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CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells.

CD44 抑制减弱 EGFR 信号,增强人 EGFR 野生型非小细胞肺癌细胞对顺铂的敏感性。

  • 影响因子:2.91
  • DOI:10.3892/ijmm.2020.4562
  • 作者列表:"Yin J","Zhang H","Wu X","Zhang Y","Li J","Shen J","Zhao Y","Xiao Z","Lu L","Huang C","Zhang Z","Du F","Wu Y","Kaboli PJ","Cho CH","Yuan D","Li M
  • 发表时间:2020-04-01
Abstract

:Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non‑small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild‑type NSCLC cells to cisplatin and how it affects wild‑type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild‑type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44‑silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild‑type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild‑type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild‑type NSCLC.

摘要

: 分化簇 44 (CD44) 作为一种跨膜糖蛋白被发现在非小细胞肺癌 (NSCLC) 中表达,与 NSLC 进展、转移和耐药显著相关。本研究旨在探讨 CD44 抑制是否改善表皮生长因子受体 (EGFR) 野生型 NSCLC 细胞对顺铂的敏感性,以及它如何影响 NSCLC 细胞中的野生型 EGFR。使用小干扰 RNA 敲除 EGFR 野生型 NSCLC 细胞系 h460 中的 CD44 表达。结果表明,CD44 下调可减少 H460 细胞的生长,促进 G0/G1 期细胞周期阻滞,诱导细胞凋亡,与顺铂合用可明显增强其作用。EGFR 信号通路的失活,包括 EGFR 磷酸化及其下游分子,靶点 ERK 、 AKT1 和 SRC,无论是否有 EGF 刺激,在 CD44 ‑ 沉默的 H460 细胞中也观察到。此外,肺腺癌组织中 CD44 表达水平与野生型 EGFR 水平呈正相关,抑制 CD44 可显著加速 EGFR 的降解,表明通过下调 CD44 增强 H460 细胞对顺铂的敏感性可能是由于 EGFR 降解所致。本研究证明抑制 CD44 使野生型 EGFR NSCLC 细胞中的 EGFR 信号失活,从而有助于抑制细胞增殖和增强顺铂的敏感性。提示 CD44 的下调可能是治疗 EGFR 野生型 NSCLC 的一种新的潜在治疗策略。

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DOI:10.1016/j.asjsur.2019.03.008
作者列表:["Esme H","Can A","Şehitogullari A"]

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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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影响因子:8.44
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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