ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma.
ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma.
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非小细胞肺癌（NSCLC）是最致命的人类癌症之一。 CDKN2A 基因座包含 INK4a 和 ARF 肿瘤抑制基因，在 NSCLC 中经常发生改变。然而，ARF在肺部肿瘤发生中的具体作用仍不清楚。 KRAS 和其他癌基因诱导 ARF 的表达，从而稳定 p53 活性并阻止细胞增殖。为了探讨 ARF 在 Kras 驱动的 NSCLC 中的作用，我们比较了 NIH/Ola 品系野生型和 Arf 敲除小鼠对尿烷诱导的肺癌发生的易感性。诱导后 25 周时，与 Arf+/+ 动物相比，Arf−/− 动物的肺肿瘤大小、恶性肿瘤和相关发病率显着增加。与野生型相比，Arf 基因敲除小鼠的肺肿瘤表现出细胞增殖和 DNA 损伤增加。 Arf−/− 动物中的一个肿瘤亚组表现为去分化和转移性，具有肺肉瘤样癌的许多特征，这是一种以前在小鼠模型中未记录的肿瘤。我们对 ARF 在 NSCLC 中的作用的发现与 Arf+/+ 小鼠的良性腺瘤强烈表达 ARF，而 ARF 表达在恶性腺癌中显着降低的观察结果一致。 ARF 表达也经常与 p53 转录靶标 p21CIP1 的表达共定位，认为 ARF 诱导 p53 检查点以阻止体内细胞增殖。总之，这些发现表明 ARF 的诱导是肺部肿瘤发生的早期反应，为肿瘤生长和恶性进展提供了强有力的屏障。
Non-small cell lung carcinoma (NSCLC) is among the deadliest of human cancers. The CDKN2A locus, which houses the INK4a and ARF tumor suppressor genes, is frequently altered in NSCLC. However, the specific role of ARF in pulmonary tumorigenesis remains unclear. KRAS and other oncogenes induce the expression of ARF, thus stabilizing p53 activity and arresting cell proliferation. To address the role of ARF in Kras-driven NSCLC, we compared the susceptibility of NIH/Ola strain wild-type and Arf knockout mice to urethane-induced lung carcinogenesis. Lung tumor size, malignancy, and associated morbidity were significantly increased in Arf−/− compared to Arf+/+ animals at 25 weeks post-induction. Pulmonary tumors from Arf knockout mice exhibited increased cell proliferation and DNA damage compared to wild-type. A subgroup of tumors in Arf−/− animals presented as dedifferentiated and metastatic, with many characteristics of pulmonary sarcomatoid carcinoma, a neoplasm previously undocumented in mouse models. Our finding of a role for ARF in NSCLC is consistent with the observation that benign adenomas from Arf+/+ mice robustly expressed ARF, while ARF expression was markedly reduced in malignant adenocarcinomas. ARF expression also frequently co-localized with expression of p21CIP1, a transcriptional target of p53, arguing that ARF induces the p53 checkpoint to arrest cell proliferation in vivo. Together, these findings demonstrate that induction of ARF is an early response in lung tumorigenesis that mounts a strong barrier against tumor growth and malignant progression.
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