Lung cancer is one of most common malignancies worldwide. We have previously identified retinoic acid‐induced gene G (Rig‐G) as a tumor suppressor in not only acute promyelocytic leukemia, but also in other solid tumors. However, the clinical significance of Rig‐G and the underlying mechanism(s) for its biological function in lung cancer remain largely unexplored. Herein, we first compared the expression of Rig‐G between lung cancer (n = 138) and normal tissues (n = 23), from public‐available data sets and our patient cohort. We further analyzed the correlation of Rig‐G expression with key clinico‐pathological features and survival outcomes in a multi‐site clinical cohort of 300 lung cancer patients. Functional studies for Rig‐G were performed in cell lines, and an animal model to support clinical findings. We found that Rig‐G was frequently downregulated in lung cancer tissues and cell lines, and correlated with poor prognosis in lung cancer patients. Overexpression of Rig‐G led to significantly reduced cell growth and suppressed migration in A549 and NCI‐H1944 cells, accompanied by reduced epithelial‐mesenchymal transition. Likewise, restoration of Rig‐G in Lewis lung carcinoma cells permitted development of fewer cancer metastases versus controls in an animal model. Gene expression profiling results identified p53 pathway as a key downstream target of Rig‐G, and p53 inhibition by pifithrin‐α caused abrogation of tumor‐suppressive effects of Rig‐G in lung cancer. In conclusion, we, for the first time, have identified Rig‐G as a novel and important tumor suppressor, which may serve as a potential therapeutic target for restoring p53 expression in lung cancer patients.

中文翻译：

---

视黄酸诱导的 G (Rig-G) 通过激活 p53 信号通路作为肺癌抑制剂的新证据


肺癌是全世界最常见的恶性肿瘤之一。我们之前已经发现视黄酸诱导的基因 G (Rig-G) 不仅是急性早幼粒细胞白血病的肿瘤抑制因子，而且在其他实体瘤中也是如此。然而，Rig-G 的临床意义及其在肺癌中的生物学功能的潜在机制在很大程度上仍未得到探索。在此，我们首先根据公开数据集和我们的患者队列比较了肺癌 (n = 138) 和正常组织 (n = 23) 之间的 Rig-G 表达。我们在 300 名肺癌患者的多中心临床队列中进一步分析了 Rig-G 表达与关键临床病理特征和生存结果的相关性。 Rig-G 的功能研究是在细胞系和动物模型中进行的，以支持临床发现。我们发现 Rig-G 在肺癌组织和细胞系中频繁下调，并且与肺癌患者的不良预后相关。 Rig-G 的过度表达导致 A549 和 NCI-H1944 细胞的细胞生长显着减少并抑制迁移，并伴有上皮间质转化减少。同样，在动物模型中，与对照组相比，Lewis 肺癌细胞中 Rig-G 的恢复可以减少癌症转移。基因表达谱结果确定 p53 通路是 Rig-G 的关键下游靶标，pifithrin-α 抑制 p53 导致 Rig-G 在肺癌中的肿瘤抑制作用消失。总之，我们首次发现 Rig-G 是一种新型且重要的肿瘤抑制因子，它可能作为恢复肺癌患者 p53 表达的潜在治疗靶点。