Kim Min Kyu, Choi Mun Ju, Lee Hyun Min, Choi Hong Seo, Park Young-Kwon, Ryu Chun Jeih
Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul 05006, Republic of Korea.
Prevention and Management Center, Ulsan University Hospital, Ulsan 44033, Republic of Korea.
Oncol Rep. 2021 Aug;46(2). doi: 10.3892/or.2021.8104. Epub 2021 Jun 10.
Lung cancer is the most frequent cause of cancer‑associated mortality worldwide. Upregulation of heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) has been reported in non‑small cell lung cancer (NSCLC) cells, but its contribution to NSCLC remains poorly understood. hnRNPA2/B1 is involved in carcinogenesis by interacting with a number of proteins; however, little is known about its interaction with p53. The results of the present study revealed that hnRNPA2/B1 expression levels were upregulated in NSCLC cells under tumorsphere culture conditions and cisplatin treatment compared with those in cells under the adherent condition and dimethyl sulfoxide treatment, respectively, suggesting that hnRNPA2/B1 expression is induced under stress conditions. hnRNPA2/B1 knockdown decreased the number and size of NSCLC cell colonies in a clonogenic survival assay and led to a decreased migratory potential of NSCLC cells, suggesting that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells. hnRNPA2/B1 knockdown induced G/G phase arrest in NSCLC cells through cyclin E degradation and phosphorylation of cyclin‑dependent kinase 2. In addition, hnRNPA2/B1 knockdown inhibited extracellular signal‑regulated kinase (ERK)1/2 phosphorylation, suggesting that hnRNPA2/B1 may promote the G/S phase transition in NSCLC cells through ERK signaling. hnRNPA2/B1 knockdown resulted in increased expression levels of p21 and p27 in NSCLC cells, as well as p53 induction and phosphorylation. Additionally, hnRNPA2/B1 knockdown inhibited human double minute 2 protein (HDM2) stability and phosphorylation, whereas overexpression of hnRNPA2 induced the opposite effects. These results suggested that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells through preventing the activation of p53, which is induced by ERK‑mediated HDM2 activation. The results of the present study also indicated that the components of the hnRNPA2/B1/ERK/p53/HDM2 signaling pathway may be novel potential molecular targets for the treatment of patients with NSCLC.
肺癌是全球癌症相关死亡的最常见原因。据报道，非小细胞肺癌（NSCLC）细胞中异质性核糖核蛋白A2/B1（hnRNPA2/B1）上调，但其对NSCLC的作用仍知之甚少。hnRNPA2/B1通过与多种蛋白质相互作用参与致癌过程；然而，其与p53的相互作用却鲜为人知。本研究结果显示，与贴壁培养条件下的细胞和二甲基亚砜处理相比，在肿瘤球培养条件下和顺铂处理的NSCLC细胞中，hnRNPA2/B1表达水平分别上调，提示hnRNPA2/B1表达在应激条件下被诱导。在克隆存活试验中，hnRNPA2/B1敲低减少了NSCLC细胞集落的数量和大小，并导致NSCLC细胞迁移潜能降低，提示hnRNPA2/B1可能促进NSCLC细胞的存活、增殖和迁移。hnRNPA2/B1敲低通过细胞周期蛋白E降解和细胞周期蛋白依赖性激酶2的磷酸化诱导NSCLC细胞G/G期阻滞。此外，hnRNPA2/B1敲低抑制细胞外信号调节激酶（ERK）1/2磷酸化，提示hnRNPA2/B1可能通过ERK信号通路促进NSCLC细胞的G/S期转换。hnRNPA2/B1敲低导致NSCLC细胞中p21和p27表达水平增加，以及p53诱导和磷酸化。此外，hnRNPA2/B1敲低抑制人双微体2蛋白（HDM2）的稳定性和磷酸化，而hnRNPA2过表达则产生相反的效果。这些结果提示，hnRNPA2/B1可能通过阻止ERK介导的HDM2激活诱导的p53激活来促进NSCLC细胞的存活、增殖和迁移。本研究结果还表明，hnRNPA2/B1/ERK/p53/HDM2信号通路的成分可能是治疗NSCLC患者的新的潜在分子靶点。
