达显著增加,Hdac10 敲除 (KO) LUAD 细胞中 SOX9 的缺失抑制了肿瘤球的生长。与 TGF-β 通路相关的基因在 Hdac10 KO 肿瘤细胞中富集,TGF-β 信号的激活有助于 Hdac10 KO LUAD 细胞的 SOX9 诱导。总的来说,我们的研究评估了 HDAC10 在肺癌发生中的功能和作用机制,这将为靶向其相关调控信号作为抗癌策略提供理论依据。

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影响因子:1.84
发表时间:2020-01-01
来源期刊:Oncology letters
DOI:10.3892/ol.2019.11149
作者列表:["Das SK","Huang YY","Li B","Yu XX","Xiao RH","Yang HF"]

METHODS::The aim of the present study was to compare the safety and efficacy of cryoablation (CA) and microwave ablation (MWA) as treatments for non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC treated with CA (n=45) or MWA (n=56) were enrolled in the present study. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS) time and adverse events (AEs). The median PFS times between the two groups were not significantly different (P=0.36): CA, 10 months [95% confidence interval (CI), 7.5-12.4] vs. MWA, 11 months (95% CI, 9.5-12.4). The OS times between the two groups were also not significantly different (P=0.07): CA, 27.5 months (95% CI, 22.8-31.2 months) vs. MWA, 18 months (95% CI, 12.5-23.5). For larger tumors (>3 cm), patients treated with MWA had significantly longer median PFS (P=0.04; MWA, 10.5 months vs. CA, 7.0 months) and OS times (P=0.04; MWA, 24.5 months vs. CA, 14.5 months) compared patients treated with CA. However, for smaller tumors (≤3 cm), median PFS (P=0.79; MWA, 11.0 months vs. CA, 13.0 months) and OS times (P=0.39; MWA, 30.0 months vs. CA, 26.5 months) between the two groups did not differ significantly. The incidence rates of AEs were similar in the two groups (P>0.05). The number of applicators, tumor size and length of the lung traversed by applicators were associated with a higher risk of pneumothorax and intra-pulmonary hemorrhage in the two groups. Treatment with CA resulted in significantly less intraprocedural pain compared with treatment with MWA (P=0.001). Overall, the present study demonstrated that CA and MWA were comparably safe and effective procedures for the treatment of small tumors. However, treatment with MWA was superior compared with CA for the treatment of large tumors.

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发表时间:2020-02-01
DOI:10.1016/j.annonc.2019.10.022
作者列表:["Mazieres J","Cropet C","Montané L","Barlesi F","Souquet PJ","Quantin X","Dubos-Arvis C","Otto J","Favier L","Avrillon V","Cadranel J","Moro-Sibilot D","Monnet I","Westeel V","Le Treut J","Brain E","Trédaniel J","Jaffro M","Collot S","Ferretti GR","Tiffon C","Mahier-Ait Oukhatar C","Blay JY"]

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