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ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target.

ARL4C与肺腺癌的起始和进展相关,并且代表治疗靶标。

  • 影响因子:4.60
  • DOI:10.1111/cas.14303
  • 作者列表:"Kimura K","Matsumoto S","Harada T","Morii E","Nagatomo I","Shintani Y","Kikuchi A
  • 发表时间:2020-03-01
Abstract

:Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP-ribosylation factor (ARF)-like (ARL) 4C (ARL4C), a member of the small GTP-binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage-dependent manner, and the expression was correlated with histologic grade, fluorine-18 fluorodeoxyglucose uptake and poor prognosis. An anti-sense oligonucleotide (ASO) against ARL4C (ARL4C ASO-1316) inhibited RAS-related C3 botulinum toxin substrate activity and nuclear import of Yes-associated protein and transcriptional coactivator with PDZ-binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO-1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO-1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.

摘要

: 肺腺癌是肺癌最常见的组织学类型,分为原位腺癌 (AIS) 、微浸润性腺癌 (MIA) 和浸润性腺癌 (IA)。非典型腺瘤样增生 (AAH) 病变可能是腺癌的前体。然而,肺腺癌逐步连续的机制尚不清楚。在这项研究中,ADP-核糖基化因子 (ARF) 样 (ARL) 4C (ARL4C),小GTP结合蛋白家族的成员,在肺腺癌的进展和ARL4C作为肺癌治疗的分子靶标的可能性进行了探讨。ARL4C经常在AAH中表达,ARL4C在永生化的人小气道上皮细胞中的表达促进细胞增殖并抑制细胞死亡。此外,ARL4C在AIS、MIA和IA中的表达频率增加,呈阶段依赖性,且表达与组织学分级、氟-18 氟脱氧葡萄糖摄取和不良预后相关。一种针对ARL4C的反义寡核苷酸 (ASO) (ARL4C ASO-1316) 抑制RAS相关的C3 肉毒毒素底物活性和Yes相关蛋白的核输入以及具有PDZ结合基序的转录共激活因子,并抑制具有KRAS或表皮生长因子受体 (EGFR) 突变的肺癌细胞的体外增殖和迁移。此外,经支气管施用ARL4C ASO-1316 抑制由这些癌细胞诱导的原位肿瘤形成。因此,ARL4C参与了癌前阶段的启动,并且与肺腺癌的逐步连续有关。无论KRAS或EGFR突变如何,ARL4C ASO-1316 对于表达ARL4C的肺腺癌患者都是有用的。

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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