Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
Cancer Sci. 2020 Mar;111(3):951-961. doi: 10.1111/cas.14303. Epub 2020 Feb 22.
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.
肺腺癌是最常见的肺癌组织学类型，分为原位腺癌（AIS）、微浸润腺癌（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，肺腺癌逐步连续体的发生机制尚不清楚。在这项研究中，探讨了 ADP-核糖基化因子（ARF）样（ARL）4C（ARL4C）在肺腺癌进展中的作用及其作为肺癌治疗的分子靶点的可能性。ARL4C 在 AAH 中频繁表达，并且在永生化的人小气道上皮细胞中表达 ARL4C 可促进细胞增殖并抑制细胞死亡。此外，ARL4C 以依赖于阶段的方式在 AIS、MIA 和 IA 中更频繁地表达，并且表达与组织学分级、氟-18 氟代脱氧葡萄糖摄取和不良预后相关。针对 ARL4C 的反义寡核苷酸（ASO）（ARL4C ASO-1316）抑制 RAS 相关 C3 肉毒杆菌毒素底物活性和 Yes 相关蛋白和含 PDZ 结合基序的转录共激活因子的核输入，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，经支气管给予 ARL4C ASO-1316 可抑制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，并与肺腺癌的逐步连续体相关。无论 KRAS 或 EGFR 突变如何，ARL4C ASO-1316 对表达 ARL4C 的肺腺癌患者都将是有用的。
